Cephalosporins General Statement (Monograph)

Drug class: Cephalosporins
VA class: AM100

Introduction

Cephalosporins are semisynthetic β-lactam antibiotics that are structurally and pharmacologically related to penicillins and cephamycins (e.g., cefotetan, cefoxitin). Cephalosporins generally are divided into 5 groups (“generations”) based on their spectra of activity.

Uses for Cephalosporins General Statement

Cephalosporins are used parenterally for the treatment of lower respiratory tract, skin and skin structure, urinary tract, and bone and joint infections caused by susceptible gram-positive or gram-negative bacteria and also are used parenterally for the treatment of meningitis and septicemia/bacteremia caused by susceptible gram-positive or gram-negative bacteria. Cephalosporins also are used parenterally for the treatment of intra-abdominal, biliary tract, and gynecologic infections (including pelvic inflammatory disease) caused by susceptible bacteria. Cefotaxime, cefoxitin, ceftriaxone, and cefuroxime are used parenterally for the treatment of uncomplicated gonorrhea or other gonococcal infections; cefepime, ceftazidime, and ceftriaxone are used for empiric anti-infective therapy in febrile neutropenic patients; and cefazolin, cefotaxime, ceftriaxone, and cefuroxime are used parenterally for perioperative prophylaxis.

Cephalosporins are used orally for the treatment of mild to moderate respiratory tract infections, including acute maxillary sinusitis, acute bacterial exacerbations of chronic bronchitis, secondary infections of acute bronchitis, and community-acquired pneumonia, caused by susceptible bacteria (e.g., Streptococcus pneumoniae, Haemophilus influenzae, H. parainfluenzae, Moraxella catarrhalis);^{307 311 338 339 341 348 663 664 677} acute bacterial otitis media caused by susceptible bacteria (e.g., S. pneumoniae, H. influenzae, M. catarrhalis);^{307 311 338 339 341 348 677} and pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A β-hemolytic streptococci).^{307 311 338 339 341 348 663 664 677} Cefaclor, cefadroxil, cefdinir, cefditoren pivoxil, cefpodoxime proxetil, cefprozil, ceftibuten, cefuroxime axetil, and cephalexin also are used orally for the treatment of mild to moderate skin and skin structure infections caused by susceptible staphylococci or streptococci.^{307 308 311 338 339 341 348 663 664} In addition, cefaclor, cefadroxil, cefixime, cefpodoxime proxetil, cefuroxime axetil, and cephalexin are used orally for the treatment of mild to moderate urinary tract infections caused by susceptible gram-negative bacteria (e.g., Escherichia coli, Klebsiella, Proteus mirabilis).^{307 308 341 348 677} Some clinicians suggest that certain oral third generation cephalosporins (cefdinir, cefpodoxime proxetil, ceftibuten) are one of several alternatives that can be used for the outpatient treatment of recurrent urinary tract infections or urinary tract infections acquired in hospitals or nursing homes since these infections are likely to be caused by multidrug-resistant gram-negative bacilli.⁷¹⁰ Certain oral cephalosporins (e.g., cefixime, cefpodoxime proxetil, cefuroxime axetil) have been used for the treatment of uncomplicated gonorrhea.^{292 338 344 348 677} (See Uses: Gonorrhea and Associated Infections.)

Prior to and during cephalosporin therapy, the causative organism should be cultured and in vitro susceptibility tests performed. In serious infections, therapy may be initiated pending results of in vitro tests. In certain serious infections when the causative organism is unknown, concomitant therapy with another anti-infective agent (e.g., an aminoglycoside) may be indicated pending results of susceptibility tests. Use of a cephalosporin does not replace surgical procedures such as incision and drainage when indicated.³³⁸

Gram-positive Bacterial Infections

First and second generation cephalosporins are used in the treatment of infections caused by susceptible staphylococci or streptococci.^{307 308 339 348} Third generation cephalosporins generally are less active than first and second generation cephalosporins against gram-positive aerobic bacteria, especially staphylococci, and usually are not used in the treatment of infections caused by gram-positive bacteria when a penicillin or a first or second generation cephalosporin could be used.⁴⁵³ Some third generation cephalosporins (e.g., cefotaxime, ceftriaxone) are considered drugs of choice for serious bacterial infections, including endocarditis or meningitis, caused by susceptible S. pneumoniae or viridans streptococci. Unlike other cephalosporins, fifth generation cephalosporins (e.g., ceftaroline) have activity against methicillin-resistant S. aureus (MRSA, also known as oxacillin-resistant S. aureus [ORSA]) and are used in the treatment of some MRSA infections.^{704 705 711 712 713 715}

Gram-negative Bacterial Infections

Use of first generation cephalosporins (cefazolin) in the treatment of gram-negative bacterial infections generally is limited to infections caused by susceptible E. coli, H. influenzae, Klebsiella, or P. mirabilis. Second and third generation cephalosporins are used in the treatment of infections caused by these organisms as well as infections caused by susceptible Enterobacter, Morganella morganii (formerly Proteus morganii), Neisseria, Providencia rettgeri (formerly P. rettgeri), or P. vulgaris; cefotaxime, ceftazidime, and ceftriaxone also are used in the treatment of infections caused by susceptible Serratia. Certain parenteral third generation cephalosporins (i.e., cefepime, cefotaxime, ceftazidime, ceftriaxone) may be drugs of choice for the treatment of infections caused by susceptible Enterobacteriaceae, including susceptible E. coli, Klebsiella pneumoniae, P. rettgeri, M. morganii, P. vulgaris, or P. stuartii and are alternatives for the treatment of infections caused by susceptible Serratia; an aminoglycoside usually is used concomitantly in severe infections.⁷¹⁰ Ceftazidime and cefepime are considered alternatives for the treatment of infections caused by susceptible Pseudomonas aeruginosa; an aminoglycoside may be used concomitantly.⁷¹⁰ Ceftazidime is more active in vitro on a weight basis against Ps. aeruginosa than most other currently available cephalosporins and is active against some strains resistant to many other cephalosporins, aminoglycosides, and extended-spectrum penicillins. Ceftaroline, a fifth generation cephalosporin, generally has activity against gram-negative aerobes that is similar to that reported with third generation cephalosporins.⁷⁰⁴

Endocarditis

Treatment

Ceftriaxone is used for the treatment of native valve or prosthetic valve endocarditis caused by viridans streptococci (e.g., S. oralis, S. milleri group, S. mitis, S. mutans, S. salivarius, S. sanguis, Gamella morbillorum) or S. bovis (nonenterococcal group D streptococcus)^{† [off-label]}.^{450 685} The drug also is used for the treatment of native valve or prosthetic valve endocarditis caused by slow-growing fastidious gram-negative bacilli termed the HACEK group^{† [off-label]} (i.e., Haemophilus parainfluenzae, H. aphrophilus, H. paraphrophilus, H. influenzae, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae, K. denitrificans).⁴⁵⁰ In addition, ceftriaxone has been used for the treatment of native or prosthetic valve endocarditis caused by E. faecalis resistant to penicillin, aminoglycosides, and vancomycin.⁴⁵⁰

IV cefazolin is used as an alternative to nafcillin or oxacillin for the treatment of staphylococcal endocarditis, including infections caused by coagulase-positive strains (S. aureus) or coagulase-negative strains (e.g., S. epidermidis^{† [off-label]}, S. lugdunensis^{† [off-label]}) in penicillin-allergic patients (nonanaphylactoid type only).^{450 685} Cefazolin also is used as an alternative to penicillin G sodium for the treatment of endocarditis caused by susceptible Streptococcus pyogenes (group A β-hemolytic streptococci)^{310 450} or S. pneumoniae^{† [off-label]}.⁴⁵⁰

For empiric treatment of culture-negative endocarditis^† in prosthetic valve recipients with early onset endocarditis (within 1 year after prosthetic valve placement), a multiple-drug regimen that includes vancomycin, gentamicin, cefepime, and rifampin is recommended.⁴⁵⁰ )

Prevention

Certain cephalosporins (cefazolin, ceftriaxone, cephalexin, cefadroxil) are used as alternatives to amoxicillin or ampicillin for prevention of α-hemolytic (viridans group) streptococcal endocarditis^† in penicillin-allergic adults and children undergoing certain dental or upper respiratory tract procedures who have underlying cardiac conditions that put them at the highest risk of adverse outcome from endocarditis.⁴⁵¹ These cephalosporins should not be used for such prophylaxis in patients with a history of immediate-type penicillin hypersensitivity (e.g., urticaria, angioedema, anaphylaxis).⁴⁵¹

The cardiac conditions identified by the American Heart Association (AHA) as those associated with the highest risk and for which endocarditis prophylaxis is recommended are prosthetic cardiac valves, previous infective endocarditis, congenital heart disease (i.e., unrepaired cyanotic congenital heart disease including palliative shunts and conduits; a completely repaired congenital heart defect where a prosthetic material or device was placed by surgery or catheter intervention within the last 6 months; repaired congenital heart disease with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device which inhibits endothelialization), and cardiac valvulopathy after cardiac transplantation.⁴⁵¹ AHA states that endocarditis prophylaxis is recommended for such patients when they undergo dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa or undergo invasive procedures of the respiratory tract that involve incision or biopsy of the respiratory mucosa (e.g., tonsillectomy, adenoidectomy).⁴⁵¹ Although endocarditis prophylaxis also may be indicated for such patients when they undergo surgical procedures that involve infected skin, skin structure, or musculoskeletal tissue, prophylaxis solely to prevent infective endocarditis is not recommended for GI or genitourinary tract procedures.⁴⁵¹

When selecting anti-infectives for prophylaxis of bacterial endocarditis, the current recommendations published by AHA should be consulted.⁴⁵¹

GI Infections

Some parenteral third generation cephalosporins are used in the treatment of GI infections caused by Salmonella^{292 503} or Shigella^{292 570 673 674} or the treatment of other uncommon infectious diarrheal illnesses, including infections caused by Vibrio^{503 582} and Yersinia.⁵⁰³

Salmonella Gastroenteritis

Anti-infective therapy generally is not indicated in otherwise healthy individuals with uncomplicated (noninvasive) gastroenteritis caused by non-typhi Salmonella (e.g., S. enteritidis, S. typhimurium) since these infections generally subside spontaneously and there is some evidence that such therapy may prolong the duration of fecal excretion of the organisms; however, the US Centers for Disease Control and Prevention (CDC),⁵⁰³ American Academy of Pediatrics (AAP),²⁹² Infectious Diseases Society of America (IDSA),⁵⁷⁰ and others⁴¹² recommend anti-infective therapy in individuals with severe Salmonella gastroenteritis and in those who are at increased risk of invasive disease. These individuals at increased risk include infants younger than 3–6 months of age; individuals older than 50 years of age; individuals with hemoglobinopathies, severe atherosclerosis or valvular heart disease, prostheses, uremia, chronic GI disease, or severe colitis; and individuals who are immunocompromised because of malignancy, immunosuppressive therapy, HIV infection, or other immunosuppressive illness.^{292 412 503 570}

When an anti-infective is considered necessary in an individual with Salmonella gastroenteritis, CDC, AAP, IDSA, and others recommend ceftriaxone, cefotaxime, a fluoroquinolone (should be used in children only if the benefits outweigh the risks and no other alternative exists), ampicillin, amoxicillin, co-trimoxazole, or chloramphenicol, depending on the susceptibility of the causative organism.^{292 412 503 570}

Shigella Infections

Ceftriaxone is used for the treatment of shigellosis^† caused by susceptible Shigella sonnei or S. flexneri^{292 570 673 674} and is an alternative to fluoroquinolones for treatment of these infections in pediatric patients or when susceptibility is unknown or strains resistant to ampicillin and co-trimoxazole are isolated.²⁹²

Vibrio Infections

Cefotaxime is one of several alternatives recommended for the treatment of severe cases of Vibrio parahaemolyticus^† infection when anti-infective therapy is indicated in addition to supportive care.⁵⁰³ V. parahaemolyticus infections can occur as the result of ingestion of contaminated undercooked or raw fish or shellfish, and some clinicians recommend use of tetracycline, doxycycline, gentamicin, or cefotaxime when treatment is considered necessary.⁵⁰³

Cefotaxime and ceftazidime are considered drugs of choice for the treatment of infections caused by V. vulnificus^†; these infections can occur as the result of ingesting raw or undercooked seafood (especially raw oysters) or through contamination of a wound with seawater or seafood drippings.^{503 582} While optimum anti-infective therapy for the treatment of V. vulnificus infections has not been identified,^{503 582} use of cefotaxime, ceftazidime, tetracycline, or doxycycline is recommended.^{503 582 710}

Yersinia Infections

Cefotaxime is suggested as a possible choice for the treatment of GI infections caused by Yersinia enterocolitica or Y. pseudotuberculosis.^{503 710} These Yersinia infections usually are self-limited and anti-infective therapy unnecessary; however, AAP, IDSA, and others recommend use of anti-infectives in immunocompromised individuals or for the treatment of severe infections or when septicemia or other invasive disease occurs.^{292 503 570} GI infections caused by Y. enterocolitica or Y. pseudotuberculosis can occur as the result of ingesting undercooked pork, unpasteurized milk, or contaminated water; infection has occurred in infants whose caregivers handled contaminated chitterlings (raw pork intestines) or tofu.⁵⁰³ Use of co-trimoxazole, an aminoglycoside (amikacin, gentamicin, tobramycin), a fluoroquinolone (e.g., ciprofloxacin), doxycycline, or cefotaxime has been recommended when treatment is considered necessary;^{503 570 710} combination therapy may be necessary.⁵⁷⁰ Some clinicians suggest that the role of oral anti-infectives in the management of enterocolitis, pseudoappendicitis syndrome, or mesenteric adenitis caused by Yersinia needs further evaluation.^{292 675}

Intra-abdominal Infections

Cefazolin,⁷⁰⁸ cefepime,^{314 708} cefotaxime,^{332 708} cefoxitin,⁷⁰⁸ ceftazidime,^{340 708} ceftriaxone,^{343 708} and cefuroxime⁷⁰⁸ are used for the treatment of intra-abdominal infections. The fixed combination of ceftazidime and avibactam⁷²⁸ and the fixed combination of ceftolozane and tazobactam⁷²⁹ are used for the treatment of complicated intra-abdominal tract infections. Certain cephalosporins (e.g., cefotaxime, ceftriaxone, cefotetan, cefoxitin) also are used for the treatment of various obstetric and gynecologic infections, including pelvic inflammatory disease. (See Uses: Pelvic Inflammatory Disease.) Because the prevalence of B. fragilis resistant to cefotetan has been increasing, some experts state that cefotetan is not recommended for empiric treatment of intra-abdominal infections.⁷⁰⁸

Although monotherapy with cefazolin, ceftriaxone, or cefuroxime is an option for initial empiric treatment of mild to moderate community-acquired biliary tract infections (cholecystitis or cholangitis) and monotherapy with cefoxitin is an option for initial empiric treatment of mild to moderate community-acquired extrabiliary intra-abdominal infections,⁷⁰⁸ cephalosporins usually should be used in conjunction with metronidazole for initial empiric treatment of community-acquired or healthcare-associated intra-abdominal infections.⁷⁰⁸

For initial empiric treatment of mild to moderately severe community-acquired extrabiliary intra-abdominal infections in adults, IDSA recommends either monotherapy with cefoxitin, ertapenem, moxifloxacin, tigecycline, or the fixed combination of ticarcillin and clavulanate sodium, or a combination regimen that includes a cephalosporin (cefazolin, cefotaxime, ceftriaxone, cefuroxime) or fluoroquinolone (ciprofloxacin, levofloxacin) in conjunction with metronidazole.⁷⁰⁸ For initial empiric treatment of high-risk or severe community-acquired extrabiliary intra-abdominal infections in adults (e.g., those with advanced age, immunocompromise, severe physiologic disturbance), IDSA recommends either monotherapy with a carbapenem (doripenem, imipenem, meropenem) or the fixed combination of piperacillin and tazobactam, or a combination regimen that includes either a cephalosporin (cefepime, ceftazidime) or fluoroquinolone (ciprofloxacin, levofloxacin) in conjunction with metronidazole.⁷⁰⁸ IDSA also recommends ceftazidime or cefepime in conjunction with metronidazole as one of several regimens that can be used for initial empiric treatment of healthcare-associated complicated intra-abdominal infections in adults and recommends a combination regimen that includes a cephalosporin (cefotaxime, ceftriaxone, ceftazidime, cefepime) in conjunction with metronidazole as one of several options that can be used for empiric treatment of community-acquired complicated intra-abdominal infections in pediatric patients.⁷⁰⁸

For additional information regarding management of intra-abdominal infections, the current IDSA clinical practice guidelines available at [Web] should be consulted.⁷⁰⁸

Meningitis and Other CNS Infections

IV cefotaxime, ceftazidime, ceftriaxone, and cefuroxime are used in adult or pediatric patients for the treatment of meningitis caused by susceptible H. influenzae, Neisseria meningitidis, or S. pneumoniae; however, cefotaxime or ceftriaxone generally are preferred when a cephalosporin is indicated for the treatment of meningitis caused by these organism. IV cefotaxime and ceftriaxone are used alone or in conjunction with an aminoglycoside for the treatment of meningitis or other CNS infections caused by susceptible Enterobacteriaceae (e.g., E. coli, Klebsiella)^{392 393} and IV ceftazidime is used in conjunction with an aminoglycoside for the treatment of meningitis caused by susceptible Ps. aeruginosa.^{393 416}

Empiric Treatment of Meningitis

Pending results of CSF culture and in vitro susceptibility testing, the most appropriate anti-infective regimen for empiric treatment of suspected bacterial meningitis should be selected based on results of CSF Gram stain and antigen tests, age of the patient, the most likely pathogen(s) and source of infection, and current patterns of bacterial resistance within the hospital and local community.^{292 392 393 397} When results of culture and susceptibility tests become available and the pathogen is identified, the empiric anti-infective regimen should be modified (if necessary) to ensure that the most effective regimen is being administered.^{392 393} There is some evidence that short-term adjunctive therapy with IV dexamethasone may decrease the incidence of audiologic and/or neurologic sequelae in infants and children with H. influenzae meningitis and possibly may provide some benefit in patients with S. pneumoniae meningitis.^{292 392 393 398} AAP and other clinicians suggest that use of adjunctive dexamethasone therapy should be considered during the initial 2–4 days of anti-infective therapy in infants and children 6–8 weeks of age or older with known or suspected bacterial meningitis and is recommended in those with suspected or proven H. influenzae infection.^{292 392 393 397} If used, dexamethasone should be initiated before or concurrently with the first dose of anti-infective.²⁹²

Bacterial meningitis in neonates usually is caused by S. agalactiae (group B streptococci), Listeria monocytogenes, or aerobic gram-negative bacilli (e.g., E. coli, K. pneumoniae).^{292 391 392 393 394 397 710} AAP recommends that neonates with suspected bacterial meningitis receive an empiric regimen of IV ampicillin and an aminoglycoside pending results of CSF culture and susceptibility testing.²⁹² An empiric regimen of IV ampicillin and IV cefotaxime or IV ceftazidime with or without gentamicin also is recommended.^{292 391 392 393 394 397 710} Because frequent use of cephalosporins in neonatal units may result in rapid emergence of resistant strains of some gram-negative bacilli (e.g., Enterobacter cloacae, Klebsiella, Serratia), AAP cautions that cephalosporins should be used for empiric treatment of meningitis in neonates only if gram-negative bacterial meningitis is strongly suspected.²⁹² Consideration should be given to including IV vancomycin in the empiric regimen if S. pneumoniae, enterococci, or Staphylococci is suspected.^{292 405 406} Because ceftriaxone should be used with caution in neonates who are hyperbilirubinemic (especially those born prematurely), cefotaxime may be the preferred cephalosporin for empiric treatment of meningitis is neonates.^{292 392} However, because premature, low-birthweight neonates are at increased risk for nosocomial infection caused by staphylococci or gram-negative bacilli, some clinicians suggest that these neonates receive an empiric regimen of IV ceftazidime and IV vancomycin.³⁹³

In infants beyond the neonatal stage who are younger than 3 months of age, bacterial meningitis usually is caused by S. agalactiae, L. monocytogenes, H. influenzae, S. pneumoniae, N. meningitidis, or aerobic gram-negative bacilli (e.g., E. coli, K. pneumoniae).^{292 391 392 393 394 397} The empiric regimen recommended for infants in this age group is IV ampicillin and either IV ceftriaxone or IV cefotaxime.^{391 392 393 394 397} Consideration should be given to including IV vancomycin in the empiric regimen if S. pneumoniae is suspected.⁴⁰⁵

In adults and children 3 months through 17 years of age, bacterial meningitis usually is caused by N. meningitidis or S. pneumoniae is N. meningitidis or S. pneumoniae.^{292 392 393 397 710} An empiric regimen of IV ceftriaxone or IV cefotaxime usually is used for empiric therapy of suspected bacterial meningitis in children 3 months through 17 years of age and in adults 18–50 years of age.^{292 392 393 394 397 710} Although an empiric regimen of IV ampicillin and IV chloramphenicol can be used as an alternative regimen in children 3 months through 17 years of age,³⁹² most clinicians prefer a cephalosporin regimen unless the drugs are contraindicated.^{292 392 393 394 397 406} Because of the increasing prevalence of penicillin-resistant S. pneumoniae that also are resistant to or have reduced susceptibility to cephalosporins, AAP and others recommend that the initial empiric cephalosporin regimen include IV vancomycin (with or without rifampin) pending results of in vitro susceptibility tests;^{292 391 397 403 405 710} vancomycin and rifampin should be discontinued if the causative organism is found to be susceptible to the cephalosporin.^{292 400 403 405 710} CDC and some clinicians have recommended that vancomycin be added to the empiric regimen in areas where there have been reports of highly penicillin-resistant strains of S. pneumoniae,^{292 405 407 408 409 410 411} but other clinicians suggest that use of ceftriaxone or cefotaxime in conjunction with vancomycin provides the optimal initial empiric regimen.^{397 400} While L. monocytogenes meningitis is relatively rare in this age group, the empiric regimen should include ampicillin if L. monocytogenes is suspected.³⁹⁴

In adults older than 50 years of age, bacterial meningitis usually is caused by S. pneumoniae, L. monocytogenes, N. meningitidis, or aerobic gram-negative bacilli, and the empiric regimen recommended for this age group is IV ampicillin given in conjunction with IV cefotaxime or IV ceftriaxone.^{393 394} Because of the increasing prevalence of penicillin-resistant S. pneumoniae, some clinicians suggest that the empiric regimen also should include IV vancomycin (with or without rifampin).³⁹³

Meningitis Caused by Streptococcus pneumoniae

IV ceftriaxone and IV cefotaxime are considered drugs of choice for the treatment of meningitis caused by susceptible S. pneumoniae.^{292 405 710} Treatment failures have been reported when these cephalosporins were used alone for the treatment of meningitis caused by S. pneumoniae with intermediate or high-level penicillin resistance (i.e., penicillin MIC 0.1 mcg/mL or greater).^{292 407 409 411 413 434} In addition, strains of S. pneumoniae with reduced susceptibility to cephalosporins have been reported with increasing frequency, and use of cefotaxime or ceftriaxone alone may be ineffective for the treatment of meningitis caused by these strains.^{396 397} For meningitis caused by S. pneumoniae with high-level resistance to penicillin (i.e., penicillin MIC 8 mcg/mL or greater), IV cefotaxime or IV ceftriaxone is used in conjunction with vancomycin with or without rifampin.⁷¹⁰ The prevalence of S. pneumoniae with reduced susceptibility to penicillin and/or cephalosporins varies geographically, and clinicians should be aware of the prevalence and pattern of S. pneumoniae drug resistance in the local community to optimize empiric regimens and initial therapy for serious pneumococcal infections.^{292 410}

Because susceptibility can no longer be assumed, S. pneumoniae isolates should be routinely tested for in vitro susceptibility.^{292 392 405 407 408} If anti-infective therapy in a patient with meningitis is initiated with an empiric regimen of IV ceftriaxone or IV cefotaxime and IV vancomycin (with or without rifampin) and results of culture and in vitro susceptibility testing indicate that pathogen involved is a strain of S. pneumoniae susceptible to the cephalosporin and susceptible or resistant to penicillin, vancomycin and rifampin can be discontinued and therapy completed using ceftriaxone or cefotaxime alone.^{292 405} If the isolate is found to have reduced susceptibility to ceftriaxone and cefotaxime and penicillin, the IV cephalosporin and IV vancomycin usually are both continued.^{292 394} If the patient’s condition does not improve or worsens or results of a second repeat lumbar puncture (performed 24–48 hours after initiation of anti-infective therapy) indicate that the anti-infective regimen has not eradicated or substantially reduced the number of pneumococci in CSF, rifampin probably should be added to the regimen or vancomycin discontinued and replaced with rifampin.^{292 405} If meningitis is caused by S. pneumoniae highly resistant to ceftriaxone (i.e., MIC 4 mcg/mL or greater), consultation with an infectious disease expert is recommended.^{292 405}

Meningitis Caused by Haemophilus influenzae

IV ceftriaxone and IV cefotaxime are considered drugs of choice for the initial treatment of meningitis caused by susceptible H. influenzae (including penicillinase-producing strains).^{292 392 393 710} AAP suggests that children with meningitis possibly caused by H. influenzae can receive an initial treatment regimen of ceftriaxone, cefotaxime, or a regimen of ampicillin given in conjunction with chloramphenicol;²⁹² some clinicians prefer ceftriaxone or cefotaxime for the initial treatment of meningitis caused by H. influenzae since these cephalosporins are active against both penicillinase-producing and nonpenicillinase-producing strains. Because of the prevalence of ampicillin-resistant H. influenzae, ampicillin should not be used alone for empiric treatment of meningitis when H. influenzae may be involved.²⁹² The incidence of H. influenzae meningitis in the US has decreased considerably since H. influenzae type b conjugate vaccines became available for immunization of infants.^{292 394 397}

Meningitis Caused by Neisseria meningitidis

While both IV ampicillin and IV penicillin G may be used for the treatment of meningitis caused by N. meningitidis,^{393 397} AAP and other clinicians suggest that IV penicillin G is the drug of choice for the treatment of these infections and IV ceftriaxone and IV cefotaxime are acceptable alternatives.^{292 393} Chloramphenicol is recommended for the treatment of N. meningitidis meningitis in patients with a history of anaphylactoid-type hypersensitivity reactions to penicillin.²⁹²

Meningitis Caused by Enterobacteriaceae

Some clinicians recommend that meningitis caused by Enterobacteriaceae (e.g., E. coli, K. pneumoniae) be treated with a third generation cephalosporins (i.e., cefotaxime, ceftazidime, ceftriaxone) with or without an aminoglycoside.^{392 393} Because ceftazidime (but not cefotaxime or ceftriaxone) is effective for the treatment of meningitis caused by Ps. aeruginosa, some clinicians suggest that a regimen of ceftazidime and an aminoglycoside may be preferred for the treatment of meningitis caused by gram-negative bacilli pending results of culture and susceptibility testing.³⁹³

Meningitis Caused by Pseudomonas aeruginosa

In patients with meningitis caused by Ps. aeruginosa, most clinicians recommend that therapy be initiated with a regimen of ceftazidime and a parenteral aminoglycoside.^{393 416} If the patient fails to respond to this regimen, concomitant use of intrathecal or intraventricular aminoglycoside therapy or use of an alternative parenteral anti-infective (e.g., aztreonam, meropenem, a quinolone) should be considered based on results of in vitro susceptibility tests.^{393 416} When treating pediatric patients with meningitis caused by Ps. aeruginosa or Enterobacteriaceae, consultation with an infectious disease expert may be beneficial.²⁹²

Meningitis Caused by Streptococcus agalactiae

For the initial treatment of meningitis or other severe infection caused by S. agalactiae (group B streptococci), a regimen of IV ampicillin or IV penicillin G given in conjunction with an aminoglycoside is recommended.^{292 393} Some clinicians suggest that IV ampicillin is the drug of choice for the treatment of group B streptococcal meningitis and that an aminoglycoside (IV gentamicin) should be used concomitantly during the first 72 hours until in vitro susceptibility testing is completed and a clinical response if observed; thereafter, ampicillin can be given alone.³⁹³

Meningitis Caused by Listeria monocytogenes

The optimal regimen for the treatment of meningitis caused by L. monocytogenes has not been established.²⁹² Cephalosporins are not active against Listeria monocytogenes, an organism that most frequently causes meningitis in neonates or immunocompromised individuals, and the drugs should not be used alone for empiric treatment of meningitis when this organisms may be involved.^{292 393 394} AAP and other clinicians generally recommend that meningitis or other severe infection caused by L. monocytogenes be treated with a regimen of IV ampicillin with or without an aminoglycoside (usually gentamicin);^{292 393 414 710} alternatively, a regimen of penicillin G used in conjunction with gentamicin can be used.^{393 414} In patients hypersensitive to penicillin, the alternative regimen for treatment of meningitis caused by L. monocytogenes is co-trimoxazole.^{292 710}

Brain Abscess and Other CNS Infections

Bacterial brain abscesses and other CNS infections (e.g., subdural empyema, intracranial epidural abscesses) often are polymicrobial and can be caused by gram-positive aerobic cocci, Enterobacteriaceae (e.g., E. coli, Klebsiella), and/or anaerobic bacteria (e.g., Bacteroides, Fusobacterium).^{292 394 415} The choice of anti-infectives for empiric therapy of these infections should be based on the predisposing condition and site of primary infection.^{394 415} Some clinicians suggest that the empiric anti-infective regimen in patients who develop the CNS infections after respiratory tract infection (e.g., otitis media, mastoiditis, paranasal sinusitis, pyogenic lung disease) should consist of an appropriate third generation IV cephalosporin (e.g., ceftriaxone, cefotaxime, ceftazidime) given in conjunction with metronidazole; employing one of these cephalosporins rather than a penicillin provides coverage against Haemophilus and facultative anaerobic gram-negative bacteria.^{394 415} If presence of staphylococci is suspected, a penicillinase-resistant penicillin (e.g., nafcillin, oxacillin) or vancomycin should be added to the empiric regimen.^{394 415} In patients who develop brain abscess, subdural empyema, or intracranial epidural abscess after trauma or neurosurgery, the empiric regimen should consist of an appropriate third generation IV cephalosporin (e.g., ceftriaxone, cefotaxime, ceftazidime) given in conjunction with a penicillinase-resistant penicillin or vancomycin.^{394 415} Prolonged anti-infective therapy (e.g., 3–6 weeks or longer) usually is required for the treatment of brain abscess, subdural empyema, or intracranial epidural abscess.^{394 415}

Otitis Media

Acute Otitis Media

Various oral cephalosporins (e.g., cefaclor, cefdinir, cefixime, cefpodoxime proxetil, cefprozil, ceftibuten, cefuroxime axetil, cephalexin) are used for the treatment of acute otitis media (AOM) caused by S. pneumoniae, H. influenzae (including β-lactamase-producing strains), or M. catarrhalis (including β-lactamase-producing strains).^{307 311 338 339 341 348 349 677 683} Parenteral ceftriaxone also is used for the treatment of AOM caused by S. pneumoniae, H. influenzae (including β-lactamase-producing strains), or M. catarrhalis (including β-lactamase-producing strains).^{343 683}

AOM is one of the most frequently diagnosed bacterial infection in children, and 65–95% of children will have at least one episode of AOM by 3 years of age.^{436 444 445 449 526 537 543 559 617 622} S. pneumoniae, H. influenzae, and M. catarrhalis are the bacteria most frequently recovered from middle ear fluid of patients with AOM; S. pyogenes and S. aureus also are recovered rarely.^{348 349 433 448 449 522 526 528 529 551 552 559 568 569 579 617 622 683} In addition, there is evidence that respiratory viruses (e.g., respiratory syncytial virus, rhinoviruses, influenza virus, parainfluenza virus, enteroviruses) may be present either alone or in combination with bacterial pathogens and may play a role in the etiology and pathogenesis of AOM in some patients.^{433 448 449 533 534 559 586 587 622 683}

Diagnosis and Management Strategies for AOM

AAP and American Academy of Family Physicians (AAFP) first issued evidence-based clinical practice guidelines for the diagnosis and management of AOM in 2004.⁶⁸³ In 2013, AAP revised and updated those guidelines after comprehensive reviews of more recent published evidence.⁶⁸³ The 2013 AAP evidence-based clinical practice guidelines provide recommendations for the diagnosis and management of uncomplicated AOM, including recurrent AOM, in children 6 months through 12 years of age and apply only to otherwise healthy children who do not have underlying conditions that may alter the natural course of AOM (e.g., tympanostomy tubes, cleft palate, genetic conditions with craniofacial abnormalities such as Down syndrome, immunodeficiencies, cochlear implants).⁶⁸³ These AAP guidelines should be consulted for additional information on diagnosis and management of AOM.⁶⁸³

Accurate diagnosis of AOM is critical for clinical decision-making since it avoids unnecessary treatment.⁶⁸³ AOM involves the presence of fluid in the middle ear accompanied by a wide spectrum of signs or symptoms of acute local or systemic illness (e.g., otalgia, otorrhea, hearing loss, swelling around the ear, vertigo, nystagmus, tinnitus, fever, irritability, headache, diarrhea, lethargy, anorexia, vomiting) that evolve as the disease progresses.^{449 528 532 543 559 683} Older children with AOM usually have a history of rapid onset of ear pain,⁶⁸³ but preverbal infants and young children may have mild or nonspecific symptoms that overlap with those of an upper respiratory tract illness.⁶⁸³

Current AAP evidence-based clinical practice guidelines for the diagnosis and management of uncomplicated AOM in children 6 months through 12 years of age state that clinicians should diagnose AOM in children who present with moderate to severe bulging of the tympanic membrane or new onset of otorrhea not due to acute otitis externa.⁶⁸³ A diagnosis of AOM also should be made in children who present with mild bulging of the tympanic membrane and recent (less than 48 hours) onset of ear pain (holding, tugging, rubbing of the ear in a nonverbal child) or intense erythema of the tympanic membrane.⁶⁸³ These guidelines state that a diagnosis of AOM should not be made in children who do not have middle ear effusion (MEE) based on pneumatic otoscopy and/or tympanometry.⁶⁸³

Current AAP evidence-based clinical practice guidelines for the diagnosis and management of uncomplicated AOM in children 6 months through 12 years of age state that management of AOM should include an assessment of pain and, if ear pain is present, the clinician should recommend treatment to reduce the pain.⁶⁸³ AOM-associated pain can be substantial during the first few days of illness and often persists longer in young children.⁶⁸³ AAP states that pain management, especially during the first 24 hours of an AOM episode, should be addressed regardless of the use of anti-infectives.⁶⁸³ Treatment for otalgia should be selected based on a consideration of the benefits and risks and, whenever possible, incorporate parent and/or caregiver and patient preference.⁶⁸³ Acetaminophen or ibuprofen are effective for mild to moderate pain, readily available, and usually the mainstay of pain management for AOM.⁶⁸³

Up to 60–80% of cases of AOM resolve spontaneously within 7–14 days,^{433 436 448 449 523 528 543 594} and routine administration of anti-infectives is not considered necessary for the treatment of all cases of AOM.^{523 528 532 541 550 588 590 592 593 594 606 683} Some clinicians have recommended that all cases of AOM be treated with an appropriate anti-infective regimen to facilitate resolution of the primary infection and associated symptoms and prevent suppurative complications or other sequelae, and state that judicious use of anti-infectives in the management of otitis media involves accurately diagnosing AOM and distinguishing AOM (which should be treated with anti-infectives) from otitis media with effusion (which usually is not treated with anti-infectives).^{532 537 539 540 541 543 546 548 549 560 562 591 622} However, for the majority of patients with uncomplicated AOM, anti-infective therapy appears to provide only minimal benefits in terms of resolution of the acute symptoms of infection (e.g., pain) and the proposed benefits of such therapy in terms of time to bacteriologic or clinical resolution of AOM or in terms of long-term consequences of otitis media (e.g., persistence of middle ear effusion, recurrence of AOM, hearing loss, need for adenoidectomy or insertion of tympanostomy tubes, mastoiditis) have never been substantiated in well-designed, placebo-controlled studies.^{550 588 592 593 594 595 683} In addition, there is evidence that overuse of anti-infectives, including overuse in the treatment of AOM, contributes to emergence of resistant bacteria (e.g., multidrug-resistant S. pneumoniae).^{588 592 594 596 615} Based on these considerations, many clinicians now recommend a management strategy for AOM that involves use of symptomatic care with analgesics and close observation via telephone contact or office visits for the majority of patients with uncomplicated AOM and use of anti-infectives only in those who do not have symptomatic improvement within 24–72 hours after diagnosis and in those who appear least likely to have spontaneous resolution and most likely to have poor outcomes (e.g., more acutely ill, those with 3 or more episodes of AOM in the past 18 months, history of serous otitis or tympanostomy tubes).^{588 595 606 683}

Current AAP evidence-based clinical practice guidelines for the diagnosis and management of uncomplicated AOM in children 6 months through 12 years of age include an initial management option of observation with close follow-up without initial use of anti-infectives in certain selected children with uncomplicated AOM based on age, illness severity, and assurance of follow-up.⁶⁸³ The recommendation for initial observation with close follow-up in select children provides an opportunity for the patient to improve without anti-infectives and is based on results of randomized, controlled studies with limitations and consideration of the benefits and risks of such a strategy.⁶⁸³

Current AAP guidelines state that anti-infective treatment should be initiated in children 6 months of age or older who have AOM (bilateral or unilateral) with severe signs or symptoms (i.e., moderate or severe otalgia, otalgia for at least 48 hours, or temperature 39°C or higher) and in children 6 through 23 months of age who have nonsevere bilateral AOM without signs or symptoms (i.e., mild otalgia for less than 48 hours and temperature less than 39°C).⁶⁸³ However, these guidelines state that a management strategy of either initiation of anti-infective treatment or observation with close follow-up can be used in children 6 through 23 months of age who have nonsevere unilateral AOM without severe signs or symptoms (i.e., mild otalgia for less than 48 hours, temperature less than 39°C) and in children 24 months of age or older with nonsevere AOM (bilateral or unilateral) without severe signs or symptoms (i.e., mild otalgia for less than 48 hours, temperature less than 39°C).⁶⁸³ The strategy of observation with close follow-up should be based on joint decision-making between the clinician and the parent and/or caregiver and must include a mechanism that ensures follow-up and initiation of anti-infective therapy if AOM worsens or fails to improve within 48–72 hours after symptom onset.⁶⁸³

If the initial management strategy was observation with close follow-up, anti-infective therapy should be initiated if symptoms worsen or there is no improvement within 48–72 hours after onset of symptoms.⁶⁸³ If the initial management strategy was anti-infective treatment, consideration should be given to changing the anti-infective regimen if symptoms worsen or fail to respond within 48–72 hours after initiation of treatment.⁶⁸³ (See Anti-infectives for AOM after Initial Treatment Failure under Uses: Otitis Media.)

After the patient has shown clinical improvement, follow-up is based on the usual clinical course of AOM.⁶⁸³ Persistent MEE is common after resolution of acute symptoms of AOM and should not be viewed as requiring anti-infective treatment.⁶⁸³ (See Otitis Media with Effusion under Uses: Otitis Media.)

Anti-infectives for Initial Treatment of AOM

When anti-infectives are indicated for treatment of AOM, the initial anti-infective agent usually is selected empirically based on efficacy against the most probable bacterial pathogens.^{526 528 537 543 557 560 568 619} Other considerations in the choice of an anti-infective for initial empiric treatment of AOM include pharmacokinetic data related to distribution of the drug into middle ear fluid, compliance issues related to patient acceptance of dosage formulation and dosage schedule, adverse effects profiles, and cost considerations;^{448 449 522 523 528 529 531 565 571 574 577 619} drug susceptibility patterns in the local community can be considered, but local surveillance data are not necessarily representative of AOM isolates found in otherwise healthy patients.⁵²²

Amoxicillin usually is considered the drug of first choice for initial empiric treatment of AOM, unless the infection is suspected of being caused by β-lactamase-producing bacteria resistant to the drug, in which case amoxicillin and clavulanate potassium is recommended.^{292 330 331 334 336 391 433 436 448 449 522 524 560 565 574 619 622 683} The fact that multidrug-resistant S. pneumoniae are being reported with increasing frequency should be considered when selecting an anti-infective agent for empiric treatment of AOM.^{522 527 538 553 563 564 565 569 583 584 619 622 633} However, AAP, AAFP, CDC, and others state that, despite the increasing prevalence of multidrug-resistant S. pneumoniae and presence of β-lactamase-producing H. influenzae or M. catarrhalis in many communities, amoxicillin remains the anti-infective of first choice for treatment of uncomplicated AOM since amoxicillin is highly effective, has a narrow spectrum of activity, is well distributed into middle ear fluid, is well tolerated, has an acceptable taste, and is inexpensive.^{292 522 527 528 537 538 557 560 561 615 619 622 683} Amoxicillin (when given in dosages of 80–90 mg/kg daily) usually is effective in the treatment of AOM caused by S. pneumoniae, including infections involving strains with intermediate resistance to penicillins, and also usually is effective in the treatment of AOM caused by most strains of H. influenzae.^{522 527 560 683} Because S. pneumoniae is the most frequent cause of AOM (25–50% of cases) and because AOM caused by S. pneumoniae is more likely to be severe and less likely to resolve spontaneously than AOM caused by H. influenzae or M. catarrhalis, it has been suggested that it may be more important to choose an empiric anti-infective based on its activity against S. pneumoniae rather than its activity against other possible pathogens.^{449 522 527 538}

Various other anti-infectives, including oral cephalosporins (cefaclor, cefdinir, cefixime, cefpodoxime proxetil, cefprozil, ceftibuten, cefuroxime axetil, cephalexin), parenteral ceftriaxone, oral macrolides (azithromycin, clarithromycin, fixed combination of erythromycin and sulfisoxazole), oral co-trimoxazole, and oral loracarbef, have been used in the treatment of AOM.^{292 330 333 334 336 391 433 436 448 449 527 557 565 574 610 616 619 622 448 522 683} These anti-infectives vary in their efficacy against AOM pathogens.⁶⁸³

Current AAP evidence-based guidelines for the diagnosis and management of uncomplicated AOM in children 6 months through 12 years of age state that high-dose amoxicillin (80–90 mg/kg daily in 2 divided doses) should be used for initial treatment when a decision has been made to use anti-infective therapy and the child has not received amoxicillin within the past 30 days or does not have concurrent purulent conjunctivitis or is not allergic to penicillin.⁶⁸³ These guidelines state that high-dose amoxicillin and clavulanate (90 mg/kg of amoxicillin and 6.4 mg/kg of clavulanate daily in 2 divided doses) should be used if the child received amoxicillin within the past 30 days or has concurrent purulent conjunctivitis or has a history of recurrent AOM unresponsive to amoxicillin.⁶⁸³ These AAP guidelines state that the preferred alternatives for initial treatment of AOM in penicillin-allergic patients are oral cephalosporins (cefdinir, cefpodoxime proxetil, cefuroxime axetil) or parenteral ceftriaxone.⁶⁸³

Results of controlled clinical studies indicate that 10-day regimens of most oral anti-infectives used in the empiric treatment of AOM are equally effective, and there is no evidence that the overall response rate to anti-infectives with a broader spectrum of activity (e.g., second and third generation cephalosporins) is any better than that reported with amoxicillin or amoxicillin and clavulanate potassium.^{443 449 527 548 555 556 557 566 567 573 609 610 619} Of the currently available oral cephalosporins, cefaclor,³⁰⁷ cefdinir,³¹¹ cefixime,⁶⁷⁷ cefpodoxime proxetil,³³⁸ cefprozil,³³⁹ ceftibuten,³⁴¹ and cefuroxime axetil^{348 576} have been used effectively for the treatment of AOM in pediatric patients. However, there is evidence that some cephalosporins (e.g., cefaclor, cefprozil) may be less effective than some other available agents for the treatment of AOM when β-lactamase-producing bacteria are present^{330 331 333 334 336 337 339 433 585 619 621 622} and some (e.g., cefixime, ceftibuten) may be less effective than some other available agents for the treatment of AOM when S. pneumoniae with reduced susceptibility to penicillin are present.^{341 448 538 584 585 615 622 677}

Duration of Initial Treatment of AOM

The optimal duration of therapy for AOM is uncertain.⁶⁸³ Anti-infectives traditionally have been administered for 7–10 days for the treatment of AOM,^{292 543 546 557 578} but shorter durations of treatment also have been used.^{540 542 543 546} The 10-day regimen was derived from the duration of treatment for S. pyogenes pharyngitis and tonsillitis.⁶⁸³ Although there is some evidence from controlled clinical studies in pediatric patients with AOM that the clinical response rate to 5-day regimens of certain oral cephalosporins (e.g., cefaclor^†,⁴⁴⁶ cefdinir,³¹¹ cefpodoxime proxetil,^{338 441 442 443} cefprozil^†,^{445 447} cefuroxime axetil^{†581 633} ) is similar to that of 10-day regimens of oral cephalosporins, amoxicillin, or amoxicillin and clavulanate potassium,^{444 446 581 633} such regimens appear to be less effective than 10-day regimens in children younger than 2 years of age.⁶⁸³

Current AAP evidence-based guidelines for the diagnosis and management of uncomplicated AOM in children 6 months through 12 years of age state that a 10-day regimen of an appropriate oral anti-infective is recommended for the treatment of AOM in children younger than 2 years of age and in those with severe symptoms.⁶⁸³ These guidelines state that a 7-day regimen of an appropriate oral anti-infective may be as effective as a 10-day regimen in children 2–5 years of age with mild to moderate AOM, and a 5- to 7-day regimen of an appropriate oral anti-infective may be adequate in children 6 years of age or older with mild to moderate AOM.⁶⁸³

Other clinicians suggest that while 5-day regimens can be considered for adults and children 2 years of age and older with mild, uncomplicated AOM,^{292 543} further study is needed to more fully evaluate efficacy of short-term regimens in infants and young children since studies to date have included only a limited number of children younger than 2 years of age.^{406 436 444 446 447 540 541 542 543 683} These clinicians state that short-term anti-infective regimens (i.e., 5 days or less) may not be appropriate for the treatment of AOM in children younger than 2 years of age or for patients with underlying disease, craniofacial abnormalities, recurrent or persistent AOM, or perforated tympanic membranes and spontaneous purulent drainage.^{292 406 436 444 447 540 541 542 543 546}

Parenteral Ceftriaxone for Treatment of AOM

Parenteral ceftriaxone has been shown to be effective for initial or repeat treatment of AOM,^{343 421 535 613 614 683} and is a good choice when the patient has persistent vomiting or cannot otherwise tolerate an oral regimen.⁶⁸³ The manufacturer recommends a single dose of IM ceftriaxone for initial treatment of AOM, but cautions that the potential advantages of this single-dose parenteral regimen should be balanced against its potentially lower clinical cure rate compared with a 10-day oral anti-infective regimen.³⁴³ AAP states that either a 1- or 3-day regimen^† of parenteral ceftriaxone can be used for initial treatment of AOM, but cautions that there is some evidence that more than a single dose of the drug may be required to prevent recurrence of middle ear infections within 5–7 days after the initial dose.⁶⁸³ A 3-day regimen^† of parenteral ceftriaxone is recommended for retreatment in patients who fail to respond to initial treatment with other anti-infectives.^{525 613 683}

The single-dose IM ceftriaxone regimen offers some practical advantages over 5- to 10-day oral anti-infective regimens since it provides a more convenient dosing schedule, ensures compliance, and can be administered to patients who have nausea and vomiting;^{421 422 423 604 614} however, ceftriaxone may be more costly than oral regimens and the drug has a spectrum of activity that is broader than necessary for the treatment of AOM.^{602 603} Some clinicians suggest that further study of the single-dose ceftriaxone regimen is needed to more fully assess the bacteriologic eradication rate, long-term efficacy, and rate of relapse, and to determine whether the single-dose regimen contributes to emergence of resistant organisms.^{422 423 424 602}

Anti-infectives for AOM after Initial Treatment Failure

Consideration can be given to changing the anti-infective regimen in children who do not have clinical improvement within 48–72 hours after the initial anti-infective regimen is started.⁶⁸³ Current AAP evidence-based clinical practice guidelines for the diagnosis and management of uncomplicated AOM in children 6 months through 12 years of age state that patients who fail to respond to an initial regimen of high-dose amoxicillin (80–90 mg/kg daily in 2 divided doses) should be retreated with high-dose amoxicillin and clavulanate (90 mg/kg of amoxicillin and 6.4 mg/kg of clavulanate daily in 2 divided doses).⁶⁸³ Those who fail to respond to an initial regimen of high-dose amoxicillin and clavulanate potassium or an initial regimen of an appropriate oral cephalosporin (cefdinir, cefpodoxime proxetil, cefuroxime axetil) should be treated with parenteral ceftriaxone (50 mg/kg daily for 3 days).⁶⁸³

There is evidence that a 3-day regimen of IM ceftriaxone (50 mg/kg once daily) can be effective for the treatment of persistent or recurrent AOM^† in pediatric patients 3 months of age or older with infections that failed to respond to treatment with other anti-infectives (e.g., amoxicillin, amoxicillin and clavulanate potassium, cefaclor, cefuroxime axetil).^{535 613} A 3-day regimen of ceftriaxone has been shown to be more effective than a 1-day regimen for retreatment in patients who fail to respond to initial treatment with another anti-infective.⁶⁸³ The 3-day ceftriaxone regimen has been effective for the treatment of persistent or relapsing otitis media caused by H. influenzae, M. catarrhalis, S. pyogenes, or penicillin-susceptible S. pneumoniae; however, treatment failures have been reported when the causative agent was S. pneumoniae with reduced susceptibility to penicillin.^{535 613}

Clindamycin (30–40 mg/kg daily in 3 divided doses) can be used (with or without a third generation cephalosporin) as an alternative for the treatment of AOM in patients who fail to respond to an initial anti-infective regimen.⁶⁸³ Although clindamycin may be effective for penicillin-resistant S. pneumoniae, it may not be effective against multidrug-resistant S. pneumoniae and lacks efficacy against H influenzae.⁶⁸³ If clindamycin is used for retreatment, concomitant use of an anti-infective active against H. influenzae and M. catarrhalis (e.g., cefdinir, cefixime, cefuroxime) should be considered.⁶⁸³

Because of reported resistance in S. pneumoniae, AAP states that co-trimoxazole and the fixed combination of erythromycin and sulfisoxazole should not be used as alternatives for the treatment of AOM in patients who fail to improve while receiving amoxicillin.⁶⁸³

Primary treatment failure of AOM occurs most frequently in children younger than 2 years of age.^{525 536 544} While primary treatment failure and persistent AOM may be the result of infection with bacteria resistant to the anti-infective administered (e.g., penicillin-resistant S. pneumoniae, β-lactamase-producing H. influenzae),^{525 529 536 537 544 552 559 565} many cases appear to be related to other factors since results of tympanocentesis indicate that the causative organism(s) often are susceptible in vitro to the primary treatment regimen or, in some cases, no bacteria are isolated.^{536 544 545 559} Patients with AOM who fail to respond to an initial anti-infective regimen often also fail to respond to a subsequent regimen, regardless of the anti-infective used.^{522 545}

If AOM persists after a series of anti-infective regimens, tympanocentesis should be considered and culture of middle ear fluid performed to make a bacteriologic diagnosis and obtain in vitro susceptibility test results.⁶⁸³ If tympanocentesis is not available, a regimen of oral clindamycin with or without an anti-infective to provide coverage against H. influenzae and M. catarrhalis (e.g., cefdinir, cefixime, cefuroxime) may be considered.⁶⁸³ Consultation with a pediatric medical subspecialist (e.g., otolaryngologist) for possible tympanocentesis, drainage, and culture and consultation with an infectious disease expert before use of unconventional anti-infectives should be considered.⁶⁸³

Recurrent AOM

Current AAP evidence-based clinical practice guidelines for the diagnosis and management of uncomplicated AOM in children 6 months through 12 years of age state that anti-infective prophylaxis should not be prescribed to reduce the frequency of episodes of AOM in children with recurrent AOM.⁶⁸³ Recurrent AOM is defined as 3 or more episodes of AOM within a 6-month period or 4 or more episodes of AOM within a 12-month period that includes at least 1 episode in the preceding 6 months.⁶⁸³ About 50% of children younger than 2 years of age who are treated for AOM will have a recurrence within 6 months.⁶⁸³ Winter season, male gender, and passive exposure to tobacco smoke have been associated with an increased likelihood of AOM recurrence.⁶⁸³ Other risk factors for recurrence include AOM symptoms lasting more than 10 days, a family history of the infection, group day-care outside the home during the first 2 years of life, and use of bottles or pacifiers.^{449 543 617 683} There is some evidence that breastfeeding for at least 4–6 months reduces episodes of AOM and recurrent AOM.^{449 617 683}

Anti-infectives (e.g., amoxicillin, sulfisoxazole) have been administered as long-term prophylaxis or suppressive therapy in children with recurrent AOM in an attempt to prevent recurrence^{292 543 547 612 617 622 645} or have been administered intermittently as prophylaxis at the first sign of an upper respiratory tract infection in children with a history of recurrent AOM.^{541 543 612 617} Although there is some evidence that anti-infective prophylaxis may decrease the incidence of new symptomatic episodes of AOM in some children with a history of recurrent AOM,^{449 527 532 543 546 547 559 683} such prophylaxis is not routinely recommended.^{292 532 543 546 617 645 683} Results of a meta-analysis indicate that use of anti-infective prophylaxis results in an average decrease of only 0.11 episodes of AOM per patient per month (slightly more than 1 episode per year).⁵⁴⁷ In addition, anti-infective prophylaxis does not provide any long-lasting benefit since any decrease in AOM episodes occurs only while prophylaxis is being given.⁶⁸³ AAP states that anti-infective prophylaxis is not appropriate for children with long-term MEE or for children with infrequent episodes of AOM.⁶⁸³ The small reduction in frequency of AOM must be weighed against the cost and potential adverse effects of anti-infective prophylaxis (e.g., allergic reactions, GI effects such as diarrhea)⁶⁸³ and concerns that prophylaxis may promote emergence of resistant bacteria, including multidrug-resistant S. pneumoniae, or alter nasopharyngeal flora and foster colonization with resistant bacteria.^{292 527 532 541 546 612 617 683}

Otitis Media with Effusion

Anti-infectives are not usually recommended for management of otitis media with effusion (OME).^{292 448 541 543 546 547 684} OME involves liquid in the middle ear (MEE) without signs and symptoms of acute ear infection.^{683 684} OME may occur as an inflammatory response after an episode of AOM or may occur spontaneously as a consequence of eustachian tube dysfunction.^{683 684} About 60–70% of children have MEE present 2 weeks after successful treatment of AOM and 10–25% still have MEE at 3 months.⁶⁸³ It is important to differentiate OME from AOM.^{683 684} Management of OME usually involves observation and close monitoring until resolution.^{683 684} Anti-infective treatment is not usually indicated because OME does not represent an acute infectious process.^{683 684} The AAFP, American Academy of Otolaryngology-Head and Neck Surgery, and AAP Subcommittee on Otitis Media with Effusion have issued evidence-based clinical practice guidelines regarding diagnosis and management of OME in children 2 months to 12 years of age (with or without developmental disabilities or underlying conditions that predispose to OME and its sequelae).⁶⁸⁴ These guidelines should be consulted for information on diagnosis and management of OME.⁶⁸⁴

Chronic Suppurative Otitis Media without Cholesteatoma

Ceftazidime has been used with some success in the treatment of chronic suppurative otitis media (CSOM) without cholesteatoma.^{598 600 601} CSOM is defined as chronic infection of the middle ear and mastoid associated with tympanic membrane perforation and otorrhea lasting more than 6 weeks, and may occur as the result of unresolved AOM and/or eustachian tube dysfunction.^{598 608 622} The most common bacteria reported in patients with CSOM are Ps. aeruginosa, Klebsiella, S. aureus, S. epidermidis, and anaerobic bacteria, including Bacteroides, Prevotella, Peptostreptococcus, and Peptococcus.^{554 598 599 600 608 622} While ceftazidime has been effective in the treatment of CSOM when gram-negative bacteria were involved, it has been ineffective when gram-positive bacteria (e.g., S. aureus) were involved.^{598 600} Because CSOM often is a mixed aerobic-anaerobic infection, anti-infectives usually used in the treatment of AOM or OME would be ineffective.^{554 622} Topical anti-infectives (e.g., ciprofloxacin otic suspension, ofloxacin otic solution, gentamicin) used in conjunction with daily aural toilet can be effective for the treatment of uncomplicated CSOM; more severe or persistent infections require treatment with a parenteral anti-infective (e.g., ceftazidime, clindamycin, ciprofloxacin, gentamicin, ticarcillin, ticarcillin disodium and clavulanate potassium).^{554 618 622 630}

Otitis Externa

Ceftazidime has been effective when used in the treatment of malignant otitis externa^† caused by Ps. aeruginosa.^{605 632} Bacterial otitis externa usually is caused by Ps. aeruginosa or S. aureus.^{631 632} Although acute bacterial otitis externa localized in the external auditory canal may be effectively treated using topical anti-infectives (e.g., ciprofloxacin otic suspension, ofloxacin otic solution), malignant otitis externa is an invasive, potentially life-threatening infection, especially in immunocompromised patients such as those with diabetes mellitus or human immunodeficiency virus (HIV) infection, and requires prompt diagnosis and long-term treatment with parenteral anti-infectives (e.g., ceftazidime and/or ciprofloxacin).^{605 632}

Pharyngitis and Tonsillitis

Oral cephalosporins (e.g., cefaclor, cefadroxil, cefdinir, cefditoren pivoxil, cefixime, cefpodoxime proxetil, cefprozil, ceftibuten, cefuroxime axetil, cephalexin) are used for the treatment of pharyngitis and tonsillitis caused by S. pyogenes (group A β-hemolytic streptococci).^{292 307 308 311 338 339 341 348 375 663 580 677} Although cephalosporins usually are effective in eradicating S. pyogenes from the nasopharynx, efficacy of the drugs in the subsequent prevention of rheumatic fever remains to be established.^{307 308 311 338 339 341 348 663 677}

Selection of an anti-infective for the treatment of S. pyogenes pharyngitis and tonsillitis should be based on the drug’s spectrum of activity, bacteriologic and clinical efficacy, potential adverse effects, ease of administration, patient compliance, and cost.^{292 375 433 435 436 580} No regimen has been found to date that effectively eradicates group A β-hemolytic streptococci in 100% of patients.³⁷⁵

Because the drugs have a narrow spectrum of activity, are inexpensive, and generally are effective with a low frequency of adverse effects, AAP,²⁹² IDSA,⁵⁸⁰ American Heart Association (AHA),³⁷⁵ and other experts⁶⁷⁸ recommend a penicillin regimen (i.e., 10 days of oral penicillin V or oral amoxicillin or a single dose of IM penicillin G benzathine) as the treatment of choice for S. pyogenes pharyngitis and tonsillitis and prevention of initial attacks (primary prevention) of rheumatic fever. Other anti-infectives (e.g., oral cephalosporins, oral macrolides, oral clindamycin) are recommended as alternatives in penicillin-allergic patients.^{292 375 378 433 435 436 580 678}

A 10-day regimen of an appropriate oral cephalosporin is recommended for the treatment of S. pyogenes pharyngitis and tonsillitis in most penicillin-allergic patients; however, cephalosporins should be avoided in those with a history of immediate (anaphylactic-type) penicillin hypersensitivity.^{375 580} If an oral cephalosporin is used, a 10-day regimen of a first generation cephalosporin (cefadroxil, cephalexin) is preferred instead of other cephalosporins with broader spectrums of activity (e.g., cefaclor, cefdinir, cefixime, cefpodoxime proxetil, cefuroxime).^{375 580} The broader spectrum cephalosporins offer no advantages over penicillins or first generation cephalosporins since they generally are more expensive and more likely to result in resistant flora.^{375 580}

Although there is some evidence that bacteriologic and clinical cure rates reported with 10-day regimens of certain oral cephalosporins (e.g., cefaclor, cefadroxil, cefdinir, cefixime, cefpodoxime proxetil, cefprozil, cefuroxime axetil, ceftibuten, cephalexin) may be slightly higher than those reported with the 10-day oral penicillin V regimen,^{375 377 378 379 381 382 433 435 436 438} analysis of data from the 10-day cephalosporin studies suggests that the difference in eradication rates may have been due to a higher rate of eradication of carriers inadvertently included in the study population.³⁷⁵ In addition, although there is some evidence that a shorter duration of therapy with certain oral cephalosporins (e.g., a 5-day regimen of cefadroxil, cefdinir, cefixime, or cefpodoxime proxetil or a 4- or 5-day regimen of cefuroxime axetil) achieves bacteriologic and clinical cure rates equal to or greater than those achieved with the traditional 10-day oral penicillin V regimen,^{375 378 382 436 438 439 440 580} AHA and IDSA state that use of cephalosporin regimens administered for 5 days or less for the treatment of S. pyogenes pharyngitis and tonsillitis cannot be recommended at this time.^{375 580}

Respiratory Tract Infections

Community-acquired Pneumonia

Some oral cephalosporins (cefdinir, cefpodoxime proxetil, cefprozil, cefuroxime axetil) and some parenteral cephalosporins (cefepime, cefotaxime, ceftaroline fosamil, ceftriaxone) are used in the treatment of community-acquired pneumonia (CAP) caused by susceptible bacteria.^{311 680 703}

Initial treatment of CAP generally involves use of an empiric anti-infective regimen selected based on the most likely pathogens and local susceptibility patterns; therapy may then be changed (if possible) to provide a more specific regimen (pathogen-directed therapy) based on results of in vitro culture and susceptibility testing.⁶⁸⁰ The most appropriate empiric regimen varies depending on the severity of illness at the time of presentation and whether outpatient treatment or hospitalization in or out of an intensive care unit (ICU) is indicated and the presence or absence of cardiopulmonary disease and other modifying factors that increase the risk of certain pathogens (e.g., penicillin- or multidrug-resistant S. pneumoniae, enteric gram-negative bacilli, Ps. aeruginosa).⁶⁸⁰

For both outpatients and inpatients, most experts recommend that an empiric regimen for treatment of CAP include an anti-infective active against S. pneumoniae since this organism is the most commonly identified cause of bacterial pneumonia and causes more severe disease than many other common CAP pathogens.^{680 682} Although monotherapy may be appropriate for empiric treatment of CAP in many outpatients and some inpatients, a combination regimen is always indicated for empiric treatment of CAP in patients requiring treatment in an ICU.⁶⁸⁰ Such patients require an empiric regimen that covers S. pneumoniae, Legionella, H. influenzae, Mycoplasma pneumoniae, Chlamydophila pneumoniae (formerly Chlamydia pneumoniae), and relevant gram-negative bacilli.⁶⁸⁰

Outpatient Regimens for CAP

Pathogens most frequently involved in CAP infections in outpatients include S. pneumoniae, M. pneumoniae, C. pneumoniae, respiratory viruses, and H. influenzae (especially in cigarette smokers).⁶⁸⁰

For empiric outpatient treatment of CAP in previously healthy individuals without risk factors for drug-resistant S. pneumoniae, IDSA and the American Thoracic Society (ATS) recommend monotherapy with a macrolide (azithromycin, clarithromycin, erythromycin) or, alternatively, doxycycline.⁶⁸⁰

For empiric outpatient treatment of CAP in patients with risk factors for drug-resistant S. pneumoniae (e.g., comorbidities such as chronic heart, lung, liver, or renal disease, diabetes mellitus, alcoholism, malignancies, asplenia, immunosuppression, history of anti-infective treatment within the last 3 months), ATS and IDSA recommend monotherapy with a fluoroquinolone with enhanced activity against S. pneumoniae (gemifloxacin, levofloxacin, moxifloxacin) or, alternatively, a combination regimen that includes a β-lactam active against S. pneumoniae (high-dose amoxicillin or fixed combination of amoxicillin and clavulanic acid or, alternatively, ceftriaxone, cefpodoxime proxetil, or cefuroxime) given in conjunction with a macrolide (azithromycin, clarithromycin, erythromycin) or, alternatively, given in conjunction with doxycycline.⁶⁸⁰

Inpatient Regimens for CAP

Pathogens most frequently involved in CAP infections in non-ICU inpatients include S. pneumoniae, M. pneumoniae, C. pneumoniae, H. influenzae, Legionella, and respiratory viruses.⁶⁸⁰ Patients with severe CAP admitted into the ICU usually have infections caused by S. pneumoniae, S. aureus, Legionella, gram-negative bacilli, or H. influenzae.⁶⁸⁰ Factors that increase the risk of Enterobacteriaceae or Ps. aeruginosa infection in CAP patients include severe CAP requiring treatment in an ICU, structural lung disease (bronchiectasis), severe chronic obstructive pulmonary disease (COPD), smoking, alcoholism, chronic corticosteroid therapy, and frequent anti-infective therapy.⁶⁸⁰ Coverage against anaerobic bacteria usually is indicated only in classic aspiration pleuropulmonary syndrome in patients who had loss of consciousness as a result of alcohol or drug overdosage or after seizures in patients with concomitant gingival disease or esophageal motility disorders.⁶⁸⁰

For empiric inpatient treatment of CAP in non-ICU patients, IDSA and ATS recommend monotherapy with a fluoroquinolone with enhanced activity against S. pneumoniae (gemifloxacin, levofloxacin, moxifloxacin) or, alternatively, a combination regimen that includes a β-lactam (usually cefotaxime, ceftriaxone, or ampicillin) given in conjunction with a macrolide (azithromycin, clarithromycin, erythromycin) or doxycycline.⁶⁸⁰

For empiric treatment of CAP in ICU patients when Pseudomonas and methicillin-resistant S. aureus (MRSA; also known as oxacillin-resistant S. aureus or ORSA) are not suspected, IDSA and ATS recommend a combination regimen that includes a β-lactam (cefotaxime, ceftriaxone, fixed combination of ampicillin and sulbactam) given in conjunction with either azithromycin or a fluoroquinolone (moxifloxacin, gemifloxacin, levofloxacin).⁶⁸⁰ If Pseudomonas is suspected, IDSA and ATS recommend an empiric combination regimen that includes an antipneumococcal, antipseudomonal β-lactam (cefepime, imipenem, meropenem, fixed combination of piperacillin and tazobactam) given in conjunction with a fluoroquinolone (ciprofloxacin, levofloxacin); a combination regimen that includes one of these antipseudomonal β-lactams, an aminoglycoside, and azithromycin; or a combination regimen that includes one of these antipseudomonal β-lactams, an aminoglycoside, and an antipneumococcal fluoroquinolone.⁶⁸⁰ If Ps. aeruginosa has been identified by appropriate microbiologic testing, the preferred treatment regimen is an antipseudomonal β-lactam (cefepime, ceftazidime, aztreonam, imipenem, meropenem, piperacillin, ticarcillin) given in conjunction with ciprofloxacin, levofloxacin, or an aminoglycoside and the preferred alternative regimen is an aminoglycoside given in conjunction with ciprofloxacin or levofloxacin.⁶⁸⁰ If community-acquired MRSA may be involved, vancomycin or linezolid should be included in the initial empiric regimen.⁶⁸⁰

Inpatient treatment of CAP is initiated with a parenteral regimen, although therapy may be changed to an oral regimen if the patient is improving clinically, is hemodynamically stable, able to ingest drugs, and has a normally functioning GI tract.⁶⁸⁰ CAP patients usually have a clinical response within 3–7 days after initiation of therapy and a switch to oral therapy generally can be made during this period.⁶⁸⁰

Acute Sinusitis

Oral cefdinir,³¹¹ cefixime^†,^{192 193} cefpodoxime proxetil,³³⁸ cefprozil,³³⁹ and cefuroxime axetil³⁴⁸ are used for the treatment of acute maxillary sinusitis caused by susceptible bacteria (e.g., S. pneumoniae, H. influenzae, M. catarrhalis). Parenteral ceftriaxone^† and cefotaxime^† are recommended as alternatives for initial treatment of severe bacterial sinusitis.^{192 193}

When anti-infective therapy is indicated for the treatment of acute bacterial sinusitis, IDSA recommends amoxicillin and clavulanate potassium and AAP recommends either amoxicillin or amoxicillin and clavulanate potassium as the drug of choice for initial empiric treatment.^{192 193} Because of variable activity against S. pneumoniae and H. influenzae, IDSA no longer recommends second or third generation oral cephalosporins for empiric monotherapy of sinusitis in adults or children.¹⁹² If an oral cephalosporin is used as an alternative for empiric treatment of acute bacterial sinusitis in children (e.g., in penicillin-allergic individuals), IDSA and AAP recommend a combination regimen that includes a third generation cephalosporin (cefixime or cefpodoxime) and clindamycin (or linezolid).^{192 193} In children who are vomiting, unable to tolerate oral therapy, or unlikely to adhere to the initial doses, treatment of acute sinusitis can be initiated with a single dose of parenteral ceftriaxone and then switched to an oral regimen if clinical improvement is observed at 24 hours.^{192 193} For patients with severe bacterial sinusitis requiring hospitalization, parenteral ceftriaxone and cefotaxime are preferred alternatives for initial treatment in penicillin-allergic patients who cannot receive amoxicillin and clavulanate potassium.^{192 193}

Septicemia

Cefotaxime,³³² ceftazidime,³⁴⁰ ceftriaxone,³⁴³ cefazolin,³¹⁰ and cefepime^†710 are used parenterally for the treatment of bacteremia/septicemia caused by susceptible bacteria (e.g., S. aureus, S. pneumoniae, H. influenzae, E. coli, K. pneumoniae, Serratia).

The choice of anti-infective for the treatment of sepsis syndrome should be based on the probable source of infection, causative organism, immune status of the patient, and local patterns of bacterial resistance.⁷¹⁰ Some experts state that, although certain parenteral cephalosporins (cefepime, cefotaxime, ceftriaxone, ceftazidime) can be used for the treatment of gram-negative sepsis, ceftazidime is less active than the other cephalosporins against gram-positive cocci and most cephalosporins (except cefepime and ceftazidime) have limited activity against Ps. aeruginosa.⁷¹⁰

For initial treatment of life-threatening sepsis in adults, some clinicians recommend that a third or fourth generation cephalosporin (cefepime, cefotaxime, ceftazidime, ceftriaxone), the fixed combination of piperacillin and tazobactam, or a carbapenem (doripenem, imipenem, meropenem) be used in conjunction with vancomycin; some experts also suggest including an aminoglycoside or fluoroquinolone during the initial few days of treatment.⁷¹⁰

Urinary Tract Infections

Some oral cephalosporins (cefaclor, cefadroxil, cefixime, cefpodoxime proxetil, cefuroxime axetil, cephalexin) and some parenteral cephalosporins (cefazolin, cefepime, ceftazidime, ceftriaxone, cefuroxime) are used for the treatment of uncomplicated and/or complicated urinary tract infections caused by susceptible bacteria.^{307 308 310 314 338 340 343 347 348 349 677} The fixed combination of ceftazidime and avibactam⁷²⁸ and the fixed combination of ceftolozane and tazobactam⁷²⁹ are used for the treatment of complicated urinary tract infections.

Chancroid

Ceftriaxone is used for the treatment of genital ulcers caused by H. ducreyi (chancroid)^†, and is considered a drug of choice for the treatment of this infection.³⁴⁴

Gonorrhea and Associated Infections

Cefoxitin,³⁴⁴ cefotaxime,³⁴⁴ ceftriaxone,^{292 343 344} and cefuroxime³⁴⁷ are used parenterally and cefixime,^{292 344 677} cefpodoxime proxetil,^{292 338} and cefuroxime axetil³⁴⁸ have been used orally for the treatment of uncomplicated gonorrhea caused by susceptible Neisseria gonorrhoeae. Cefoxitin, cefotaxime^†,²⁹² ceftriaxone^†,³⁴⁴ and cefuroxime³⁴⁷ also have been used parenterally for the treatment of disseminated gonorrhea and other gonococcal infections.

Ceftriaxone is considered the drug of choice for the treatment of most N. gonorrhoeae infections, including uncomplicated gonococcal infections of the cervix, urethra, rectum, and pharynx; disseminated gonococcal infections; gonococcal conjunctivitis; gonococcal meningitis and endocarditis; gonococcal epididymitis or proctitis in adults and adolescents; gonococcal ophthalmia neonatorum; and uncomplicated gonorrhea or disseminated gonococcal infections in neonates and children.^{292 344} Ceftriaxone also is used in conjunction with other agents for empiric anti-infective prophylaxis in sexual assault victims^†.³⁴⁴ CDC states that ceftriaxone is the most effective cephalosporin for the treatment of gonorrhea⁷¹⁶ and, unlike most other drugs, is effective for the treatment of gonorrhea at all sites, including cervical, urethral, rectal, and pharyngeal gonococcal infections.³⁴⁴ Other parenteral or oral cephalosporins do not offer any advantages over ceftriaxone.³⁴⁴

N. gonorrhoeae with reduced susceptibility to ceftriaxone and/or cefixime or other cephalosporins have been reported with increasing frequency during the last decade in the US and elsewhere (e.g., Asia, Europe, Canada);^{344 716 717 718 719 720 721 722 723 724 725 726 727} some treatment failures have been reported.^{720 723 725} There have been rare reports of N. gonorrhoeae with high-level ceftriaxone resistance in some countries (Japan, France, Spain).^{717 721 727} Although the overall prevalence of isolates with reduced susceptibility to cephalosporins remains low in the US, potential emergence of high-level cephalosporin resistance in N. gonorrhoeae is a major concern since available treatment options are limited if cephalosporins cannot be used.^{716 722}

Susceptibility of N. gonorrhoeae in the US is being monitored by the CDC Gonococcal Isolate Surveillance Project (GISP).⁷¹⁶ GISP data from 2000–2010 indicate that the percentage of US N. gonorrhoeae isolates with elevated ceftriaxone MICs (MICs 0.125 mcg/mL or greater) increased from 0.1 to 0.3% and the percentage with elevated cefixime MICs (MICs 0.25 mcg/mL or greater) increased from 0.2 to 1.4%.⁷¹⁶ All 2009–2010 isolates with decreased susceptibility to cefixime were resistant to ciprofloxacin and tetracycline, but were susceptible to azithromycin.⁷¹⁶ GISP data regarding N. gonorrhoeae isolates from men who have sex with men indicate that the percentage of isolates with elevated ceftriaxone MICs increased from 0% in 2006 to 1% in 2011 and the percentage of isolates with elevated cefixime MICs increased from 0.2% in 2006 to 3.8% in 2011.⁷²² More recent GISP data indicate that the proportion of isolates in the US with decreased susceptibility to ceftriaxone or cefixime has remained low.³⁴⁴ During 2013, no isolates with decreased susceptibility to ceftriaxone or cefixime (i.e., MICs 0.5 mcg/mL or greater) were identified.³⁴⁴

Because of concerns related to reports of N. gonorrhoeae with reduced susceptibility to cephalosporins, CDC now recommends that IM ceftriaxone be used in conjunction with oral azithromycin for the treatment of uncomplicated gonorrhea (dual treatment).^{344 722} The theoretical basis of this recommendation is that combination therapy using 2 anti-infectives with different mechanisms of action may improve treatment efficacy and potentially delay emergence and spread of cephalosporin resistance.^{344 722} In addition, CDC no longer recommends use of cefixime or any other oral cephalosporin as first-line treatment for gonococcal infections.⁷²² Cefixime should only be used as an alternative for the treatment of urogenital or rectal gonococcal infections when ceftriaxone is unavailable or cannot be used.^{344 722}

CDC recommends that healthcare providers treating gonorrhea remain vigilant for treatment failures (evidenced by persistent symptoms or a positive follow-up test despite treatment) and report any occurrence of treatment failure to local or state health departments.^{716 722} If there is evidence of treatment failure, relevant clinical specimens should be cultured and in vitro susceptibility testing performed.^{344 722} In addition, an infectious disease specialist, an STD/HIV Prevention Training Center ([Web]), or the CDC (404-639-8659) should be consulted for treatment advice and the case should be reported to CDC through local or state health departments within 24 hours of diagnosis.^{344 722}

Although a test-of-cure is not necessary for individuals with uncomplicated urogenital or rectal gonorrhea who are treated with a recommended or alternative regimen, those with pharyngeal gonorrhea who are treated with an alternative regimen should return 14 days after treatment for a test-of-cure.³⁴⁴ To minimize transmission, individuals treated for gonorrhea should be instructed to abstain from sexual activity for 7 days after treatment and until all sexual partners have been adequately treated.³⁴⁴ The patient's recent sexual partners (i.e., individuals having sexual contact with the infected patient within the 60 days preceding onset of symptoms or gonorrhea diagnosis) should be referred for evaluation, testing, and presumptive dual treatment.³⁴⁴

Uncomplicated Gonorrhea

For the treatment of uncomplicated cervical, urethral, or rectal gonorrhea in adults and adolescents, CDC states that a combination regimen that includes a single 250-mg dose of IM ceftriaxone and oral azithromycin (single 1-g dose) is the treatment of choice.³⁴⁴ Both drugs should be administered together on the same day, preferably simultaneously and under direct supervision.³⁴⁴

If necessary because ceftriaxone is not available or cannot be used and the patient has urogenital or rectal gonorrhea, CDC recommends an alternative combination regimen that includes a single 400-mg dose of oral cefixime and oral azithromycin (single 1-g dose).³⁴⁴

Disseminated Gonococcal Infections

CDC recommends that patients with disseminated gonococcal infections be hospitalized for initial treatment, especially when compliance may be a problem, when the diagnosis is uncertain, or when the patient has purulent synovial effusions or other complications.³⁴⁴ All patients with disseminated infections should be evaluated for clinical evidence of endocarditis and meningitis.³⁴⁴ Consultation with an infectious disease expert is advised.³⁴⁴

For treatment of disseminated gonococcal infections classified as arthritis and arthritis-dermatitis syndrome^†, CDC recommends that adults and adolescents receive a combination regimen of IM or IV ceftriaxone (1 g every 24 hours) and oral azithromycin (single 1-g dose);³⁴⁴ the recommended alternative is IV cefotaxime (1 g IV every 8 hours) and oral azithromycin (single 1-g dose).³⁴⁴ At 24–48 hours after substantial improvement, therapy can be switched to an oral anti-infective selected based on in vitro susceptibility testing.³⁴⁴ Total treatment duration for gonococcal arthritis and arthritis-dermatitis syndrome is at least 7 days.³⁴⁴

For treatment of disseminated gonococcal infections that involve meningitis and endocarditis^†, CDC recommends that adults and adolescents receive a combination regimen of IV ceftriaxone (1–2 g every 12–24 hours) and oral azithromycin (single 1-g dose).³⁴⁴ The parenteral regimen should be continued for 10–14 days for the treatment of gonococcal meningitis or for at least 4 weeks for the treatment of gonococcal endocarditis.³⁴⁴

Leptospirosis

Ceftriaxone and cefotaxime have been used in the treatment of severe leptospirosis^† caused by Leptospira.^{292 690 693 694 695} Leptospirosis is a spirochete infection that may range in severity from a self-limited systemic illness to a severe, life-threatening illness that includes jaundice, renal failure, hemorrhage, cardiac arrhythmias, pneumonitis, and hemodynamic collapse (Weil syndrome).^{292 691 693}

Penicillin G generally has been considered the drug of choice for the treatment of moderate to severe leptospirosis.^{292 690 691 695} Other anti-infectives recommended for the treatment of severe leptospirosis include cephalosporins (ceftriaxone, cefotaxime), aminopenicillins (ampicillin, amoxicillin), tetracyclines (doxycycline, tetracycline), or macrolides (azithromycin).^{292 691 693 694 695}

Lyme Disease

Oral cefuroxime axetil, IV ceftriaxone, and IV cefotaxime are used for the treatment of Lyme disease^†.^{292 329 348 470 471 472 473 474 476 480 481 482 483 484 485 486 487 488 489 492 493 514 666} First generation cephalosporins (e.g., cephalexin) are ineffective and should not be used for the treatment of Lyme disease.^{329 666 671} Although other second or third generation cephalosporins may be effective, the only cephalosporins currently recommended by IDSA, AAP, and other clinicians for the treatment of Lyme disease are cefuroxime axetil, ceftriaxone, and cefotaxime.^{292 329 470 471 472 473 474 476 480 481 482 483 484 485 486 487 488 489 492 493 514 666}

Lyme disease (Lyme borreliosis) is a tick-born spirochetal disease.^{292 329 471 472 505 506 507} In the US, Lyme disease is caused by the spirochete Borrelia burgdorferi, which is transmitted by the bite of Ixodes scapularis or I. pacificus ticks.^{292 329 471 472 505 506 507} In addition to B. burgdorferi, I. scapularis may be simultaneously infected with and transmit Anaplasma phagocytophilum (causative agent of human granulocytotropic anaplasmosis [HGA, formerly known as human granulocytic ehrlichiosis]) and/or Babesia microti (causative agent of babesiosis).^{329 687} Because coinfection with A. phagocytophilum and/or B. microti can occur in patients with Lyme disease in geographic areas where these other pathogens are endemic, these diseases should be considered in the differential diagnosis of patients being evaluated for Lyme disease.^{329 687} Since cephalosporins are ineffective for the treatment of HGA and/or babesiosis, diagnosing such coinfections is critical to ensure that appropriate anti-infectives are used for treatment.^{329 687}

Early Lyme Disease

Erythema migrans

IDSA, AAP, and other clinicians recommend oral doxycycline, oral amoxicillin, or oral cefuroxime axetil as first-line therapy for the treatment of the early localized or early disseminated Lyme disease^† associated with erythema migrans, in the absence of specific neurologic manifestations or advanced atrioventricular (AV) heart block.^{292 329 470 471 472 473 474 480 482 513 514 666} IDSA states that a 14-day regimen (range 14–21 days) of any of these oral anti-infectives (doxycycline, amoxicillin, cefuroxime axetil) may be used for initial treatment of early Lyme disease since all 3 drugs have been shown to be effective for the treatment of erythema migrans and associated symptoms in prospective clinical studies.³²⁹ Doxycycline offers the advantage of also being effective for the treatment of HGA coinfection (but not babesiosis coinfection).^{292 329}

Although IV ceftriaxone is effective for early Lyme disease manifested as erythema migrans, it is not superior to the recommended oral anti-infectives and is more likely to cause serious adverse effects; therefore, IV ceftriaxone is not usually recommended for the treatment of early Lyme disease in the absence of neurologic involvement or advanced AV heart block.^{329 666}

Transplacental transmission of B. burgdorferi appears to occur rarely, if at all,⁶⁶⁶ and epidemiologic studies in pregnant women have not documented an association between exposure to Lyme disease prior to conception or during pregnancy and subsequent fetal death, congenital malformations, or prematurity.^{480 487} IDSA, AAP, and other clinicians state that pregnant or nursing women need not be treated differently than other patients with Lyme disease, except that they should not receive doxycycline.^{292 329 480 666}

Early Neurologic Lyme Disease

Although oral anti-infectives (e.g., doxycycline, amoxicillin, cefuroxime axetil) generally are effective for the treatment of the early Lyme disease associated with erythema migrans in the absence of specific neurologic manifestations, parenteral anti-infectives are recommended for the treatment of early Lyme disease when there are acute neurologic manifestations such as meningitis or radiculopathy.^{292 329 470 471 472 498 499 501 502 513 515 516 666} Radiculopathy, cranial neuropathy, and mononeuropathy multiplex may be manifestations of acute peripheral nervous system involvement.³²⁹ In the US, cranial neuropathy is the most common manifestation of early neurologic Lyme disease; seventh cranial nerve palsy is the most common of the cranial neuropathies and bilateral involvement may occur.³²⁹ Cranial nerve palsies in patients with Lyme disease frequently are associated with lymphocytic CSF pleocytosis, with or without symptoms of meningitis.³²⁹ Although anti-infectives may not hasten resolution of seventh cranial nerve palsy associated with B. burgdorferi infection, anti-infectives should be given to prevent further sequelae.³²⁹

IDSA and other clinicians recommend a 14-day regimen (range: 10–28 days) of IV ceftriaxone as first-line therapy for the treatment of acute neurologic Lyme disease manifested by meningitis or radiculopathy; IV cefotaxime and IV penicillin G sodium are the preferred alternatives.^{292 329 666} It has been suggested that IV ceftriaxone may be preferable to IV penicillin G for serious manifestations of early disseminated or late Lyme disease (i.e., those involving major organs) based on ceftriaxone’s greater in vitro and in vivo activity against B. burgdorferi, excellent CSF penetration, and prolonged serum concentrations achievable with once-daily administration of the drug.^{329 471 472 504 509 510 511 512} Although IV cefotaxime appears to be as effective as IV ceftriaxone or IV penicillin G sodium for the treatment of acute neurologic Lyme disease and does not cause the biliary complications reported with ceftriaxone, ceftriaxone has the advantage of once-daily dosing.^{329 470 514 516 666 686} In patients with acute neurologic manifestations who are intolerant of cephalosporins and penicillin, there is some evidence that oral doxycycline may be an adequate alternative that can be considered for use in adults and children 8 years of age or older; because doxycycline is well absorbed orally, IV doxycycline should only be needed rarely.³²⁹

Some clinicians suggest that a 14-day regimen (range: 14–21 days) of oral anti-infectives (amoxicillin, doxycycline, cefuroxime axetil) may be used in patients with cranial nerve palsy without clinical evidence of meningitis (i.e., those with normal CSF examinations or those for whom CSF examination is deemed unnecessary because there are no clinical signs of meningitis); however, a 14-day parenteral regimen (range: 10–28 days) is indicated when there is both clinical and laboratory evidence of CNS involvement and meningitis.^{292 329} Although there is some experience using oral anti-infectives in patients with seventh cranial nerve palsy, it is unclear whether an oral regimen would be as effective for patients with other cranial neuropathies.³²⁹

Lyme Carditis

IDSA states that patients with AV heart block and/or myopericarditis associated with early Lyme disease may be treated with a 14-day regimen (range: 14–21 days) of oral or parenteral anti-infectives.³²⁹ Although there is no evidence to date to suggest that a parenteral regimen is more effective than an oral regimen for the treatment of Lyme carditis, a parenteral regimen usually is recommended for initial treatment of hospitalized patients; an oral regimen can be used to complete therapy and for the treatment of outpatients.^{292 329 470 666} When a parenteral regimen is used, IV ceftriaxone or, alternatively, IV cefotaxime or IV penicillin G sodium is recommended.^{292 329 470 666} When an oral regimen is used, oral amoxicillin, oral doxycycline, or oral cefuroxime axetil is recommended.^{292 329 470 666}

Because of the potential for life-threatening complications, hospitalization and continuous monitoring is advisable for patients who are symptomatic (syncope, dyspnea, chest pain) and also is recommended for those with second- or third-degree AV block or first-degree heart block when the PR interval is prolonged to 0.3 seconds or longer.^{329 666} Patients with advanced heart block may require a temporary pacemaker and consultation with a cardiologist is recommended.^{329 666}

Borrelial Lymphocytoma

Although experience is limited, IDSA states that available data indicate that borrelial lymphocytoma^† may be treated with a 14-day regimen (range: 14–21 days) of oral doxycycline, oral amoxicillin, or oral cefuroxime axetil in the dosages used for the treatment of erythema migrans.³²⁹

Late Lyme Disease

Lyme Arthritis

Patients with uncomplicated Lyme arthritis^† without clinical evidence of neurologic disease generally can be treated with a 28-day regimen of oral doxycycline, oral amoxicillin, or oral cefuroxime axetil.^{292 329 470 480 666 669} However, patients with Lyme arthritis and concomitant neurologic disease should receive a 14-day parenteral regimen (range: 14–28 days) of IV ceftriaxone or, alternatively, IV cefotaxime or IV penicillin G sodium.^{292 329 470 666} While oral regimens are easier to administer, associated with fewer serious adverse effects, and less expensive than IV regimens, some patients with Lyme arthritis treated with oral anti-infectives have subsequently developed overt neuroborreliosis, which may require IV therapy for successful resolution.³²⁹ Therefore, additional study is needed to fully evaluate the comparative safety and efficacy of oral versus IV anti-infectives for the treatment of Lyme arthritis.³²⁹

In patients who have persistent or recurrent joint swelling after a recommended oral regimen, IDSA and other clinicians recommend retreatment with the oral regimen or a switch to a parenteral regimen.^{329 470 480 666} Some clinicians prefer retreatment with an oral regimen for patients whose arthritis substantively improved but did not completely resolve; these clinicians reserve parenteral regimens for those patients whose arthritis failed to improve or worsened.³²⁹ It has been suggested that clinicians should consider allowing several months for joint inflammation to resolve after initial treatment before an additional course of anti-infectives is given.³²⁹

Late Neurologic Lyme Disease

IDSA and other clinicians recommend that patients with late neurologic Lyme disease^† affecting the CNS or peripheral nervous system (e.g., encephalopathy, neuropathy) receive a 14-day regimen (range: 14–28 days) of IV ceftriaxone or, alternatively, IV cefotaxime or IV penicillin G sodium.³²⁹ Response to anti-infective treatment usually is slow and may be incomplete in patients with late neurologic Lyme disease.³²⁹ IDSA states that retreatment is not recommended unless relapse is shown by reliable objective measures.³²⁹

Acrodermatitis Chronica Atrophicans

IDSA states that available data indicate that acrodermatitis chronica atrophicans^† may be treated with a 21-day regimen (range: 14–28 days) of oral doxycycline, oral amoxicillin, or oral cefuroxime axetil in the dosages used for the treatment of erythema migrans.³²⁹ It is unclear whether a parenteral regimen would be more effective than an oral regimen.³²⁹

Nocardiosis

Cephalosporins (ceftriaxone, cefotaxime, cefoxitin, cefuroxime) have been used for the treatment of nocardiosis^† caused by Nocardia.^{292 697 698 699 700 701 702}

Co-trimoxazole (fixed combination of sulfamethoxazole and trimethoprim) usually is considered the drug of choice for the treatment of nocardiosis.²⁹² Other drugs that have been used alone or in combination regimens for the treatment of nocardiosis include a sulfonamide alone (sulfadiazine, sulfamethoxazole [not commercially available as a single-entity preparation in the US]), amikacin, tetracyclines, cephalosporins (ceftriaxone, cefotaxime, cefuroxime), cefoxitin, carbapenems (imipenem or meropenem), fixed combination of amoxicillin and clavulanate, clarithromycin, cycloserine, or linezolid.^{292 697 698 700 701 702 710}

Anti-infective agents for the treatment of invasive nocardiosis or for the treatment of nocardiosis in patients unable to tolerate sulfonamides should be selected based on results of in vitro susceptibility testing.²⁹² If nocardiosis involves the CNS or if the infection is disseminated or overwhelming, some clinicians suggest that amikacin and ceftriaxone should be included in the treatment regimen during the first 4–12 weeks of therapy or until there is clinical improvement.²⁹² A regimen of amikacin and ceftriaxone has been effective for the treatment of disseminated N. asteroides infection complicated by cerebral abscess.⁶⁹⁸

Pelvic Inflammatory Disease

Several parenteral cephalosporins (cefotaxime^{332 344} , ceftriaxone^{343 344} ) and closely related cephamycins (cefotetan^{313 344} , cefoxitin³⁴⁴ ) have been used in the treatment of acute pelvic inflammatory disease (PID); these drugs are inactive against C. trachomatis and should not be used alone in the treatment of PID.³⁴⁴

PID is an acute or chronic inflammatory disorder in the upper female genital tract and can include any combination of endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis.^{344 417} PID generally is a polymicrobial infection frequently caused by sexually transmitted organisms, especially N. gonorrhoeae and/or Chlamydia trachomatis; however, organisms that can be part of the normal vaginal flora (e.g., anaerobic bacteria, Gardnerella vaginalis, H. influenzae, enteric gram-negative bacilli, S. agalactiae) also have been associated with PID.³⁴⁴ In addition, cytomegalovirus or mycoplasma (e.g., Mycoplasma hominis, M. genitalium, Ureaplasma urealyticum) may be involved in some cases.^{344 417 418} PID is treated with an empiric regimen that provides broad-spectrum coverage.^{344 417 418} The regimen should be effective against N. gonorrhoeae and C. trachomatis and also probably should be effective against anaerobes, gram-negative facultative bacteria, and streptococci.^{344 417 419} The optimum empiric regimen for the treatment of PID has not been identified.³⁴⁴ A wide variety of parenteral and oral regimens have been shown to achieve clinical and microbiologic cure in randomized studies with short-term follow-up;^{344 418 419} however, only limited data are available to date regarding elimination of infection in the endometrium and fallopian tubes or intermediate or long-term outcomes, including the impact of these regimens on the incidence of long-term sequelae of PID (e.g., tubal infertility, ectopic pregnancy, pain).^{344 419}

Parenteral Regimens for PID

When a parenteral regimen is indicated for the treatment of PID, CDC generally recommends a 2-drug regimen of cefoxitin (2 g IV every 6 hours) or cefotetan (2 g IV every 12 hours) given in conjunction with doxycycline (100 mg IV or orally every 12 hours) or a 2-drug regimen of clindamycin (900 mg IV every 8 hours) and gentamicin (usually a 2-mg/kg IV or IM loading dose followed by 1.5 mg/kg every 8 hours).³⁴⁴ While certain parenteral cephalosporins (e.g., cefotaxime, ceftriaxone) also have been used for the treatment of PID,^{344 417 418 420} CDC states that only limited data are available regarding use of these cephalosporins in patients with PID and they are less active than cefotetan or cefoxitin against anaerobic bacteria.³⁴⁴ CDC states that only limited data are available to support the use of other parenteral regimens for the treatment of acute PID, although a regimen of IV ampicillin and sulbactam given with oral or IV doxycycline provides broad-spectrum coverage and is effective against C. trachomatis, N. gonorrhoeae, and anaerobes in women with tubo-ovarian abscess.³⁴⁴

Oral Regimens for PID

Data are not available regarding use of oral cephalosporins for the treatment of PID.³⁴⁴ When acute PID that is mild to moderately severe is treated with an oral regimen, CDC recommends a regimen that consists of a single dose of IM ceftriaxone, IM cefoxitin (with oral probenecid), or IM cefotaxime given in conjunction with a 14-day regimen of oral doxycycline (with or without oral metronidazole).³⁴⁴ The optimal parenteral cephalosporin for this regimen is unclear; although cefoxitin has better anaerobic coverage, ceftriaxone has better coverage against N. gonorrhoeae.³⁴⁴

For additional information regarding treatment of PID, the current CDC sexually transmitted diseases treatment guidelines available at [Web] should be consulted.³⁴⁴

Syphilis

Ceftriaxone has some activity against Treponema pallidum¹⁷³ and there is some limited evidence that the drug may be effective for the treatment of syphilis^†.^{216 228 260 344} Penicillin G is the drug of choice for the treatment of all stages of syphilis and data to support the use of penicillin alternatives are limited.³⁴⁴

CDC states that, based on limited clinical studies, biologic plausibility, and pharmacologic properties, ceftriaxone may be an effective alternative for the treatment of primary or secondary syphilis^† or neurosyphilis^† in penicillin-allergic patients.³⁴⁴ However, optimal dosage and duration of ceftriaxone therapy for these infections have not been defined and the possibility of cross-allergenicity with penicillin should be considered.³⁴⁴ Although ceftriaxone might be effective for the treatment of latent syphilis^† in penicillin-allergic patients, CDC states that the only acceptable alternatives to penicillin for the treatment of these infections are doxycycline or tetracycline.³⁴⁴ Decisions regarding the treatment of syphilis in penicillin-allergic patients should be made in consultation with a specialist.³⁴⁴

For the treatment of infants with clinical evidence of congenital syphilis^†, CDC states that use of ceftriaxone can be considered if there is a penicillin shortage and penicillin G sodium and penicillin G procaine are unavailable.³⁴⁴ However, because studies that strongly support ceftriaxone for the treatment of congenital syphilis have not been conducted, the drug should be used with careful clinical and serologic follow-up and in consultation with a specialist in the treatment of infants with congenital syphilis.³⁴⁴

For additional information regarding treatment of syphilis, the current CDC sexually transmitted diseases treatment guidelines available at [Web] should be consulted.³⁴⁴

Empiric Therapy in Febrile Neutropenic Patients

Cefepime has been used alone or in conjunction with other anti-infectives for empiric anti-infective therapy of presumed bacterial infections in febrile neutropenic adults or pediatric patients.^{314 457 459 466 467 468 469} Ceftazidime^{†454 455 457 459 468} and ceftriaxone^{†454 455} also have been used for empiric anti-infective therapy in febrile neutropenic patients, but are not generally recommended.^{453 457 463} Ceftazidime is no longer considered a reliable drug for empiric monotherapy in febrile neutropenic patients because of poor activity against gram-positive bacteria and decreasing potency against gram-negative bacteria;⁴⁵⁷ ceftriaxone monotherapy may not provide adequate coverage against some potential pathogens (e.g., Ps. aeruginosa).^{453 463}

Successful treatment of infections in granulocytopenic patients requires prompt initiation of empiric anti-infective therapy (even when fever is the only sign or symptom of infection) and appropriate modification of the initial regimen if the duration of fever and neutropenia is protracted, if a specific site of infection is identified, or if organisms resistant to the initial regimen are present.^{457 458 459 460 462} The initial empiric regimen should be chosen based on the underlying disease and other host factors that may affect the degree of risk, on local epidemiologic data regarding usual pathogens in these patients and in vitro susceptibility of bacterial isolates recovered from other patients in the same health-care facility, and the individual patient's pattern of colonization and resistance.^{457 458 460 461 462} The fact that gram-positive bacteria have become a predominant pathogen in febrile neutropenic patients should be considered when selecting an empiric anti-infective regimen.^{457 458 460} However, although gram-positive bacteria reportedly account for about 60% and gram-negative bacteria account for about 35% of microbiologically documented infections, gram-negative infections are associated with greater mortality.⁴⁵⁷

No empiric regimen has been identified that would be appropriate for initial treatment of all febrile neutropenic patients.^{457 458 460 462} IDSA recommends use of a parenteral empiric regimen in most febrile neutropenic patients; use of an oral regimen (e.g., oral ciprofloxacin and oral amoxicillin and clavulanate potassium) should be considered only for selected adults at low risk for complications who have adequate and stable renal and hepatic function, an expected duration of neutropenia less than 7 days, and no active medical comorbidities.⁴⁵⁷ All other patients are considered high risk and should receive an initial IV empiric regimen consisting of an antipseudomonal β-lactam (e.g., cefepime, imipenem, meropenem, fixed-combination of piperacillin and tazobactam).⁴⁵⁷ Other anti-infectives (e.g., aminoglycosides, fluoroquinolones, and/or vancomycin) may be added to the regimen for the management of complications (e.g., pneumonia) or when antimicrobial resistance is suspected or proven.⁴⁵⁷ Vancomycin and other anti-infectives active against aerobic gram-positive cocci are not usually included in the initial empiric regimen except in certain clinical scenarios, including suspected catheter-related infections, skin and soft tissue infections, pneumonia, or hemodynamic instability.⁴⁵⁷

Regardless of the initial regimen selected, patients should be reassessed daily and the anti-infective regimen altered (if indicated) based on the presence or absence of fever, identification of the causative organism, and the clinical condition of the patient; anti-infectives active against gram-positive organisms may be discontinued after 2 days if there is no evidence of such infections.⁴⁵⁷

Published protocols for the treatment of infections in febrile neutropenic patients should be consulted for specific recommendations regarding selection of the initial empiric anti-infective regimen, when to change the initial regimen, possible subsequent regimens, and duration of anti-infective therapy in these patients.⁴⁵⁷ In addition, consultation with an infectious disease expert knowledgeable about infections in immunocompromised patients is advised.⁴⁵⁷

Perioperative Prophylaxis

Cefazolin, cefotaxime, ceftriaxone, and cefuroxime have been used perioperatively to reduce the incidence of infections in patients undergoing certain contaminated or potentially contaminated surgical procedures or undergoing certain clean surgical procedures where the development of infection at the surgical site would have severe consequences.^{310 332 340 343 347 354 355 356 357 358 360 374 629 639 640 641 643 644} Perioperative prophylaxis with an appropriate anti-infective agent can decrease the incidence of infection, particularly surgical site infections, after some procedures.³⁶⁰

Because cefazolin has a narrow spectrum of activity that covers the most likely surgical site pathogens, has a moderately long serum half-life, and has been shown to be effective, it is considered by many clinicians to be the drug of choice for perioperative prophylaxis for a wide variety of procedures.³⁶⁰ Cefazolin is considered a drug of choice for perioperative prophylaxis in patients undergoing certain cardiac surgery (e.g., coronary artery bypass, placement of pacemaker or other cardiac device), noncardiac thoracic surgery (e.g., lobectomy), vascular surgery (arterial surgery involving the abdominal aorta, a prosthesis, or a groin incision or lower extremity amputation for ischemia), head and neck surgery involving incisions through oral or pharyngeal mucosa, neurosurgery (e.g., craniotomy, spinal surgery), orthopedic surgery (e.g., total joint replacement, surgical repair of closed fractures, internal fixation of compound or open fractures), GI surgery (gastroduodenal, esophageal, biliary tract, colorectal, appendectomy, bariatric), genitourinary surgery (e.g., open or laparoscopic surgery including percutaneous renal surgery, procedures with entry into the urinary tract or implantation of a prosthesis), and gynecologic and obstetric surgery (cesarean section or vaginal, abdominal, or laparoscopic hysterectomy).^{360 374} Cefazolin also is recommended as a drug of choice for perioperative prophylaxis in patients undergoing heart, lung, heart-lung, pancreas, and pancreas-kidney transplantation.³⁷⁴

Cefuroxime is considered a drug of choice for cardiac procedures (e.g., coronary artery bypass, placement of pacemaker or other cardiac device).^{360 374} Cefuroxime also is considered a drug of choice for perioperative prophylaxis in patients undergoing clean head and neck surgery involving placement of prosthesis (excluding tympanostomy) and is a drug of choice when used in conjunction with metronidazole for perioperative prophylaxis in patients undergoing clean-contaminated cancer surgery of the head and neck or other clean-contaminated head and neck procedures (excluding tonsillectomy and functional endoscopic sinus procedures).³⁷⁴

Cefotaxime used in conjunction with ampicillin is considered a regimen of choice for perioperative prophylaxis in patients undergoing liver transplantation^†.³⁷⁴

Ceftriaxone is recommended as one of several options for perioperative prophylaxis in patients undergoing biliary tract procedures, but should not be used in patients undergoing cholecystectomy for noninfected biliary conditions.³⁷⁴

A first or second generation cephalosporin (cefazolin, cefuroxime) generally is preferred when a cephalosporin is used for perioperative prophylaxis.^{360 374} Third generation cephalosporins (cefotaxime, ceftriaxone, ceftazidime) and fourth generation cephalosporins (cefepime) are not usually recommended for perioperative prophylaxis because they are expensive, some are less active than first or second generation cephalosporins against staphylococci, they have spectrums of activity wider than necessary for organisms encountered in elective surgery, and their use for prophylaxis may promote emergence of resistant organisms.^{360 374}

If cefazolin is used for perioperative prophylaxis in patients undergoing certain GI procedures (e.g., colorectal surgery, appendectomy) that might involve exposure to B. fragilis or other anaerobic bowel bacteria or in patients undergoing head and neck surgery involving incisions through oral or pharyngeal mucosa, it should be used in conjunction with metronidazole to provide anaerobic coverage.^{360 374}

Published guidelines and protocols for perioperative prophylaxis should be consulted for additional information regarding specific procedures.^{360 374}

Cardiac Surgery

Perioperative prophylaxis can decrease the incidence of infection after cardiac surgery.^{360 639} For cardiac procedures lasting longer than 400 minutes, the risk of postoperative infection is decreased if intraoperative anti-infective doses are given in addition to a preoperative dose.³⁶⁰ Regarding the use of postoperative doses in patients undergoing cardiac surgery, there are data to support use of a single preoperative dose or prophylaxis continued for 24 hours postoperatively; however, there is no evidence of benefit beyond 48 hours and no evidence to support continuing prophylaxis after wound closure or until all indwelling drains and intravascular catheters are removed.^{360 374}

Results of a pooled analysis of 7 placebo-controlled studies indicate that perioperative prophylaxis reduces the incidence of infection after permanent pacemaker implantation.⁶³⁹ In patients receiving implantation of permanent pacemakers and cardioverter-defibrillators, studies indicate that perioperative prophylaxis reduces the incidence of wound infection, inflammation, and skin erosion.³⁶⁰

For perioperative prophylaxis in patients undergoing cardiac surgery, many clinicians recommend IV cefazolin or IV cefuroxime.^{360 374} Although routine use of vancomycin for perioperative prophylaxis is not recommended, IV vancomycin is considered an alternative for perioperative prophylaxis in cardiac surgery patients at institutions where methicillin-resistant S. aureus (MRSA; also known as oxacillin-resistant S. aureus or ORSA) and methicillin-resistant S. epidermidis frequently cause postoperative wound infection or in patients who were previously colonized with MRSA or are allergic to penicillins or cephalosporins.³⁶⁰

Noncardiac Thoracic Surgery

Although studies evaluating use of perioperative prophylaxis in patients undergoing pulmonary surgery are sparse, such prophylaxis is routinely used.³⁶⁰ In one randomized, double-blind, placebo-controlled study in patients undergoing noncardiac thoracic surgery, a single preoperative dose of cefazolin decreased the incidence of postoperative surgical site infection, but did not affect the incidence of postoperative empyema or nosocomial pneumonia.⁶⁴¹ Although there is evidence from a placebo-controlled study that multiple doses of a cephalosporin (cefazolin) can prevent infection after closed-tube thoracostomy for chest trauma,⁶⁴⁰ some clinicians suggest that insertion of chest tubes for other indications, such as spontaneous pneumothorax, does not require prophylaxis.³⁶⁰

For perioperative prophylaxis in patients undergoing noncardiac thoracic surgery, many clinicians recommend IV cefazolin or IV ampicillin and sulbactam.^{360 374} Although routine use of vancomycin for perioperative prophylaxis is not recommended, IV vancomycin may be considered an alternative for perioperative prophylaxis in patients undergoing noncardiac thoracic surgery at institutions where MRSA and methicillin-resistant S. epidermidis frequently cause postoperative wound infection or in patients who were previously colonized with MRSA or are allergic to penicillins or cephalosporins.³⁶⁰ In patients allergic to penicillins and cephalosporins, a reasonable alternative is clindamycin or vancomycin used in conjunction with gentamicin, ciprofloxacin, levofloxacin, or aztreonam.^{360 374}

GI Surgery

Esophageal and Gastroduodenal Surgery

Perioperative prophylaxis is not usually indicated for patients undergoing routine gastroesophageal endoscopy, but is recommended for high-risk patients undergoing esophageal or gastroduodenal procedures.³⁶⁰

Although there are no controlled studies evaluating efficacy, perioperative prophylaxis is used routinely in patients undergoing bariatric surgery, including adjustable gastric banding, vertical banded gastroplasty, Roux-en-y bypass, and biliopancreatic diversion.³⁶⁰

For perioperative prophylaxis in high-risk patients undergoing esophageal or gastroduodenal surgery (e.g., those who are morbidly obese or have GI obstruction, decreased gastric acidity, decreased GI motility, gastric bleeding, malignancy or perforation, or immunosuppression), many clinicians recommend IV cefazolin as the drug of choice.^{360 374} Dosage may need to be increased in morbidly obese patients.³⁶⁰ In patients allergic to penicillins and cephalosporins, a reasonable alternative is clindamycin or vancomycin used in conjunction with gentamicin, ciprofloxacin, levofloxacin, or aztreonam.^{360 374}

Biliary Tract Surgery

Perioperative prophylaxis is recommended for patients undergoing biliary tract surgery who are at high risk of infection (e.g., those older than 70 years of age or those with acute cholecystitis, a nonfunctioning gallbladder, obstructive jaundice, or common duct stones).³⁶⁰ In high-risk patients undergoing endoscopic retrograde cholangiopancreatography (ERCP), perioperative prophylaxis is recommended only if complete biliary drainage is unlikely to be achieved.³⁶⁰ Perioperative prophylaxis is not considered necessary for low-risk patients undergoing elective laparoscopic cholecystectomy^{360 374 635} since there is no evidence that such prophylaxis provides any benefit in these patients.⁶³⁵

For perioperative prophylaxis in high-risk patients undergoing biliary tract surgery (e.g., those older than 70 years of age or those with acute cholecystitis, nonfunctioning gallbladder, obstructive jaundice, or common duct stones), many clinicians recommend IV cefazolin as the drug of choice.^{360 374} Alternatives include other cephalosporins (cefotetan, cefoxitin, ceftriaxone) or ampicillin and sulbactam.³⁷⁴ In patients allergic to penicillins and cephalosporins, a reasonable alternative is clindamycin or vancomycin used in conjunction with gentamicin, ciprofloxacin, levofloxacin, or aztreonam.^{360 374}

Colorectal Surgery

There is evidence that perioperative prophylaxis can decrease the incidence of infection after colorectal surgery, and such prophylaxis usually is recommended.³⁶⁰

For perioperative prophylaxis in patients undergoing colorectal surgery, many clinicians recommend a parenteral regimen of IV cefoxitin or IV cefotetan, IV cefazolin (or IV ceftriaxone) used in conjunction with IV metronidazole, or IV ampicillin and sulbactam.^{360 374} In patients allergic to penicillins and cephalosporins, a reasonable alternative is clindamycin used in conjunction with gentamicin, ciprofloxacin, levofloxacin, or aztreonam.^{360 374}

Alternatively, an oral prophylaxis regimen of oral neomycin with either oral erythromycin or oral metronidazole can be used.³⁶⁰ Many clinicians use both an oral regimen and a parenteral regimen for perioperative prophylaxis in patients undergoing colorectal surgery,^{360 374 637} and there is some evidence that use of an oral regimen (with mechanical bowel preparation) in conjunction with a parenteral regimen is more effective than use of a parenteral regimen alone.³⁶⁰

In a randomized, prospective study in patients undergoing elective colorectal surgery, the overall incidence of intra-abdominal septic complications in those who received mechanical bowel preparation and an oral regimen (erythromycin and neomycin) alone was similar to that in those who received both the oral regimen and a parenteral regimen (cefoxitin); however, the incidence of abdominal wound infection was higher in those who received the oral regimen alone (14.6%) than in those who received the combined oral and parenteral regimen (5%).⁶³⁸

Appendectomy

There is evidence that perioperative prophylaxis can reduce the incidence of infection after surgery for acute appendicitis.³⁶⁰

For perioperative prophylaxis in patients undergoing nonperforated appendectomy, many clinicians recommend IV cefoxitin or IV cefotetan or IV cefazolin used in conjunction with IV metronidazole.^{360 374} In patients allergic to penicillins and cephalosporins, a reasonable alternative is clindamycin or vancomycin used in conjunction with gentamicin, ciprofloxacin, levofloxacin, or aztreonam.^{360 374}

If perforation has occurred, anti-infectives are continued postoperatively for about 5 days.³⁶⁰

Genitourinary Surgery

Cystoscopy

Perioperative prophylaxis generally is not recommended in patients with sterile urine undergoing cystoscopy without manipulation (dilation, biopsy, fulguration, resection or ureteral instrumentation).^{360 374} When cystoscopy with manipulation is planned, urine cultures are positive or unavailable, or an indwelling urinary catheter is present, many clinicians recommend that patients receive treatment with an appropriate anti-infective before surgery to sterilize the urine or receive a single preoperative dose of an anti-infective selected based on the most likely infecting organisms.³⁶⁰

If perioperative prophylaxis is indicated in individuals undergoing cystoscopy who are at high risk (urine culture positive or unavailable, preoperative urinary catheter, transrectal prostatic biopsy, placement of prosthetic material) or in individuals undergoing cystoscopy with manipulation or upper urinary tract instrumentation (shockwave lithotripsy, ureteroscopy), many clinicians recommend oral or IV ciprofloxacin, oral co-trimoxazole, or IV cefazolin.^{360 374}

Open or Laparoscopic Surgery

There is evidence that perioperative prophylaxis decreases the incidence of postoperative bacteriuria and septicemia in patients with sterile urine undergoing transurethral prostatectomy and transrectal prostatic biopsies.³⁶⁰ Prophylaxis also is used for patients undergoing ureteroscopy, shock wave lithotripsy, percutaneous renal surgery, or open laparoscopic procedures or undergoing placement of a urologic prosthesis (penile implant, artificial sphincter, synthetic pubovaginal sling, bone anchors for pelvic floor reconstruction).³⁶⁰

For perioperative prophylaxis in individuals undergoing open or laparoscopic surgery (including percutaneous renal surgery, procedures with entry into the urinary tract, or procedures involving implantation of a prosthesis), many clinicians recommend IV cefazolin.³⁶⁰ In patients allergic to penicillins and cephalosporins, a reasonable alternative is clindamycin used in conjunction with gentamicin, ciprofloxacin, levofloxacin, or aztreonam.³⁶⁰

Gynecologic and Obstetric Surgery

Perioperative prophylaxis decreases the incidence of infection after vaginal and abdominal hysterectomy.³⁶⁰ In addition, there is evidence that perioperative prophylaxis can prevent infection after elective and nonelective cesarean section, including emergency cesarean section in high-risk situations (e.g., active labor, premature rupture of membranes), and after elective abortions, including second trimester abortions or first trimester abortion in high-risk women.^{360 374 623} A pooled analysis of results of randomized, placebo-controlled studies in women who underwent therapeutic abortion before 16 weeks’ gestation indicates that perioperative prophylaxis reduces the overall risk of postabortal infection by 42% compared with placebo.⁶²³

Many clinicians suggest that the preferred agents for perioperative prophylaxis in women undergoing vaginal, abdominal, or laparoscopic hysterectomy are IV cefoxitin, IV cefotetan, IV cefazolin, or IV ampicillin and sulbactam.^{360 374} IV cefazolin generally is the preferred agent for prophylaxis in women undergoing cesarean section;^{360 374} oral doxycycline is recommended for prophylaxis in those undergoing abortion.³⁶⁰

Head and Neck Surgery

There is evidence that perioperative prophylaxis decreases the incidence of surgical site infection after oncologic head and neck operations involving incisions through the oral or pharyngeal mucosa.³⁶⁰ Perioperative prophylaxis has not been shown to be beneficial in patients undergoing tonsillectomy, nasal septoplasty, or functional endoscopic sinus procedures.^{360 374} Perioperative prophylaxis is not indicated for clean head and neck surgery.³⁷⁴

For perioperative prophylaxis in patients undergoing head or neck surgery involving incisions through oral or pharyngeal mucosa, many clinicians recommend IV clindamycin, IV cefazolin used in conjunction with IV metronidazole, or IV ampicillin and sulbactam.³⁶⁰ Other clinicians recommend cefazolin or cefuroxime for perioperative prophylaxis in patients undergoing clean head and neck surgery involving placement of prosthesis (excluding tympanostomy).³⁷⁴ For patients undergoing clean-contaminated cancer surgery of the head and neck or other clean-contaminated head and neck procedures (excluding tonsillectomy and functional endoscopic sinus procedures), these experts recommend cefazolin used in conjunction with metronidazole, cefuroxime used in conjunction with metronidazole, or ampicillin and sulbactam.³⁷⁴

Neurosurgery

There is evidence that perioperative use of an anti-infective agent active against staphylococci can decrease the incidence of infection after craniotomy.³⁶⁰ Although some studies in patients undergoing implantation of permanent CSF shunts showed lower infection rates in those receiving perioperative prophylaxis, the benefit of such prophylaxis in patients undergoing ventriculostomy placement remains uncertain.³⁶⁰

Although the rate of postoperative infections is low in patients undergoing spinal surgery involving conventional lumbar discectomy, many clinicians use perioperative prophylaxis in such patients because of the serious consequences of a surgical site infection.³⁶⁰ The risk of infection is higher after prolonged spinal surgery or spinal procedures involving fusion or insertion of foreign material, and perioperative prophylaxis generally is used in these patients.³⁶⁰

For perioperative prophylaxis in patients undergoing neurosurgery, many clinicians recommend IV cefazolin.^{360 374} Although routine use of vancomycin for perioperative prophylaxis is not recommended, IV vancomycin may be considered an alternative for perioperative prophylaxis in patients undergoing neurosurgery at institutions where MRSA and methicillin-resistant S. epidermidis frequently cause postoperative wound infection or in patients who were previously colonized with MRSA or are allergic to penicillins or cephalosporins.³⁶⁰

Ophthalmic Surgery

Data are limited regarding the effectiveness of anti-infective prophylaxis in patients undergoing ophthalmic surgery; however, many clinicians use a topical or subconjunctival anti-infective for prophylaxis in patients undergoing such surgery.³⁶⁰ Some clinicians state that there is no evidence that perioperative prophylaxis is needed for procedures that do not invade the globe.³⁶⁰ While there is no consensus regarding the most effective drug, route, or duration of perioperative prophylaxis in patients undergoing ophthalmic surgery, many clinicians recommend use of a topical aminoglycoside (gentamicin, tobramycin), topical fluoroquinolone (ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin), or a topical preparation containing neomycin, polymyxin b sulfate, and gramicidin; some clinicians also recommend subconjunctival injection of cefazolin or intracameral cefazolin or cefuroxime.^{360 374}

Orthopedic Surgery

There is evidence that perioperative prophylaxis with an anti-infective agent active against staphylococci can decrease the incidence of both early and delayed infection in patients undergoing joint replacement or surgical repair of closed fractures.³⁶⁰ Perioperative prophylaxis can decrease the rate of infection in patients with hip and other closed fractures undergoing procedures that involve internal fixation with nails, plates, screws, or wires and in patients with compound or open fractures.³⁶⁰ However, additional study is needed to determine whether single-dose regimens or regimens continued for 24 hours are most effective.³⁶⁰ A retrospective review concluded that anti-infective prophylaxis is not indicated for patients undergoing arthroscopic surgery procedures.³⁶⁰

For perioperative prophylaxis in patients undergoing orthopedic surgery, many clinicians recommend IV cefazolin.^{360 374} Although routine use of vancomycin for perioperative prophylaxis is not recommended, IV vancomycin may be considered an alternative for perioperative prophylaxis in patients undergoing orthopedic surgery at institutions where MRSA and methicillin-resistant S. epidermidis frequently cause postoperative wound infection or in patients who were previously colonized with MRSA or are allergic to penicillins or cephalosporins.³⁶⁰

Vascular Surgery

There is evidence that perioperative prophylaxis with a cephalosporin can decrease the incidence of postoperative surgical site infection after arterial reconstructive surgery on the abdominal aorta, vascular operations on the leg that include a groin incision, or amputation of a lower extremity for ischemia.³⁶⁰ Many clinicians also recommend perioperative prophylaxis in patients undergoing implantation of any vascular prosthetic material (e.g., grafts for vascular access in hemodialysis); however, such prophylaxis generally is not indicated for carotid endarterectomy or brachial artery repair without prosthetic material.³⁶⁰ Although perioperative prophylaxis is not routinely recommended for endovascular stenting, prophylaxis may be justified in patients with certain risk factors (e.g., repeat intervention within 7 days, prolonged indwelling arterial sheath, procedure duration longer than 2 hours, presence of other infected implants, immunosuppression).³⁶⁰

For perioperative prophylaxis in patients undergoing vascular surgery (e.g., arterial surgery involving a prosthesis, the abdominal aorta, or a groin incision; lower extremity amputation for ischemia), many clinicians recommend IV cefazolin.^{360 374} Although routine use of vancomycin for perioperative prophylaxis is not recommended, IV vancomycin may be considered an alternative for perioperative prophylaxis in patients undergoing vascular surgery at institutions where MRSA and methicillin-resistant S. epidermidis frequently cause postoperative wound infection or in patients who were previously colonized with MRSA or are allergic to penicillins or cephalosporins.³⁶⁰

Timing and Number of Doses

When perioperative prophylaxis is indicated in patients undergoing surgery, administration of an appropriate anti-infective should be timed to ensure that bactericidal concentrations of the drug are established in serum and tissues by the time the initial surgical incision is made;^{360 374} therapeutic concentrations of the drug should then be maintained in serum and tissues for the duration of the procedure.³⁷⁴

An IV dose of the appropriate anti-infective should be given within 60 minutes before the initial incision.³⁶⁰ However, if vancomycin or a fluoroquinolone is used, the anti-infective infusion should be started within 1–2 hours before the initial incision to minimize the risk of an adverse effect occurring around the time of anesthesia induction and to ensure adequate tissue levels of the drug at the time of the initial incision.^{360 374}

Single-dose perioperative prophylaxis may be sufficient.³⁷⁴ However, if surgery is prolonged (more than 3–4 hours), major blood loss occurs, or other factors are present that shorten the half-life of the drug (e.g., extensive burns), additional doses should be administered during the procedure to ensure adequate serum and tissue concentrations of the anti-infective throughout the procedure.^{360 374} Intraoperative doses may not be warranted if there are factors that prolong the half-life of the drug (e.g., renal impairment).³⁷⁴ For prolonged procedures in patients with normal renal function, some clinicians suggest that intraoperative doses be administered during the procedure at intervals that correspond to 1–2 times the half-life of the drug.³⁶⁰ If intraoperative doses are necessary, the redosing interval should be measured from the time of administration of the preoperative dose, not from the beginning of the procedure.³⁷⁴

For most procedures, the duration of prophylaxis should be less than 24 hours.^{360 374} There is no evidence to support continuing prophylaxis after wound closure or until all indwelling drains and intravascular catheters are removed.^{360 374}

Prevention of Perinatal Group B Streptococcal Disease

In certain penicillin-allergic women, cefazolin is used as an alternative to penicillin G or ampicillin for prevention of perinatal group B streptococcal (GBS) disease^†.³⁵⁹

Pregnant women who are colonized with GBS in the genital or rectal areas can transmit GBS infection to their infants during labor and delivery resulting in invasive neonatal infection that can be associated with substantial morbidity and mortality.³⁵⁹ Intrapartum anti-infective prophylaxis for prevention of early-onset neonatal GBS disease is administered selectively to women at high risk for transmitting GBS infection to their neonates.³⁵⁹ CDC, AAP, and other experts recommend routine universal prenatal culture-based screening for GBS colonization (vaginal and rectal cultures) in all pregnant women at 35–37 weeks of gestation, unless GBS bacteriuria is known to be present during the current pregnancy or the woman had a previous infant with invasive GBS disease.³⁵⁹ These experts state that anti-infective prophylaxis to prevent perinatal GBS disease is indicated in pregnant women identified as GBS carriers during the routine prenatal GBS screening performed at 35–37 weeks during the current pregnancy, in women with GBS bacteriuria identified at any time during the current pregnancy, and in women who had a previous infant diagnosed with invasive GBS disease.³⁵⁹ Anti-infective prophylaxis to prevent perinatal GBS disease also is indicated in women with unknown GBS status at the time of onset of labor (i.e., culture not done, incomplete, or results unknown) if delivery is at less than 37 weeks of gestation, the duration of amniotic membrane rupture is 18 hours or longer, intrapartum temperature is 38°C or higher, or an intrapartum NAAT was positive for GBS.³⁵⁹

When intrapartum prophylaxis is indicated in the mother to prevent GBS disease in the neonate, it should be given at onset of labor or rupture of membranes.³⁵⁹ CDC, AAP, and other experts recommend penicillin G (5 million units IV initially followed by 2.5–3 million units IV every 4 hours until delivery) as the regimen of choice and ampicillin (2 g IV initially followed by 1 g IV every 4 hours until delivery) as the preferred alternative.³⁵⁹ If intrapartum GBS prophylaxis is indicated in a penicillin-allergic woman who is not at high risk for anaphylaxis (i.e., does not have a history of anaphylaxis, angioedema, respiratory distress, or urticaria after receiving a penicillin or cephalosporin), CDC, AAP, and others recommend IV cefazolin (2 g IV initially followed by 1 g IV every 8 hours until delivery).³⁵⁹ If intrapartum prophylaxis is indicated in a penicillin-allergic woman who is at high risk for anaphylaxis (e.g., history of anaphylaxis, angioedema, respiratory distress, or urticaria after receiving a penicillin or cephalosporin), IV clindamycin (900 mg IV every 8 hours until delivery) is recommended if the GBS isolate is susceptible to the drug;³⁵⁹ alternatively, IV vancomycin (1 g IV every 12 hours until delivery) can be used if the isolate is resistant to clindamycin.³⁵⁹

For additional information regarding prevention of perinatal group B streptococcal disease, the current CDC guidelines available at [Web] should be consulted.³⁵⁹

Cephalosporins General Statement Dosage and Administration

Administration

Cephalosporins, in appropriate forms, may be administered orally, IV, by deep IM injection, or intraperitoneally. In general, orally administered cephalosporins should not be relied on for the treatment of the initial phase of severe infections or in patients with nausea and vomiting. Cephalosporins should be given IV in patients with meningitis, septicemia, endocarditis, or other severe or life-threatening infections. Cephalosporins have been administered by regional perfusion^†, subconjunctivally^†, intraventricularly^†, or intrathecally^†, but the risk of CNS toxicity must be considered with the latter route. (See Cautions: Other Adverse Effects.)

Dosage

The duration of cephalosporin therapy depends on the type of infection. Generally, therapy should be continued for a minimum of 48–72 hours after the patient becomes asymptomatic or evidence of eradication of the infection has been obtained. In infections caused by β-hemolytic streptococci, therapy should be continued for at least 10 days. At least 4–6 weeks of therapy may be required in serious infections such as septicemia, endocarditis, or osteomyelitis.

Dosage in Renal Impairment

In patients with impaired renal function, decreases in doses and/or frequency of administration of cephalosporins may be required and should be based on the degree of renal impairment, severity of the infection, susceptibility of the causative organism, and serum concentrations of the cephalosporins.

Cautions for Cephalosporins General Statement

Cephalosporins generally are well tolerated and with only a few exceptions, adverse effects reported with the various cephalosporin derivatives are similar.³⁵¹ The most frequent adverse effects reported with oral cephalosporins include GI effects (diarrhea, nausea, vomiting), headache, and rash and the most frequent adverse effects reported with parenteral cephalosporins include local reactions at the injection site, adverse GI effects, and adverse hematologic effects.³⁵¹ Although not reported with other cephalosporins, some previously available cephalosporins (e.g., cefamandole, cefoperazone) and structurally related cephamycins (e.g., cefotetan) that contain an N-methylthiotetrazole (NMTT) side chain have been associated with an increased risk of hypoprothrombinemia and disulfiram-like reactions.^{309 312 313 390} In addition, while the clinical importance is unclear, derivatives that contain an NMTT side chain have caused adverse testicular effects in animal studies.^{309 312 313 353}

Dermatologic and Sensitivity Reactions

Hypersensitivity reactions have been reported in approximately 5% or less of patients receiving a cephalosporin.³⁵¹ These reactions include urticaria, pruritus, rash (maculopapular, erythematous, or morbilliform), fever and chills, eosinophilia, joint pain or inflammation, edema, facial edema, erythema, genital and anal pruritus, angioedema, shock, hypotension, vasodilatation, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, and exfoliative dermatitis. Anaphylaxis, including a few fatalities, has occurred rarely with cephalosporins.

Serum sickness-like reactions consisting of erythema multiforme or maculopapular pruritic rash or urticaria accompanied by arthritis, arthralgia, and fever have been reported rarely in patients receiving cefaclor.^{307 351 427 428 429 430 431} These reactions usually have occurred in pediatric patients younger than 6 years of age, most often with second or subsequent courses of the drug.^{307 426 430 431} While serum sickness-like reactions have been reported rarely in patients receiving other cephalosporins (i.e., cefprozil, cephalexin) or other β-lactam antibiotics (i.e., amoxicillin, loracarbef),^{341 427 428 431 432} these reactions been reported more frequently with cefaclor than with any other anti-infective agent.^{427 428 429}

Hematologic Effects

Positive direct and indirect antiglobulin (Coombs’) test results have been reported in 3% or more of patients receiving a cephalosporin. (See Laboratory Test Interferences: Immunohematology Tests.) The mechanism of this reaction is usually nonimmunologic in nature; a cephalosporin-globulin complex coats the erythrocytes and reacts nonspecifically with Coombs’ serum. Nonimmunologic positive Coombs’ test results are most likely to occur in patients who have received large doses of a cephalosporin or who have impaired renal function or hypoalbuminemia.

Other adverse hematologic effects of cephalosporins include rare, mild and transient neutropenia, thrombocythemia or thrombocytopenia, leukocytosis, granulocytosis, monocytosis, lymphocytopenia, basophilia, and reversible leukopenia. Transient lymphocytosis has been reported occasionally in infants and children receiving cefaclor. Rarely, decreased hemoglobin and/or hematocrit, anemia, and agranulocytosis have been reported with some cephalosporins. Aplastic anemia, pancytopenia, hemolytic anemia, and epistaxis or hemorrhage also have been reported with cephalosporin therapy. Immune-mediated hemolytic anemia with extravascular hemolysis, including some fatalities, have been reported in patients receiving cefotaxime,⁶²⁷ ceftriaxone,⁶²⁶ or cefotetan.⁶²⁸

Prolonged prothrombin time (PT), prolonged activated partial thromboplastin time (APTT), and/or hypoprothrombinemia (with or without bleeding) have been reported rarely with cefaclor, cefixime, cefoperazone (no longer available in the US), cefotaxime, cefotetan, cefoxitin, ceftizoxime (no longer commercially available in the US), ceftriaxone, and cefuroxime.^{316 317 318 319 320 321 323 324 343 677} Although the true incidence of hypoprothrombinemia and bleeding complications during therapy with these drugs has not been established, these effects have been reported most frequently with drugs that contain an NMTT side chain (e.g., cefamandole, cefoperazone [drugs no longer commercially available in the US]) and have usually occurred in geriatric, debilitated, or other patients with vitamin K deficiency or in patients with severe renal failure or following radical GI surgery.^{316 317 318 319 320 321 323 324} The mechanism(s) of the hypoprothrombinemic effect of these drugs has not been clearly established.^{316 317 318 319 320 321 323 324} While hypoprothrombinemia with some of the drugs may result in part from a reduction in vitamin K-producing bacteria in the GI tract,^{316 317 318 319 320 321 323 324} there is evidence that a direct effect on hepatic synthesis of prothrombin or prothrombin precursors is involved.^{316 317 318 319 320 321 323 324} The NMTT side chain apparently interferes with vitamin K metabolism and regeneration and inhibits γ-carboxylation of glutamic acid, the vitamin K-dependent step in the hepatic synthesis of prothrombin.^{316 320 321 324} Hypoprothrombinemia has usually been reversed by administration of vitamin K. Vitamin K should be administered when indicated to treat hypoprothrombinemia associated with use of other cephalosporins.

Renal and Genitourinary Effects

Renal effects that have occurred occasionally with administration of a cephalosporin include transient increases in BUN and serum creatinine concentrations, renal dysfunction, and toxic nephropathy. Nephrotoxicity has been reported rarely with cephalexin and cefazolin and acute renal failure has been reported with cefazolin³¹⁰ and cefixime.⁶⁷⁷ Reversible interstitial nephritis has occurred rarely during cefaclor therapy, and purpuric nephritis has been reported with oral cefpodoxime proxetil therapy in postmarketing experience outside the US. Renal toxicity is most likely to occur in patients older than 50 years of age, patients with prior renal impairment, or patients who are receiving other nephrotoxic drugs. (See Drug Interactions: Nephrotoxic Drugs.) All cephalosporins should be administered with caution and in reduced dosage in the presence of markedly impaired renal function. In patients with suspected renal impairment, careful clinical observation and renal function tests should be performed prior to and during cephalosporin therapy.

Genitourinary effects reported with cephalosporin therapy include vaginitis, vaginal candidiasis, genital pruritus, and menstrual irregularities.

Hepatic Effects

Transient increases in serum AST (SGOT), ALT (SGPT), γ-glutamyl transferase (γ-glutamyl transpeptidase, GGT, GGTP), and alkaline phosphatase concentrations have occurred occasionally with cephalosporin therapy. Increased serum concentrations of bilirubin and/or LDH have been reported with many cephalosporins; decreased serum albumin and/or total protein also have been reported. Hepatic dysfunction, including cholestasis, also has been reported with cephalosporin therapy. Hepatitis and/or jaundice have been reported with cefazolin,³¹⁰ cefixime,⁶⁷⁷ and ceftazidime.³⁴⁰ These hepatic effects are generally mild and disappear when cephalosporin therapy is discontinued.

Acute liver injury has been reported with oral cefpodoxime proxetil therapy in postmarketing experience outside the US.

GI Effects

The most frequent adverse reactions to orally administered cephalosporins are nausea, vomiting, and diarrhea. These effects are usually mild and transient, but rarely may be severe enough to require discontinuance of the drug. Other adverse GI effects that have occurred with some of the oral cephalosporins include abdominal pain, tenesmus, epigastric pain/dyspepsia, decreased appetite/anorexia, glossitis, flatulence, candidiasis (e.g., oral thrush), taste alteration, decreased salivation, and heartburn. Adverse GI effects also can occur with IM or IV cephalosporins.

Treatment with anti-infectives alters the normal flora of the colon leading to overgrowth of Clostridium difficile.^{302 307 308 310 311 314 332 339 340 343 347 348 349 677 703} C. difficile infection (CDI) and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) have been reported with nearly all systemic anti-infectives, including cephalosporins, and may range in severity from mild diarrhea to fatal colitis.^{301 302 303 304 305 307 308 310 311 314 332 339 340 343 347 348 349 677 703} C. difficile produces toxins A and B which contribute to the development of CDAD;^{302 303 308 310 311 314 332 339 340 343 347 348 349 677 703} hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.^{308 310 311 314 332 339 340 343 347 348 349 677 703}

CDAD should be considered in the differential diagnosis in patients who develop diarrhea during or after anti-infective therapy.^{301 302 303 304 305 307 308 310 311 314 332 339 340 343 347 348 349 677 703} Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.^{308 310 311 314 332 339 340 343 347 348 349 677 703} If CDAD is suspected or confirmed, anti-infective therapy not directed against C. difficile should be discontinued whenever possible.^{301 302 304 305 308 310 311 314 332 339 340 343 347 348 349 677 703} Patients should be managed with appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.^{301 302 303 304 305 308 310 311 314 332 339 340 343 347 348 349 677 703} Antiperistaltic agents (e.g., opiates, diphenoxylate with atropine) should be avoided since they may obscure symptoms and precipitate toxic megacolon.^{302 305}

Local Effects

Local reactions are quite common following IM or IV administration of some parenteral cephalosporins; phlebitis and thrombophlebitis occasionally occur with IV administration of the drugs. Although reports are conflicting and results of many studies inconclusive, there appears to be little difference in the overall incidence of mild phlebitis and thrombophlebitis among the currently available IV cephalosporins.

Nervous System Effects

Nervous system effects that have occurred following oral, IM, or IV administration of cephalosporins include dizziness, headache, malaise, fatigue, nightmares, and vertigo. Hyperactivity, nervousness or anxiety, agitation, hallucinations, insomnia, somnolence, weakness, hot flushes, alteration in color perception, confusion, and hypertonia also have been reported during therapy with some cephalosporins, although a causal relationship has not necessarily been established. Mild to moderate hearing loss has been reported in a few pediatric patients receiving cefuroxime sodium for the treatment of meningitis.

In patients with renal insufficiency, elevated concentrations of ceftazidime reportedly may lead to seizures, encephalopathy, asterixis, and neuromuscular excitability. Seizures also have been reported with cefixime⁶⁷⁷ and cefuroxime.³⁴⁷ Rarely, toxic paranoid reactions have occurred in patients with renal impairment receiving oral cephalexin. Life-threatening or fatal encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures, and nonconvulsive status epilepticus have been reported in patients receiving cefepime.³¹⁴ Most cases of cefepime-associated neurotoxicity have occurred in patients with renal impairment who received a cefepime dosage that exceeded the recommended dosage for such patients; however, some cases occurred in patients who received a dosage appropriately adjusted for renal impairment.³¹⁴

Intrathecal administration of cephalosporins, particularly in large doses, has resulted in CNS toxicity evidenced by hallucinations, nystagmus, and seizures. (See Cautions: Precautions and Contraindications.)

Other Adverse Effects

Other adverse effects reported with cephalosporin therapy include chest pain, pleural effusion, pulmonary infiltrate, dyspnea or respiratory distress, cough, and rhinitis. Increased or decreased serum glucose concentration also has been reported. Fungal skin infection, exacerbation of acne, and ocular itching have been reported rarely in patients receiving oral cefpodoxime proxetil therapy.

An anamnestic photosensitivity (photo recall)-like dermatitis, characterized by a pruritic, erythematous, maculopapular eruption distributed in the area of a recent sunburn on the upper abdomen and chest, has been reported in at least one patient receiving concomitant IV therapy with cefazolin and gentamicin sulfate. Whether this phenomenon was caused by one or both drugs has not been determined; however, the reaction resolved within 48 hours following discontinuance of both drugs.

Precautions and Contraindications

Prior to initiation of cephalosporin therapy, careful inquiry should be made concerning previous hypersensitivity reactions to cephalosporins, penicillins, and other drugs. Cephalosporins are contraindicated in patients with a history of allergic reactions to cephalosporin antibiotics. There is clinical and laboratory evidence of partial cross-sensitivity among bicyclic β-lactam antibiotics including penicillins, cephalosporins, cephamycins, and carbapenems.^{310 316 325 352} There appears to be little cross-sensitivity between bicyclic β-lactam antibiotics and monobactams (e.g., aztreonam).^{316 325 326 327 328} Although the true incidence of cross-sensitivity among the β-lactam antibiotics has not been definitely established,^{316 325 352} it has been clearly documented and may occur in up to 10–15% of patients with a history of penicillin hypersensitivity.^{292 310 339 350} Some patients have had severe reactions, including anaphylaxis, to both penicillins and cephalosporins.³⁵⁰ Cephalosporins should be used with caution in individuals hypersensitive to penicillins.^{310 338 339 350} Some clinicians suggest that cephalosporins should be avoided in patients who have had an immediate-type (anaphylactic) hypersensitivity reaction to penicillins and should be administered with caution to patients who have had a delayed-type (e.g., rash, fever, eosinophilia) reaction to penicillins or other drugs.^{292 351} If an allergic reaction occurs during cephalosporin therapy, the drug should be discontinued and the patient treated with appropriate therapy (e.g., epinephrine, corticosteroids, and maintenance of an adequate airway and oxygen) as indicated.

To reduce development of drug-resistant bacteria and maintain effectiveness of cephalosporins and other antibacterials, the drugs should be used only for the treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.^{308 310 340} When selecting or modifying anti-infective therapy, results of culture and in vitro susceptibility testing should be used.^{308 310 340} In the absence of such data, local epidemiology and susceptibility patterns should be considered when selecting anti-infectives for empiric therapy.^{308 310 340}

Patients should be advised that antibacterials (including cephalosporins) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).^{308 310 340} Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with cephalosporins or other antibacterials in the future.^{308 310 340}

Prolonged use of a cephalosporin may result in the overgrowth of nonsusceptible organisms, especially Enterobacter, Pseudomonas, enterococci, or Candida. If superinfection occurs, appropriate therapy should be instituted.

Cephalosporins should be used with caution in patients with a history of GI disease, particularly colitis.^{310 339 340 343} Because C. difficile-associated diarrhea and colitis has been reported with the use of cephalosporins, it should be considered in the differential diagnosis of patients who develop diarrhea during or following therapy with the drugs.^{302 310 339 340 343} (See Cautions: GI Effects.) Patients should be advised that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued; however, they should contact a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.^{310 339 343}

Seizures have been reported with several cephalosporins (e.g., ceftazidime, cefuroxime, cefepime), particularly in patients with renal impairment in whom dosage of the drug was not reduced.^{311 314 332 338 347 348} (See Cautions: Nervous System Effects.) If seizures occur during cephalosporin therapy, the drug should be discontinued and anticonvulsant therapy initiated as clinically indicated.^{311 314 332 338 347 348} If neurotoxicity associated with cefepime therapy occurs, consideration should be given to discontinuing the drug or making appropriate dosage adjustments based on the patient's renal function.³¹⁴

Because some cephalosporins have been associated with a decrease in prothrombin activity, some manufacturers state that prothrombin time (PT) should be monitored when these drugs are used in patients with renal or hepatic impairment, in patients with poor nutritional status, in patients receiving a protracted course of anti-infective therapy, or in those previously stabilized on anticoagulant therapy.^{310 343 347 348} Vitamin K should be administered if indicated.^{310 343 347 348}

Geriatric Precautions

No overall differences in safety and efficacy have been reported with use of cephalosporins in those 60 years of age and older compared with younger adults,^{307 308 310 314 332 339 340} Although clinical experience has revealed no evidence of age-related differences, the possibility of increased sensitivity in some geriatric individuals cannot be ruled out.^{307 308 310 332 339 340}

Cephalosporins are substantially eliminated in urine and the risk of toxicity may be increased in patients with impaired renal function.^{307 308 310 314 332 339 340} Because geriatric patients are more likely to have decreased renal function, use caution when selecting dosage for such patients and consider monitoring renal function.^{307 308 310 314 332 339 340}

Pregnancy, Fertility, and Lactation

Pregnancy

Although there have been no reports of adverse effects to the fetus to date, safe use of cephalosporins during pregnancy has not been definitely established. The drugs should be used during pregnancy only when clearly needed.

Fertility

Adverse testicular effects (e.g., reduced testicular weight, seminiferous tubule degeneration, delayed maturity of germinal epithelium, reduced germinal cell population, vacuolation of Sertoli cell cytoplasm) have been reported in prepubertal rats receiving certain previously available cephalosporins (e.g., cefamandole, cefoperazone) and structurally related cephamycins (e.g., cefotetan) that contain an NMTT side chain;^{309 312 313 314 315} impaired fertility also has been reported, particularly with high dosages.^{309 313 315} The relevance of these findings to humans is not known.^{309 312 313 314 315}

Lactation

Because cephalosporins are distributed into milk, the drugs should be used with caution in nursing women.

Drug Interactions

Nephrotoxic Drugs

Concomitant use of nephrotoxic agents such as aminoglycosides, colistin, polymyxin B, or vancomycin may increase the risk of nephrotoxicity with some cephalosporins and probably should be avoided, if possible.

Alcohol

Disulfiram-like reactions have occurred when alcohol was ingested within 48–72 hours after administration of some previously available cephalosporins (e.g., cefamandole, cefoperazone) and structurally related cephamycins (e.g., cefotetan) that contain an N-methylthiotetrazole (NMTT) side chain.^{309 312 313} The reactions appear to result from accumulation of acetaldehyde and do not occur if alcohol is ingested prior to the first dose of the antibiotic.^{309 312 313}

Estrogens or Progestins

Some cephalosporins (e.g., ceftazidime) may affect gut flora, leading to lower estrogen reabsorption and reduced efficacy of oral contraceptives containing estrogen and progesterone.³⁴⁰

Probenecid

Concomitant administration of oral probenecid competitively inhibits tubular secretion resulting in higher and more prolonged serum concentrations of most cephalosporins.

Other Anti-infective Agents

In vitro studies indicate that the antibacterial activity of cephalosporins may be additive or synergistic with aminoglycosides or penicillins against some organisms. Although some in vitro studies showed additive or synergistic antibacterial activity between chloramphenicol and a cephalosporin, there is more recent in vitro evidence of antagonism between cephalosporins (e.g., cefotaxime, ceftazidime, ceftriaxone) and chloramphenicol against a variety of gram-negative and -positive bacteria, particularly when chloramphenicol was added to the medium before the β-lactam. In addition, at least one case of in vivo antagonism has been reported in an infant with Salmonella enteritidis meningitis. Therefore, it is recommended that combined therapy with chloramphenicol and a cephalosporin be avoided, particularly when bactericidal activity is considered important.

Laboratory Test Interferences

Immunohematology Tests

Positive direct and indirect antiglobulin (Coombs’) test results have been reported in 3% or more of patients receiving a cephalosporin. (See Cautions: Hematologic Effects.) This reaction may interfere with hematologic studies or transfusion cross-matching procedures. In addition, positive Coombs’ test results may occur in neonates whose mother received a cephalosporin prior to delivery.

Tests for Urinary Glucose

Cephalosporins can cause false-positive results in urine glucose determinations using cupric sulfate solution (Benedict’s reagent, Clinitest); glucose oxidase tests (Clinistix) are unaffected by the drugs.

Tests for Creatinine

Some cephalosporins, in high concentrations, may cause falsely elevated serum or urine creatinine values when the Jaffé reaction is used. In one in vitro study, high concentrations of ceftriaxone (50 mcg/mL or greater) caused falsely elevated serum creatinine values when a manual method was used; however, other studies indicate that the drug does not interfere with automated methods for determining serum or urinary creatinine concentrations.

Mechanism of Action

Cephalosporins are usually bactericidal in action. The antibacterial activity of the cephalosporins, like penicillins and cephamycins, results from inhibition of mucopeptide synthesis in the bacterial cell wall. Although the exact mechanisms of action of cephalosporins have not been fully elucidated, β-lactam antibiotics bind to several enzymes in the bacterial cytoplasmic membrane (e.g., carboxypeptidases, endopeptidases, transpeptidases) that are involved in cell-wall synthesis and cell division. It has been hypothesized that β-lactam antibiotics act as substrate analogs of acyl-d-alanyl-d-alanine, the usual substrate for these enzymes. This interferes with cell-wall synthesis and results in the formation of defective cell walls and osmotically unstable spheroplasts. Cell death following exposure to β-lactam antibiotics usually results from lysis, which appears to be mediated by bacterial autolysins such as peptidoglycan hydrolases.

The target enzymes of β-lactam antibiotics have been classified as penicillin-binding proteins (PBPs) and appear to vary substantially among bacterial species. The affinities of various β-lactam antibiotics for different PBPs appear to explain the differences in morphology that occur in susceptible organisms following exposure to different β-lactam antibiotics and may also explain differences in the spectrum of activity of β-lactam antibiotics that are not caused by the presence or absence of β-lactamases.

Spectrum

In general, cephalosporins are active in vitro against many gram-positive aerobic bacteria, some gram-negative aerobic bacteria, and some anaerobic bacteria; however, there are substantial differences among the cephalosporins in spectra of activity as well as levels of activity against susceptible bacteria. Cephalosporins are inactive against fungi and viruses.

Classification of Cephalosporins and Closely Related β-Lactam Antibiotics Based on Spectra of Activity

Currently available cephalosporins are generally divided into 5 groups based on their spectra of activity: first, second, third, fourth, and fifth generation cephalosporins. Closely related β-lactam antibiotics (e.g., cephamycins) also may be classified in these groups because of their similar spectra of activity.

First Generation Cephalosporins

• cefadroxil

• cefazolin

• cephalexin

First generation cephalosporins usually are active in vitro against gram-positive cocci including penicillinase-producing and nonpenicillinase-producing Staphylococcus aureus and S. epidermidis; Streptococcus pyogenes (group A β-hemolytic streptococci); S. agalactiae (group B streptococci); and S. pneumoniae. First generation cephalosporins have limited activity against gram-negative bacteria, although some strains of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Shigella may be inhibited in vitro by the drugs. First generation cephalosporins are inactive against enterococci, including Enterococcus faecalis (formerly S. faecalis), methicillin-resistant S. aureus (MRSA; also known as oxacillin-resistant S. aureus, ORSA), Bacteroides fragilis, Citrobacter, Enterobacter, Listeria monocytogenes, Proteus other than P. mirabilis, Providencia, Pseudomonas, and Serratia.

Susceptible strains of S. aureus, S. pneumoniae, S. pyogenes, or S. agalactiae usually are inhibited in vitro by cefazolin concentrations of 0.1–1 mcg/mL or cephalexin concentrations of 0.1–12 mcg/mL. S. epidermidis may be inhibited in vitro by cefazolin concentrations of 0.1–12.5 mcg/mL, although some strains require concentrations greater than 32 mcg/mL for in vitro inhibition. Susceptible strains of E. coli, K. pneumoniae, or P. mirabilis generally are inhibited in vitro by cefazolin concentrations of 0.8–12.5 mcg/mL.

Second Generation Cephalosporins

• cefaclor

• cefoxitin (a cephamycin)

• cefprozil

• cefuroxime

Second generation cephalosporins usually are active in vitro against bacteria susceptible to first generation cephalosporins. In addition, the second generation drugs are active in vitro against most strains of Haemophilus influenzae (including ampicillin-resistant strains). Although the specific spectra of activity differ, second generation cephalosporins generally are more active in vitro against gram-negative bacteria than first generation cephalosporins. However, cefaclor is less active than other second generation cephalosporins against gram-negative bacteria. The second generation drugs may be active in vitro against some strains of Acinetobacter, Citrobacter, Enterobacter, E. coli, Klebsiella, Neisseria, Proteus, Providencia, and Serratia that are resistant to the first generation drugs. Cefoxitin also has some activity in vitro against B. fragilis. Second generation cephalosporins are inactive against enterococci (e.g., E. faecalis), MRSA, and Pseudomonas.

Third Generation Cephalosporins

• cefdinir

• cefditoren

• cefixime

• cefotaxime

• cefotetan (a cephamycin)

• cefpodoxime

• ceftazidime

• ceftibuten

• ceftriaxone

Third generation cephalosporins usually are less active in vitro against susceptible staphylococci than first generation cephalosporins; however, the third generation drugs have an expanded spectrum of activity against gram-negative bacteria compared with the first and second generation drugs. Third generation cephalosporins generally are active in vitro against gram-negative bacteria susceptible to the first and second generation drugs, and most also are active in vitro against some strains of Citrobacter, Enterobacter, E. coli, Klebsiella, Neisseria, Proteus, Morganella, Providencia, and Serratia that may be resistant to first and second generation cephalosporins. Cefdinir, cefixime, and cefpodoxime are inactive against most strains of Enterobacter and Pseudomonas and have limited in vitro activity against anaerobic bacteria; cefixime also is inactive against most staphylococci. Cefditoren has increased activity, similar to first generation cephalosporins, against gram-positive bacteria, unlike other third generation cephalosporins.⁶⁶⁴ Third generation cephalosporins are inactive against MRSA and generally are inactive against enterococci (e.g., E. faecalis) and L. monocytogenes. Some parenteral third generation cephalosporins (ceftazidime) have activity in vitro against Ps. aeruginosa.⁷¹⁵

Fourth Generation Cephalosporins

• cefepime

Fourth generation cephalosporins, like third generation cephalosporins, have an expanded spectrum of activity against gram-negative bacteria compared with the first and second generation drugs.^{383 384 385} However, fourth generation cephalosporins are active in vitro against some gram-negative bacteria, including Pseudomonas aeruginosa and certain Enterobacteriaceae, that generally are resistant to third generation cephalosporins.^{383 384 385} In addition, fourth generation cephalosporins may be more active against gram-positive bacteria than some third generation drugs (e.g., ceftazidime).^{383 384 385 387} Cefepime has a spectrum of activity against aerobic gram-positive and gram-negative bacteria that is similar to that of cefotaxime and ceftriaxone and has activity against Ps. aeruginosa that appears to approach that of ceftazidime.^{384 385 387} However, cefepime is more active than third generation cephalosporins against Enterobacteriaceae that produce inducible β-lactamases.^{383 384 386} The extended spectrum of activity of cefepime is related to the fact that the drug penetrates the outer membrane of gram-negative bacteria more rapidly than most other cephalosporins and the fact that the drug is more resistant to inactivation by chromosomally and plasmid-mediated β-lactamases than most other cephalosporins.^{383 384 385 386 387 388} In addition, inducible β-lactamases have a low affinity for cefepime and the drug is hydrolyzed by these enzymes at a slower rate than third generation cephalosporins such as ceftazidime.^{383 387} Cefepime is inactive against MRSA, enterococci, and L. monocytogenes.^{383 384 386 387}

Fifth Generation Cephalosporins

• ceftaroline fosamil

• ceftolozane

Like third and fourth generation cephalosporins, fifth generation cephalosporins have an expanded spectrum of activity that includes both gram-positive and gram-negative bacteria.^{704 705 711 712 713 714 715} Fifth generation cephalosporins also usually have activity against methicillin-resistant Staphylococcus aureus (MRSA; also known as oxacillin-resistant S. aureus, ORSA).^{704 705 711 712 713 715}

In Vitro Susceptibility Testing

When in vitro susceptibility testing is performed according to the standards of the Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards [NCCLS]), clinical isolates identified as susceptible to a cephalosporin are inhibited by drug concentrations usually achievable when the recommended dosage is used for the site of infection.⁶⁷⁶ Clinical isolates classified as intermediate have minimum inhibitory concentrations (MICs) that approach usually attainable blood and tissue concentrations and response rates may be lower than for strains identified as susceptible.⁶⁷⁶ Therefore, the intermediate category implies clinical applicability in body sites where the drug is physiologically concentrated or when a higher than usual dosage can be used.⁶⁷⁶ This intermediate category also includes a buffer zone which should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins.⁶⁷⁶ If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to a cephalosporin, the strain is not inhibited by drug concentrations generally achievable with usual dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and clinical efficacy of the drug against the isolate has not been reliably demonstrated in clinical studies.⁶⁷⁶

Because of differences in spectra of activity, the first generation cephalosporins (cefazolin), second generation cephalosporins (cefaclor, cefprozil, cefuroxime), third generation cephalosporins (cefdinir, cefditoren, cefixime, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftriaxone), fourth generation cephalosporins (cefepime), and fifth generation cephalosporins (ceftaroline) should be tested individually to determine in vitro susceptibility.⁶⁷⁶

CLSI states that in vitro susceptibility test results for cephalothin (no longer commercially available in the US) should only be used to predict susceptibility of Enterobacteriaceae to certain oral cephalosporins (i.e., cefadroxil, cephalexin, cefpodoxime).⁶⁷⁶ Although older data suggest that cephalothin results could predict susceptibility to some other cephalosporins, recent data are not available to confirm this.⁶⁷⁶

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test in vitro susceptibility, individual disks containing cefaclor (30 mcg), cefazolin (30 mcg), cefdinir (5 mcg), cefditoren (5 mcg), cefepime (30 mcg), cefixime (5 mcg), cefotaxime (30 mcg), cefotetan (30 mcg), cefoxitin (30 mcg), cefpodoxime (10 mcg), cefprozil (30 mcg), ceftaroline (30 mcg), ceftazidime (30 mcg), ceftibuten (30 mcg), ceftriaxone (30 mcg), or cefuroxime (30 mcg) should be used.⁶⁷⁶ There is no class susceptibility disk that can be used to test susceptibility to all cephalosporins.⁶⁷⁶

The disk-diffusion procedure should not be used to test in vitro susceptibility of Streptococcus pneumoniae to cephalosporins; in vitro susceptibility should be evaluated using broth or agar dilutions tests.⁶⁷⁶

For detailed information on interpretation of disk diffusion zone diameters for disk susceptibility tests performed according to CLSI standardized procedures, see specialized references.⁶⁷⁶

Dilution Susceptibility Tests

When broth or agar dilution susceptibility tests are used to test in vitro susceptibility to cephalosporins, each drug must be tested individually.⁶⁷⁶

For detailed information on interpretation of MICs (mcg/mL) for diffusion susceptibility tests performed according to CLSI standardized procedures, see specialized references.⁶⁷⁶

Resistance

Bacterial resistance to cephalosporins may be natural or acquired and may result from one or a combination of factors. Some bacteria are not affected by concentrations of a cephalosporin that are lethal to other bacteria because their cell surfaces are not permeable to the drug or because their metabolic pathways are not inhibited by the drug. A major mechanism of bacterial resistance to cephalosporins is the production of β-lactamases which inactivate the drugs by hydrolyzing the β-lactam ring. However, absence or presence of a β-lactamase does not entirely dictate susceptibility or resistance to a cephalosporin. Bacterial resistance usually results both from the production of a β-lactamase and the presence of permeability barriers to the drug. The β-lactamases produced by different bacterial species differ in physical, chemical, and functional properties. Staphylococcal β-lactamases are usually inducible, extracellular penicillinases. A variety of β-lactamases are produced by gram-negative bacteria; some are chromosome-mediated inducible cephalosporinases and a few are determined by plasmid-mediated resistance factors.

Cephalosporins General Statement Pharmacokinetics

Absorption

Cefazolin sodium, cefepime hydrochloride, cefotaxime sodium, ceftaroline fosamil, ceftazidime, ceftriaxone sodium, and cefuroxime sodium are not appreciably absorbed from the GI tract and must be given parenterally.

Cefaclor, cefadroxil, cefprozil, ceftibuten dihydrate, cephalexin, and cephalexin hydrochloride are well absorbed from the GI tract. Following oral administration, bioavailability of cefdinir averages 16–25%. Approximately 30–50% of an oral dose of cefixime and 50% of an oral dose of cefpodoxime proxetil is absorbed from the GI tract. Cefditoren pivoxil,⁶⁶³ cefpodoxime proxetil,³³⁸ and cefuroxime axetil³⁴⁸ are prodrugs and are inactive until hydrolyzed in vivo to cefditoren, cefpodoxime, and cefuroxime, respectively, by nonspecific esterases in the intestinal lumen and blood. Ceftaroline fosamil also is a prodrug that is inactive until it is converted in vivo to ceftaroline by a plasma phosphatase following IV administration.^{703 704}

Administration with food does not affect the rate of absorption or peak serum concentrations of cefadroxil. While the rate of absorption of cefixime or cefprozil may be decreased by the presence of food in the GI tract, the extent of absorption and peak plasma concentrations of the drug generally are not affected. Compared with administration in the fasting state, administration of cefdinir with a high-fat meal decreases the rate and extent of absorption of the drug. Administration of cefditoren pivoxil with a moderate- or high-fat meal increases the rate and extent of absorption, compared with administration in the fasting state.⁶⁶³ The effect of food on oral bioavailability of cefaclor, cefpodoxime proxetil, ceftibuten, and cefuroxime axetil varies depending on the formulation of the drugs administered.

Distribution and Elimination

Following absorption, most cephalosporins are widely distributed to tissues and fluids, including pleural fluid, synovial fluid, and bone. Following oral administration, cefdinir, cefixime, cefpodoxime, ceftibuten, cefprozil, and cefuroxime are distributed into middle ear fluid, tonsils, sinus tissue, and bronchial mucosa. Following oral administration, cefditoren has been shown to distribute into tonsils and skin blister fluid.⁶⁶³ Although the total quantity of some cephalosporins distributed into bile is low, therapeutic concentrations of some of the drugs (e.g., cefazolin, cefepime, cefixime) generally are obtained if biliary obstruction is not present. Only low concentrations of first or second generation cephalosporins diffuse into CSF following oral, IM, or IV administration even when meninges are inflamed; however, therapeutic concentrations of cefotaxime, ceftazidime, ceftriaxone, or cefuroxime generally are attained in CSF following IM or IV administration, especially if meninges are inflamed. Cefepime also is distributed into CSF following parenteral administration.

Cephalosporins readily cross the placenta, and fetal serum concentrations may be 10% or more of maternal serum concentrations. Cephalosporins are distributed in low concentrations into milk.

Serum cephalosporin concentrations may be higher and the serum half-lives prolonged in patients with impaired renal function.

Cefaclor, cefadroxil, cefazolin, cefdinir, cefditoren, cefixime, cefpodoxime, cefprozil, ceftazidime, ceftolozane, cefuroxime, and cephalexin are not appreciably metabolized. Cefuroxime axetil, cefditoren pivoxil, and cefpodoxime proxetil are rapidly hydrolyzed to their respective microbiologically active forms, cefuroxime, cefditoren, and cefpodoxime, by nonspecific esterases in the intestinal mucosa and/or blood following oral administration. The axetil moiety of cefuroxime is metabolized to acetaldehyde and acetic acid; hydrolysis of cefditoren pivoxil results in the formation of pivalate, which is absorbed and excreted as pivaloylcarnitine in urine. Cefepime is partially metabolized in vivo. Cefotaxime is partially metabolized (presumably in the liver, kidneys, and other tissues) to desacetyl metabolites which also have antibacterial activity, although less than that of the parent compounds. Ceftriaxone is metabolized to a small extent to microbiologically inactive metabolites in the intestines after biliary excretion.

Cephalosporins and their metabolites are rapidly excreted by the kidneys. Cefaclor, cefadroxil, cefazolin, cefditoren, cefixime, cefotaxime, cefpodoxime, cefprozil, cefuroxime, and cephalexin are excreted by both glomerular filtration and tubular secretion; cefepime, ceftazidime, ceftolozane, and ceftriaxone are excreted principally by glomerular filtration. The same system of anion transport is responsible for the tubular secretion of cephalosporins as for other β-lactam antibiotics and probenecid. Oral probenecid administered shortly before or with most cephalosporins usually slows the rate of excretion of the antibiotic and produces higher and more prolonged serum concentrations, especially with those cephalosporins excreted principally by tubular secretion. Most cephalosporins are removed by hemodialysis or peritoneal dialysis.

Chemistry and Stability

Chemistry

Cephalosporins are semisynthetic antibiotic derivatives of cephalosporin C, a substance produced by the fungus Cephalosporium acremonium. The drugs are β-lactam antibiotics structurally and pharmacologically related to penicillins and cephamycins (e.g., cefoxitin). All commercially available cephalosporins contain the 7-aminocephalosporanic acid (7-ACA) nucleus, which is composed of a β-lactam ring fused with a 6-membered dihydrothiazine ring instead of the 5-membered thiazolidine ring of penicillins. Cleavage at any point in the β-lactam ring system of cephalosporins results in complete loss of antibacterial activity.

Addition of various groups at R¹ (position 7) and R² (position 3) of the cephalosporin nucleus results in derivatives with differences in spectra of activity, stability against hydrolysis by β-lactamases, protein binding, GI absorption, or susceptibility to desacetylation. Many commercially available oral cephalosporins (e.g., cefdinir, cefditoren pivoxil, cefixime, cefpodoxime proxetil, ceftibuten) and parenteral cephalosporins (e.g., cefepime, cefotaxime, ceftazidime, ceftriaxone) contain an aminothiazolyl side chain at position 7 of the cephalosporin nucleus. The aminothiazolyl side chain enhances antibacterial activity, particularly against Enterobacteriaceae, and generally results in enhanced stability against β-lactamases. Unlike other commercially available cephalosporins, ceftaroline contains a 1,3-thiazole ring, linked to the 3-position of the cephem ring by a sulfur, which appears to contribute to activity against methicillin-resistant Staphylococcus aureus (MRSA; also known as oxacillin-resistant S. aureus or ORSA).⁷⁰⁴ Some previously available cephalosporins (e.g., cefamandole, cefoperazone) and structurally related cephamycins (e.g., cefotetan) contain an N-methylthiotetrazole (NMTT) side chain at position 6 of the cephalosporin nucleus.^{312 313} The NMTT side chain enhances antibacterial activity, helps to prevent metabolism of the drugs, and also may be associated with certain adverse effects (e.g., hypoprothrombinemia, disulfiram-like reactions).^{312 313 390}

Stability

In solution, most cephalosporins are stable for only short periods of time unless frozen.

Cephalosporins are potentially physically and/or chemically incompatible with some drugs including aminoglycosides, but the compatibility depends on the specific drug and several other factors (e.g., concentration of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific compatibility information.

Releated Monographs

For specific dosages and additional information on chemistry and stability, spectrum, resistance, pharmacokinetics, uses, cautions, drug interactions, and laboratory test interferences of the cephalosporins, see the individual monographs in 8:12.06. The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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