Natural Penicillins General Statement (Monograph)

Drug class: Natural Penicillins
VA class: AM110

Introduction

Natural penicillins are β-lactam antibiotics that are active against many gram-positive and -negative aerobic cocci, some gram-positive aerobic and anaerobic bacilli, and many spirochetes.

Uses for Natural Penicillins General Statement

Natural penicillins are used principally for the treatment of infections caused by susceptible gram-positive aerobic cocci, gram-negative aerobic cocci, gram-positive aerobic bacilli, gram-positive anaerobic bacteria, and spirochetes. The drugs also have been used prophylactically to prevent serious infections caused by some of these organisms.

Penicillin G potassium and penicillin G sodium are frequently referred to as aqueous, crystalline penicillin G and are used parenterally when rapid and high serum concentrations of penicillin G are required, as in the treatment of endocarditis, meningitis, pericarditis, septicemia, severe pneumonia, or other serious infections caused by organisms susceptible to penicillin G.

IM penicillin G benzathine and IM penicillin G procaine are used only for the treatment of moderately severe infections caused by organisms susceptible to low concentrations of penicillin G, for prophylaxis of infections caused by these organisms, or as follow-up therapy to IM or IV penicillin G potassium or sodium. These long-acting, depot, or repository forms of penicillin G are effective for the treatment and prophylaxis of some infections when given as a single IM dose or when given once or twice weekly for several weeks. Penicillin G benzathine and penicillin G procaine also are commercially available in fixed-combination preparations containing both salts. The procaine salt provides higher initial penicillin G concentrations than the benzathine salt, and penicillin G benzathine provides lower but more prolonged penicillin G concentrations. Some clinicians question the rationale of these fixed combinations, however, because bacteria that are susceptible to low penicillin G concentrations are not killed more rapidly by the higher concentrations attained with the procaine salt, and bacteria that are only susceptible to the higher penicillin G concentrations attained with penicillin G procaine are not affected by the low concentrations that are maintained by penicillin G benzathine. The fixed combination preparations containing penicillin G benzathine and penicillin G procaine should not be used for the treatment of any form of syphilis and should not be used for the treatment of yaws, pinta, or bejel.

Endocarditis

IV penicillin G potassium or sodium is used for the treatment of endocarditis caused by susceptible Streptococcus pyogenes (group A β-hemolytic streptococci; GAS), S. agalactiae^{† [off-label]} (group B streptococci; GBS), other β-hemolytic streptococci (e.g., groups C, H, G, L, and M), or S. pneumoniae. The American Heart Association (AHA) states that IV penicillin G is a reasonable choice for the treatment of endocarditis caused by susceptible S. pyogenes, S. agalactiae, groups C and G streptococci, and highly penicillin-susceptible S. pneumoniae (penicillin MIC 0.1 mcg/mL or less), but concomitant use of gentamicin during the initial weeks of penicillin G treatment should be considered if endocarditis is caused by streptococci groups B, C, or G.

For the treatment of endocarditis caused by viridans group streptococci^{† [off-label]} or nonenterococcal group D streptococci^{† [off-label]}, including S. gallolyticus^{† [off-label]} (formerly S. bovis) that are highly susceptible to penicillin (penicillin MIC 0.12 mcg/mL or less), AHA states that IV penicillin G (with or without gentamicin) is a reasonable regimen. If endocarditis is caused by viridans group streptococci^{† [off-label]} or S. gallolyticus^† relatively resistant to penicillin (penicillin MIC greater than 0.12 mcg/mL but less than 0.5 mcg/mL), AHA states that IV penicillin G should be used in conjunction with gentamicin. These recommendations include endocarditis involving native valves or prosthetic valves or other prosthetic material caused by these bacteria.

AHA states that IV penicillin G in conjunction with gentamicin is a reasonable regimen for the treatment of native valve endocarditis caused by viridans group streptococci^†, Abiotrophia defectiva^†, or Granulicatella^† with penicillin MIC of 0.5 mcg/mL or greater.

For the treatment of endocarditis involving native valves or prosthetic valves or other prosthetic material caused by Enterococcus faecalis^†, E. faecium^†, or other enterococcal species susceptible to both penicillin G and gentamicin, AHA states that IV penicillin G in conjunction with gentamicin is a reasonable choice. AHA states that it is reasonable to substitute streptomycin for gentamicin in this regimen if enterococci are susceptible to penicillin and streptomycin, but resistant to gentamicin.

IV penicillin G has been used for the treatment of endocarditis caused by nonpenicillinase-producing staphylococci. AHA states that IV penicillin G may be considered for the treatment of native valve endocarditis caused by penicillin-susceptible S. aureus or coagulase-negative staphylococci in pediatric patients; however, penicillin G is not included in AHA recommendations for the treatment of staphylococcal endocarditis in adults.

AHA recommends that treatment of endocarditis should be managed in consultation with an infectious disease expert, especially when endocarditis is caused by S. pneumoniae, β-hemolytic streptococci, enterococci, or staphylococci.

For additional information regarding the treatment of endocarditis, current guidelines from AHA should be consulted.

Pharyngitis and Tonsillitis

Natural penicillins (IM penicillin G benzathine, oral penicillin V potassium) are drugs of choice for the treatment of pharyngitis and tonsillitis caused by S. pyogenes (group A β-hemolytic streptococci; GAS) and prevention of initial attacks (primary prevention) of rheumatic fever. These natural penicillins also are used for secondary prophylaxis to prevent recurrence of rheumatic fever (see Prevention of Rheumatic Fever Recurrence under Uses).

Acute pharyngitis is most frequently caused by viruses (e.g., adenovirus, coronavirus, influenza virus, parainfluenza virus, rhinovirus, respiratory syncytial virus), but may be caused by bacteria or other organisms (e.g., groups A, C, and G streptococci, Corynebacterium diphtheriae, Arcanobacterium haemolyticum, Neisseria gonorrhoeae, Mycoplasma pneumoniae, Chlamydia pneumoniae). S. pyogenes is the most frequent bacterial cause of acute pharyngitis (15–30% of cases of acute pharyngitis in pediatric patients and 5–15% of cases in adults). Although pharyngitis caused by group A β-hemolytic streptococci generally is associated with certain clinical characteristics (sore throat usually with sudden onset, pain on swallowing, fever, tonsillopharyngeal erythema with or without exudates, anterior cervical lymphadenitis) and may be associated with other signs and symptoms (headache, nausea, vomiting, abdominal pain, red and swollen uvula, petechiae on the palate, excoriated nares, scarlatiniform rash), these findings are not specific for this organism. Because a diagnosis of group A β-hemolytic streptococci cannot be made with certainty based on clinical evaluation alone, AHA and the American Academy of Pediatrics (AAP) state that the diagnosis can be suspected on clinical and epidemiologic grounds but that a decision to treat should be made only after laboratory confirmation that the pharyngitis is caused by group A β-hemolytic streptococci.

Anti-infective treatment usually is indicated for all patients with group A β-hemolytic streptococcal pharyngitis and tonsillitis because inadequately treated S. pyogenes infection of the upper respiratory tract may result in serious sequelae (e.g., rheumatic fever, acute glomerulonephritis) or purulent complications (e.g., otitis media, sinusitis, peritonsillar or retropharyngeal abscesses, suppurative cervical adenitis). There is evidence that prompt initiation of appropriate anti-infective treatment of S. pyogenes pharyngitis and tonsillitis shortens the clinical course, decreases the risk of suppurative sequelae, prevents acute rheumatic fever, and decreases the risk of transmission to close contacts. However, effectiveness of anti-infective treatment of S. pyogenes pharyngitis and tonsillitis for prevention of poststreptococcal glomerulonephritis has not been established.

Selection of an anti-infective for the treatment of S. pyogenes pharyngitis or 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. No regimen has been found to date that effectively eradicates group A β-hemolytic streptococci in 100% of patients.

Because the drugs have a narrow spectrum of activity, are inexpensive, and generally are effective with a low frequency of adverse effects, AHA, AAP, and the Infectious Diseases Society of America (IDSA) recommend a penicillin regimen (i.e., a single dose of IM penicillin G benzathine or 10 days of oral penicillin V potassium or oral amoxicillin) as the treatment of choice for S. pyogenes pharyngitis and tonsillitis. Other anti-infectives (narrow-spectrum oral cephalosporins, oral macrolides, oral clindamycin) are recommended as alternatives in penicillin-allergic patients.

Treatment with either a single dose of IM penicillin G benzathine or a 10-day regimen of oral penicillin V generally eradicates S. pyogenes from the pharynx and prevents acute rheumatic fever if initiated within 9 days after the onset of pharyngitis. In studies in children and adults 1–25 years of age with group A β-hemolytic streptococcal pharyngitis, 5–7 days of treatment with oral penicillin V potassium eradicated the organism from the pharynx in 69–82% of patients, but the recommended 10-day treatment regimen of the drug eradicated the organism in 82–94% of patients. Experts state that the single-dose IM penicillin G benzathine regimen may be preferred in patients who are unlikely to complete the 10-day regimen of oral penicillin V potassium or amoxicillin, in patients with a personal or family history of rheumatic fever or rheumatic heart disease, or when there are environmental factors (e.g., crowded living conditions) that place the individual at increased risk for development of rheumatic fever.

Follow-up laboratory evaluation after treatment of group A β-hemolytic streptococcal pharyngitis or tonsillitis generally is indicated only in patients who remain symptomatic, develop recurring symptoms, or have a history of rheumatic fever and are at unusually high risk for recurrence.

Retreatment of S. pyogenes Pharyngitis

If signs and symptoms of pharyngitis recur shortly after initial treatment (i.e., within a few weeks) and presence of S. pyogenes is documented, retreatment with the original or an alternative regimen is recommended. Initial treatment failures may occur more frequently with oral penicillins than with IM penicillin G benzathine because of poor adherence to the oral regimen. If compliance with a 10-day oral regimen is a concern, IM penicillin G benzathine should be used for retreatment. If initial treatment failed, some clinicians suggest retreatment with the original regimen or use of IM penicillin G benzathine if an oral regimen was used initially or retreatment with an alternative regimen (e.g., a narrow-spectrum oral cephalosporin such as cephalexin, oral fixed combination of amoxicillin and clavulanate [amoxicillin/clavulanate], oral clindamycin, oral macrolide). If an individual has multiple, recurrent episodes of symptomatic pharyngitis within a period of months to years, it may be difficult to determine whether these are true episodes of S. pyogenes infection or whether the patient is a long-term pharyngeal carrier of S. pyogenes who is experiencing repeated episodes of nonstreptococcal (e.g., viral) pharyngitis.

Asymptomatic Chronic Pharyngeal Carriers of S. pyogenes

Anti-infective treatment of asymptomatic chronic pharyngeal carriers of S. pyogenes is not usually indicated and these individuals should not receive repeated courses of anti-infectives. However, eradication of the carrier state may be desirable in certain situations (e.g., during a local outbreak of acute rheumatic fever or acute poststreptococcal glomerulonephritis, during an outbreak of S. pyogenes pharyngitis in a closed or partially closed community, when multiple episodes of documented symptomatic S. pyogenes pharyngitis are occurring within a family for many weeks despite appropriate treatment, when there is a personal or family history of acute rheumatic fever, when tonsillectomy is being considered in an individual solely because of frequent S. pyogenes infections). In such situations, recommended regimens include oral clindamycin, a narrow-spectrum oral cephalosporin, oral amoxicillin/clavulanate, oral azithromycin, or a regimen of oral rifampin in conjunction with either IM penicillin G benzathine or oral penicillin V.

Meningitis and Other CNS Infections

IV penicillin G potassium or sodium is used alone or in conjunction with other anti-infectives for the treatment of meningitis caused by susceptible Listeria monocytogenes, Neisseria meningitidis, S. agalactiae^† (group B streptococci; GBS), or S. pyogenes or other β-hemolytic streptococci (e.g., groups C, H, G, L, and M).

IV penicillin G potassium or sodium is used for the treatment of meningitis or ventriculitis caused by susceptible S. pneumoniae (penicillin MIC less than 0.1 mcg/mL). Treatment failures have been reported and the possibility of S. pneumoniae with intermediate resistance or complete resistance to penicillin G should be considered.

IV penicillin G potassium or sodium is recommended for the treatment of healthcare-associated ventriculitis and meningitis caused by susceptible Cutibacterium acnes^† (formerly Propionibacterium acnes).

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. 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.

Actinomycosis

IV penicillin G potassium or sodium is used for the treatment of actinomycosis caused by Actinomyces (e.g., A. israelii). IV penicillin G is a drug of choice for the treatment of all forms of actinomycosis, including cervicofacial, respiratory (pulmonary, bronchial, laryngeal), abdominal, and CNS infections. Prolonged treatment usually is necessary. Many clinicians recommend that patients with severe actinomycosis (e.g., pulmonary infections) receive 2–6 weeks of treatment with IV penicillin G potassium or sodium followed by 6–12 additional months of treatment with an oral regimen (e.g., penicillin V or amoxicillin). A shorter duration of treatment may be sufficient for less extensive disease (e.g., cervicofacial). Surgical procedures should be performed as indicated, but do not eliminate the need for anti-infective therapy.

Cervicofacial actinomycosis has been effectively treated with oral penicillin V^† given for 3–8 weeks or longer.

Anthrax

Natural penicillins (IV penicillin G potassium or sodium, IM penicillin G procaine, oral penicillin V) are used for the treatment of anthrax (clinically apparent inhalational, cutaneous, GI, or meningeal anthrax) caused by susceptible Bacillus anthracis. Natural penicillins (IM penicillin G procaine, oral penicillin V^†) also are used as alternatives for inhalational anthrax (postexposure) to reduce the incidence or progression of disease following suspected or confirmed exposure to aerosolized B. anthracis spores if penicillin susceptibility is confirmed.

Postexposure Prophylaxis (Inhalational Anthrax)

Ciprofloxacin and doxycycline usually are the initial drugs of choice for postexposure prophylaxis following suspected or confirmed exposure to aerosolized B. anthracis spores, including exposures that occur in the context of biologic warfare or bioterrorism. If exposure is confirmed and results of in vitro testing indicate that the organism is susceptible to penicillin, then consideration can be given to changing the postexposure prophylaxis regimen to a penicillin (e.g., oral amoxicillin, oral penicillin V, IM penicillin G procaine). Although monotherapy with a penicillin is not recommended for the treatment of clinically apparent inhalational anthrax when high concentrations of the organism are likely to be present, penicillins may be considered an option for anti-infective prophylaxis in some situations, including when ciprofloxacin and doxycycline are contraindicated, since the likelihood of β-lactamase induction resulting in an increase in penicillin MICs is lower when only a small number of vegetative cells are present. If a penicillin is used for prophylaxis following exposure to aerosolized B. anthracis spores in the context of biologic warfare or bioterrorism when penicillin-susceptible strains are involved, AAP and the US Centers for Disease Control and Prevention (CDC) recommend oral amoxicillin or oral penicillin V.

Following natural, occupational, or bioterrorism-related exposures to aerosolized B. anthracis spores, anti-infective postexposure prophylaxis should be initiated immediately or as soon as possible. The optimum duration of postexposure prophylaxis after an inhalation exposure to B. anthracis spores is unclear. Because of the possible persistence of anthrax spores in lung tissue following an aerosol exposure, CDC and other experts recommend that the total duration of anti-infective prophylaxis should be at least 60 days.

Treatment of Cutaneous Anthrax

Natural penicillins (e.g., IM penicillin G procaine, oral penicillin V) generally have been considered drugs of choice for the treatment of mild, uncomplicated cutaneous anthrax caused by susceptible B. anthracis that occurs as the result of naturally occurring or endemic exposures to anthrax.

For the treatment of cutaneous anthrax that occurs following exposure to B. anthracis spores in the context of biologic warfare or bioterrorism, the initial drugs of choice are ciprofloxacin or doxycycline. If penicillin susceptibility is confirmed, consideration can be given to changing to a penicillin (oral amoxicillin or oral penicillin V) in infants and children, in pregnant or lactating women, or when the drugs of choice are not tolerated or not available; oral amoxicillin may be preferred, especially in infants and children. A multiple-drug parenteral regimen is recommended for initial treatment of cutaneous anthrax when there are signs of systemic involvement, extensive edema, or lesions on the head and neck. (See Treatment of Systemic Anthrax under Uses.)

For young children (i.e., younger than 2 years of age), CDC has recommended that initial treatment of cutaneous anthrax should be IV (not oral) and a multiple-drug anti-infective regimen should be considered since it is not known whether infants and young children are at increased risk of systemic dissemination of cutaneous anthrax.

Although 3–10 days of anti-infective treatment may be adequate for the treatment of mild, uncomplicated cutaneous anthrax that occurs as the result of natural or endemic exposures to anthrax, some experts recommend a treatment duration of 7–14 days. CDC and other experts recommend that anti-infectives be continued for 60 days if cutaneous anthrax occurred as the result of exposure to aerosolized B. anthracis spores (e.g., in the context of biologic warfare or bioterrorism) since the possibility of inhalational anthrax would also exist. Although anti-infective therapy may limit the size of the cutaneous anthrax lesion and it usually becomes sterile within the first 24 hours of treatment, the lesion will still progress through the black eschar stage despite effective treatment.

Treatment of Systemic Anthrax

IV penicillin G potassium or sodium generally has been considered a drug of choice for the treatment of clinically apparent inhalational, GI, or meningeal anthrax or anthrax septicemia caused by susceptible B. anthracis that occurs as the result of natural or endemic exposures to the organism. Concomitant use of other anti-infectives (e.g., streptomycin or other aminoglycoside, clindamycin, clarithromycin, rifampin, vancomycin) may also be indicated.

IV penicillin G potassium or sodium is considered an alternative for use in multiple-drug parenteral regimens for initial treatment of systemic anthrax (inhalational anthrax, GI anthrax, meningoencephalitis, sepsis, or cutaneous anthrax with systemic involvement, lesions on the head or neck, or extensive edema) caused by penicillin-susceptible B. anthracis that occurs in the context of biologic warfare or bioterrorism. Strains of B. anthracis with naturally occurring penicillin resistance have been reported rarely, and there are published reports of B. anthracis strains that have been engineered to have penicillin and tetracycline resistance as well as resistance to other anti-infectives (e.g., macrolides, chloramphenicol, rifampin). Therefore, it has been postulated that exposures to B. anthracis that occur in the context of biologic warfare or bioterrorism may involve bioengineered resistant strains and this concern should be considered when selecting initial therapy for the treatment of anthrax that occurs as the result of bioterrorism-related exposures or for postexposure prophylaxis following such exposures. In addition, although B. anthracis strains isolated during bioterrorism-related exposures that occurred in the US during September and October 2001 were susceptible to penicillin and amoxicillin in vitro, additional tests indicated that some of these strains had constitutive and inducible β-lactamases and there is in vitro evidence that exposure of some penicillin-susceptible B. anthracis strains to penicillins can induce β-lactamases. Because of concerns regarding possible penicillin resistance or induction of penicillin resistance during treatment, CDC states that use of a penicillin alone is not recommended for the treatment of inhalational anthrax that occurs as the result of biologic warfare or bioterrorism when high concentrations of the organism are likely to be present, although penicillin can be included in appropriate multiple-drug regimens.

CDC recommends that treatment of inhalational anthrax that occurs as the result of exposure to B. anthracis spores in the context of biologic warfare or bioterrorism should be initiated with a multiple-drug parenteral regimen that includes ciprofloxacin or doxycycline and 1 or 2 anti-infectives predicted to be effective. The multiple-drug parenteral regimen usually is continued for at least 2–3 weeks until the patient is clinically stable when an oral anti-infective regimen may be substituted for the parenteral regimen. Because of the possible persistence of anthrax spores in lung tissue, the total duration of anti-infective treatment of inhalational anthrax that occurs as the result of exposure to aerosolized spores in the context of biologic warfare or bioterrorism should be 60 days.

Clostridium Infections

C. botulinum

IV penicillin G potassium or sodium has been used as an adjunct in the treatment of wound botulism caused by germination of Clostridium botulinum spores in a contaminated wound and resultant in vivo toxin production. Anti-infectives have no known direct effects on botulinum toxin and therefore are not usually indicated in the management of the various forms of botulism, except for the treatment of concurrent infections.

Botulism is a potentially fatal neuroparalytic illness caused by neurotoxins produced by C. botulinum, but may rarely be caused by other related species (e.g., C. baratii, C. butyricum) that also can produce neurotoxins. C. botulinum form spores that are ubiquitous in the environment in soil and water sediments and can germinate into vegetative bacteria that produce toxins. The various forms of naturally occurring human botulism based on the mode of acquisition of the toxin include wound botulism (exogenous spores within a contaminated wound germinate and produce toxin), foodborne botulism (exogenous toxin is ingested in contaminated food), infant botulism (endogenous spores within the intestine of the infant germinate and produce toxin), and adult or child intestinal botulism (intestinal colonization with toxin production and there is no evidence of an exogenous source such as food or wound contamination). Botulism also could potentially occur from iatrogenic overdose or misinjection of commercially available botulinum toxins used for cosmetic or therapeutic purposes or from inhalation of aerosolized botulinum toxin (e.g., in the context of biologic warfare or bioterrorism). Botulism is not transmitted person to person.

Botulism can vary from a mild illness to fulminate disease that progresses rapidly and can be fatal within a short time after the onset of symptoms. All forms of human botulism result in similar neurologic signs (i.e., descending flaccid paralysis, dysphagia, dysarthria, diplopia, dysphonia, ptosis, and respiratory muscle impairment leading to death). The initial symptoms of naturally occurring foodborne botulism may also include GI effects such as abdominal cramps, nausea, vomiting, or diarrhea.

Treatment strategies for most forms of botulism include intensive supportive care (including aggressive use of respiratory care) and prompt administration of botulinum antitoxin. For the treatment of botulism caused by toxin serotypes A, B, C, D, E, F, or G, botulism antitoxin (equine) heptavalent is available in the US from CDC. Timely administration of botulinum antitoxin early in the course of the illness (within 48 hours of symptom onset and ideally within 24 hours) is important since it can minimize the extent and severity of paralysis and may prevent progression to respiratory compromise or reduce the duration of mechanical ventilation and intensive care; however, the antitoxin will not reverse existing paralysis.

Wound botulism occurs when anaerobic conditions in a wound allow germination of C. botulinum spores and in vivo toxin production. The median incubation period for wound botulism associated with trauma is 7 days (range: 4–21 days). Although management of wound botulism involves use of botulinum antitoxin, supportive care, and wound debridement, adjunctive use of a parenteral anti-infective active against anaerobes (e.g., penicillin G, metronidazole) may be indicated to eradicate C. botulinum at the wound site. Because C. botulinum resistant to penicillin G has been reported, in vitro susceptibility testing is recommended if adjunctive use of the drug is being considered for management of wound botulism.

Foodborne botulism results from ingestion of exogenous botulinum toxin produced in food contaminated with C. botulinum spores, including improperly canned vegetables (especially low-acid vegetables), fruits, and meats; home-canned or fermented fish; herb-infused oils; nonpreserved foods served in restaurants or delicatessens (e.g., potatoes baked in aluminum foil and then held at room temperature, cheese sauce, bottled garlic, other condiments or foods kept warm for extended periods). Symptoms of foodborne botulism usually are evident within 12–72 hours after ingestion, but may be evident as soon as 2 hours or as long as 8 hours after ingestion of the toxin. The mainstay of treatment of foodborne botulism is use of botulinum antitoxin and supportive care.

Infant botulism and intestinal botulism (adult or child) are treated with botulinum antitoxin and supportive care. If infant botulism is caused by toxin serotypes A or B, botulism immune globulin IV can be used for treatment. Anti-infectives are not effective and should not be used in the treatment of infant botulism or intestinal botulism, unless clearly indicated for a concurrent infection.

Treatment of botulism that occurs as a result of a bioterrorism incident would be the same as that for naturally occurring botulism and includes prompt administration of botulinum antitoxin and supportive care. Antitoxin should be given to patients with neurologic signs of botulism as soon as feasible after clinical diagnosis; administration of antitoxin should not be delayed for microbiologic testing. Administration of botulinum antitoxin for postexposure prophylaxis following a bioterrorism-related exposure is not recommended, but may be considered after a known high-risk exposure in certain situations.

C. perfringens

IV penicillin G potassium or sodium is the drug of choice for the treatment of myonecrosis and gas gangrene caused by C. perfringens or other Clostridium species. IDSA recommends that IV penicillin G be used in conjunction with IV clindamycin for clostridial myonecrosis; if there is no definitive etiologic diagnosis, these experts recommend a broad-spectrum anti-infective regimen (e.g., vancomycin used in conjunction with the fixed combination of piperacillin and tazobactam [piperacillin/tazobactam], fixed combination of ampicillin and sulbactam [ampicillin/sulbactam], or a carbapenem). Anti-infectives are used as an adjunct to debridement and excision of the infected area.

Foodborne illness caused by C perfringens usually is self-limited and anti-infectives are not indicated.

C. tetani

IV penicillin G potassium or sodium has been used as an adjunct to tetanus immune globulin (TIG) in the treatment of tetanus. Tetanus is a neurologic disease caused by neurotoxin produced by C. tetani. The role of anti-infectives in the treatment of tetanus is unclear. Anti-infectives cannot neutralize toxin already formed and cannot eradicate C. tetani spores, which may revert to toxin-producing vegetative forms. In addition, the nature of wounds that become contaminated with C. tetani generally makes the organism inaccessible to anti-infectives. If an anti-infective is used for adjunctive treatment of tetanus to decrease the number of vegetative C. tetani, oral or IV metronidazole usually is the drug of choice and parenteral penicillin G is an alternative.

Diphtheria

Treatment of Diphtheria

IV penicillin G potassium or sodium or IM penicillin G procaine^† is used as an adjunct to diphtheria antitoxin in the treatment of diphtheria caused by toxigenic strains of Corynebacterium diphtheriae.

Use of diphtheria antitoxin (not commercially available in the US, but may be available from CDC) is the most important aspect of treatment of respiratory diphtheria. For adjunctive anti-infective treatment of diphtheria, a 14-day regimen of IV penicillin G, IM penicillin G procaine, or oral or parenteral erythromycin usually is recommended. Anti-infective therapy may eliminate C. diphtheriae from infected sites, prevent spread of the organism and further toxin production, and prevent transmission to close contacts by eliminating the diphtheria carrier state; however, anti-infectives appear to be of no value in neutralizing diphtheria toxin and do not replace treatment with diphtheria antitoxin.

Patients usually are no longer contagious 48 hours after initiation of appropriate anti-infective therapy. Eradication of C. diphtheriae should be confirmed 24 hours after completion of anti-infective treatment by 2 consecutive negative cultures taken 24 hours apart. Because diphtheria infection does not necessarily confer immunity, active immunization with an age-appropriate preparation containing diphtheria toxoid adsorbed should be initiated or completed during convalescence.

Prevention of Diphtheria in Close Contacts

IM penicillin G benzathine is used for prevention of diphtheria in asymptomatic household contacts of patients with respiratory or cutaneous diphtheria^†. CDC, US Public Health Service Advisory Committee on Immunization Practices (ACIP), and AAP recommend that, irrespective of their immunization status, all household or other close contacts of individuals with suspected or proven diphtheria should have samples taken for C. diphtheriae cultures, receive appropriate anti-infective prophylaxis, and be kept under surveillance for evidence of the disease for 7 days. Although efficacy of anti-infective prophylaxis in preventing secondary disease is presumed and not proven, prophylaxis should be initiated promptly and should not be delayed pending culture results. In addition, contacts of patients with diphtheria should receive an immediate dose of an age-appropriate preparation containing diphtheria toxoid adsorbed if they are inadequately immunized against diphtheria, immunization status is unknown, or they have not received a booster dose within the last 5 years.

CDC, ACIP, and AAP recommend that either a single dose of IM penicillin G benzathine or a 7- to 10-day regimen of oral erythromycin be used for chemoprophylaxis in contacts of patients with diphtheria. IM penicillin G benzathine may be preferred when there are concerns about compliance with the oral regimen. In addition, contacts who are inadequately immunized against diphtheria or whose immunization status is unknown should receive an immediate booster dose of an age-appropriate preparation containing diphtheria toxoid adsorbed and the primary immunization series should be completed according to the recommended schedule. Contacts who are fully immunized should receive an immediate booster dose of an age-appropriate diphtheria toxoid preparation if 5 or more years have elapsed since their last booster dose. Use of diphtheria antitoxin in unimmunized close contacts is not recommended because there is no evidence that such therapy has any additional benefit for contacts who receive recommended prophylaxis with IM penicillin G benzathine or oral erythromycin.

Elimination of Diphtheria Carrier State

Natural penicillins (IM penicillin G potassium or sodium, IM penicillin G procaine, IM penicillin G benzathine^†) have been used to eliminate the diphtheria carrier state in individuals identified as carriers of toxigenic C. diphtheriae.

For elimination of the diphtheria carrier state, AAP recommends a 10- to 14-day regimen of oral erythromycin or a single dose of IM penicillin G benzathine. In one study, a single dose of IM penicillin G benzathine eradicated the carrier state in 84% of carriers, but 10 days of treatment with oral erythromycin or oral clindamycin eradicated the carrier state in 92–93% of carriers.

Follow-up cultures should be obtained 24 hours after completion of the anti-infective regimen; individuals who continue to harbor C. diphtheriae after treatment should receive additional treatment with a 10-day course of oral erythromycin with follow-up cultures. Unimmunized diphtheria carriers should receive active immunization with an age-appropriate preparation containing diphtheria toxoid adsorbed; immunized carriers who have not received a booster dose within the last year should receive a booster dose of an age-appropriate diphtheria toxoid adsorbed preparation.

Erysipelothrix Infections

IV penicillin G potassium or sodium and IM penicillin G procaine are used for the treatment of infections caused by Erysipelothrix rhusiopathiae.

Parenteral penicillin G is the drug of choice for the treatment of serious infections caused by E. rhusiopathie, including endocarditis, and 4–6 weeks of treatment with IV penicillin G potassium or sodium is recommended.

Although uncomplicated localized cutaneous E. rhusiopathiae infections (i.e., erysipeloid) may resolve spontaneously within 3–4 weeks, anti-infective treatment may shorten the time to healing and reduce the risk of relapse. IM penicillin G procaine has been used for the treatment of erysipeloid; oral regimens (e.g., amoxicillin) often are recommended when anti-infective treatment is indicated for such infections.

Fusobacterium Infections

Natural penicillins have been used for the treatment of acute necrotizing ulcerative gingivitis (Vincent’s infection, trench mouth, Fusobacterium gingivitis or pharyngitis). Oral penicillin V potassium may be effective for the treatment of mild to moderate oropharyngeal infections caused by penicillin-susceptible Fusobacterium, but IM penicillin G procaine or IM or IV penicillin G potassium or sodium should be used for the treatment of moderately severe to severe cases.

In vitro susceptibility testing is recommended when selecting an anti-infective for the treatment of Fusobacterium infections. The increased prevalence of resistance to penicillins in organisms that cause oropharyngeal or odontogenic infections, including F. necrophorum and F. nucleatum, should be considered. Some experts recommend a combination regimen of a β-lactam anti-infective active against aerobic oral and respiratory tract pathogens (e.g., cefotaxime, ceftriaxone, cefuroxime) in conjunction with metronidazole or clindamycin for the treatment of invasive Fusobacterium infections; others recommend monotherapy with ampicillin/sulbactam, piperacillin/tazobactam, or a carbapenem.

Neisseria Infections

N. gonorrhoeae Infections

Although natural penicillins (penicillin G procaine, penicillin G potassium or sodium) were used in the past for the treatment of uncomplicated gonorrhea or disseminated gonococcal infections caused by penicillin-susceptible N. gonorrhoeae, penicillins should not be used for the treatment of gonococcal infections. CDC has not recommended use of penicillins for the treatment of uncomplicated or disseminated gonococcal infections for over 30 years because of the widespread prevalence of penicillinase-producing N. gonorrhoeae (PPNG) resistant to penicillins. Ceftriaxone is the drug of choice for the treatment of gonococcal infections.

N. meningitidis Infections

IM or IV penicillin G potassium or sodium has been considered a preferred or alternative drug for the treatment of infections caused by N. meningitidis, including upper respiratory tract infections, bacteremia, and meningitis (see Meningitis and Other CNS Infections under Uses). However, penicillin-resistant N. meningitidis have been reported and in vitro susceptibility testing is advised. In addition, treatment with penicillin G does not eliminate the meningococcal carrier state and should not be used for chemoprophylaxis in asymptomatic N. meningitidis carriers. Other anti-infectives (e.g., ceftriaxone, ciprofloxacin, rifampin) are recommended to eliminate nasopharyngeal carriage of N. meningitidis.

Pasteurella Infections

Penicillin G potassium or sodium is used for the treatment of infections caused by Pasteurella multocida. IV penicillin G is considered a drug of choice for the treatment of local infections caused by P. multocida (e.g., wound infections including dog, cat, or other animal bites) and meningitis, bacteremia, osteomyelitis, endocarditis, or other serious P. multocida infection.

Rat-bite Fever

Natural penicillins are used for the treatment of rat-bite fever caused by Streptobacillus moniliformis (erythema arthriticum epidemicum, Haverhill fever, streptobacillary fever) or Spirillum minus (sodoku).

IV penicillin G potassium or sodium usually is the drug of choice for the treatment of rat-bite fever and is effective for both the streptobacillary form and the spirillary form of the disease. For initial treatment of S. moniliformis endocarditis, IV penicillin G usually is used in conjunction with an aminoglycoside (streptomycin or gentamicin). Tetracyclines or streptomycin are considered alternatives (e.g., for penicillin-allergic patients).

Although IM penicillin G procaine has been used for the treatment of rat-bite fever, CDC and other clinicians state that IV penicillin G potassium or sodium is more appropriate and is preferred.

Oral penicillin V has been used in the treatment of rat-bite fever as follow-up therapy in patients who responded to initial treatment with IV penicillin G.

Spirochetal Infections

Leptospirosis

Penicillin G is used in the treatment of leptospirosis^† caused by Leptospira. Penicillin G is the drug of choice for the treatment of severe leptospirosis; other anti-infectives (e.g., amoxicillin, ampicillin, azithromycin, cefotaxime, ceftriaxone, doxycycline, tetracycline) also have been used for the treatment of infections caused by Leptospira.

Many Leptospira infections are self-limited and the effectiveness of anti-infectives in the treatment of mild disease is difficult to assess and has been questioned. Some studies indicate that the duration of systemic symptoms (e.g., fever) may be shortened and the incidence of renal, hepatic, meningeal, and hemorrhagic complications may be reduced if parenteral penicillin G is initiated early in the course of the disease (e.g., by the fourth day of the illness); however, delayed anti-infective treatment may not alter the course of the disease.

Anti-infective therapy of leptospirosis, including treatment with penicillin G, may provoke a Jarisch-Herxheimer reaction. (See Jarisch-Herxheimer Reaction under Cautions.)

Lyme Disease

Natural penicillins (IV penicillin G sodium or potassium, oral penicillin V) are used in the treatment of Lyme disease^† caused by Borrelia burgdorferi.

Although oral penicillin V has been used in the treatment of early localized Lyme disease manifested as erythema migrans^† and has been effective and well tolerated, some experts state that comparative efficacy data are limited and additional study is needed to identify the optimal dosage of penicillin V. IDSA, American Academy of Neurology (AAN), American College of Rheumatology (ACR), and others recommend that erythema migrans be treated with a 10-day regimen of oral doxycycline or a 14-day regimen of oral amoxicillin or oral cefuroxime axetil.

IV penicillin G potassium or sodium has been used for the treatment of neurologic Lyme disease^† and the treatment of Lyme arthritis^†. For the treatment of meningitis, cranial neuropathy, radiculoneuropathy, or other peripheral nervous system manifestations in patients with Lyme disease, IDSA, AAN, and ACR recommend treatment with IV ceftriaxone, IV cefotaxime, IV potassium G, or oral doxycycline. For the treatment of Lyme arthritis, IDSA, AAN, and ACR recommend use of oral anti-infectives (doxycycline, amoxicillin, cefuroxime axetil) based on comparative efficacy of oral and IV regimens; if an IV regimen is used in patients with Lyme arthritis (e.g., arthritis symptoms persist after an oral anti-infective regimen), these experts recommend IV ceftriaxone. IV ceftriaxone also is preferred for initial treatment of Lyme carditis in hospitalized patients.

For additional information on the treatment of Lyme disease, current treatment guidelines from IDSA, AAN, and ACR available at the IDSA website [Web] should be consulted.

Syphilis

Parenteral penicillin G is the treatment of choice for all stages and forms of syphilis caused by Treponema pallidum subsp pallidum, including primary syphilis infection (presents as a single painless ulcer or chancre at the infection site, but may present as multiple, atypical, or painful lesions), secondary syphilis (manifestations include rash, mucocutaneous lesions, and lymphadenopathy), latent syphilis (detected by serologic testing but lacking clinical manifestations of primary, secondary, or tertiary syphilis), tertiary syphilis (may present with cardiac involvement, gummatous lesions, tabes dorsalis, general paresis), neurosyphilis, and congenital syphilis. The most appropriate parenteral penicillin G preparation (penicillin G benzathine, penicillin G procaine, penicillin G potassium or sodium), dosage, and duration of treatment depend on the disease stage and clinical manifestations. Oral penicillin V and the fixed-combinations of parenteral penicillin G benzathine and penicillin G procaine should not be used in the treatment of syphilis.

Primary and Secondary Syphilis in Adults

IM penicillin G benzathine is the drug of choice for the treatment of primary and secondary syphilis in adults. This recommendation is based on long-term experience that indicates that the drug is effective in achieving clinical resolution (i.e., healing of lesions and prevention of sexual transmission) and preventing late sequelae. CDC and other experts recommend a single dose of IM penicillin G benzathine (2.4 million units) for the treatment of primary and secondary syphilis in adults. There is no evidence that additional doses of IM penicillin G benzathine result in enhanced efficacy in such patients; however, some experts recommend that pregnant women with primary or secondary syphilis receive a second dose of IM penicillin G benzathine 1 week after the initial dose (see Syphilis During Pregnancy under Uses).

Invasion of CSF by T. pallidum accompanied by CSF abnormalities is common in adults who have primary or secondary syphilis, but has unknown significance. In the absence of clinical neurologic findings, no evidence supports variation from the recommended treatment regimen for patients with primary or secondary syphilis. Development of symptomatic neurosyphilis is rare in such patients if the recommended treatment regimen is used. Therefore, routine CSF analysis is not usually recommended for adults with primary or secondary syphilis, unless there are clinical symptoms or signs of neurologic or ophthalmic involvement. Any patient with syphilis who also has signs or symptoms of neurologic disease (e.g., cranial nerve dysfunction, meningitis, stroke, altered mental state) or ocular syphilis (e.g., uveitis, neuroretinitis, optic neuritis) should be fully evaluated for neurosyphilis and syphilitic eye disease with CSF and ocular slit-lamp and other ophthalmic examinations.

Only limited data are available to support use of alternatives to penicillin G for the treatment of primary or secondary syphilis. CDC states that nonpregnant adults with primary or secondary syphilis who are hypersensitive to penicillin can receive oral doxycycline (100 mg twice daily for 14 days) or oral tetracycline hydrochloride (500 mg 4 times daily for 14 days). Compliance may be better with doxycycline than with tetracycline. Limited data indicate that IM or IV ceftriaxone (1 g daily for 10 days) is effective in the treatment of primary or secondary syphilis; however, CDC cautions that the optimal dose and duration of ceftriaxone for the treatment of syphilis have not been established. Although there are some data suggesting that azithromycin (single 2-g oral dose) has been effective for the treatment of primary or secondary syphilis in some populations, T. pallidum resistant to azithromycin and other macrolides have been reported and azithromycin treatment failures have been documented in the US. Therefore, azithromycin should not be used for the treatment of syphilis. Careful clinical and serologic follow-up is essential if a nonpenicillin regimen is used. If compliance and follow-up with an alternative regimen cannot be ensured in patients with primary or secondary syphilis who are hypersensitive to penicillins, they should be desensitized, if necessary, and treated with the appropriate penicillin G benzathine regimen.

Latent Syphilis in Adults

Latent syphilis occurs during the period after infection with T. pallidum when patients are seroreactive but have no other evidence of syphilis. Treatment of latent syphilis is intended to prevent the occurrence of or progression to late complications. Patients with latent syphilis who acquired syphilis within the preceding year are classified as having early latent syphilis (early nonprimary, nonsecondary). Individuals also can be classified as having early latent syphilis if, within the year preceding the evaluation, they had a documented seroconversion or fourfold or greater increase in nontreponemal test titers sustained for more than 2 weeks (in a previously treated individual), unequivocal symptoms of primary or secondary syphilis, or a sexual partner documented as having primary, secondary, or early latent syphilis. Other asymptomatic patients should be considered to have latent syphilis of unknown duration or late latent syphilis (duration exceeding 1 year).

IM penicillin G benzathine is considered the drug of choice for the treatment of latent syphilis in adults. CDC and others recommend that adults with early latent syphilis receive a single dose of IM penicillin G benzathine (2.4 million units) and that adults with late latent syphilis or latent syphilis of unknown duration receive a multiple-dose regimen of IM penicillin G benzathine (2.4 million units once weekly for 3 successive weeks).

Individuals who have been diagnosed with latent syphilis and have neurologic or ocular signs and symptoms (e.g., cognitive dysfunction, motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsies, symptoms or signs of meningitis or stroke) should be evaluated for neurosyphilis, ocular syphilis, or otosyphilis according to their clinical presentation.

Effectiveness of possible alternatives to penicillin G for the treatment of latent syphilis has not been well documented. CDC states that nonpregnant adults with clearly defined early latent syphilis who are hypersensitive to penicillins should respond to alternative regimens recommended for treatment of primary and secondary syphilis in penicillin-allergic patients (see Primary and Secondary Syphilis in Adults under Uses). The only acceptable alternatives for the treatment of late latent syphilis or syphilis of unknown duration are oral doxycycline (100 mg twice daily for 28 days) or oral tetracycline hydrochloride (500 mg 4 times daily for 28 days). Although ceftriaxone is a plausible alternative for the treatment of latent syphilis, the optimal dose and duration have not been defined and use of the drug should be considered in consultation with a specialist. Careful clinical and serologic follow-up is essential if a nonpenicillin regimen is used. If compliance and follow-up with an alternative regimen cannot be ensured in patients with latent syphilis who are hypersensitive to penicillins, they should be desensitized, if necessary, and treated with the appropriate penicillin G benzathine regimen.

Tertiary Syphilis in Adults

IM penicillin G benzathine is considered the drug of choice for the treatment of tertiary syphilis in adults. CDC and others recommend that adults with tertiary syphilis receive a multiple-dose regimen of IM penicillin G benzathine (2.4 million units once weekly for 3 weeks). CSF examinations are recommended prior to initiation of treatment in patients with symptomatic late syphilis. Some experts recommend that all patients with cardiovascular syphilis receive a treatment regimen recommended for neurosyphilis (see Neurosyphilis under Uses). CDC recommends that patients with cardiovascular or gummatous syphilis be managed in consultation with an expert.

Adults with tertiary syphilis who are hypersensitive to penicillins should be treated in consultation with an infectious disease specialist.

Neurosyphilis, Ocular Syphilis, and Otosyphilis

CNS involvement can occur during any stage of syphilis. CSF laboratory abnormalities are common in individuals with early syphilis, even in the absence of clinical neurologic findings. All patients with clinical signs or symptoms suggestive of neurosyphilis (e.g., cognitive dysfunction, motor or sensory deficits, cranial nerve palsies, signs or symptoms of meningitis or stroke) should receive CSF examinations before initiation of treatment.

Syphilitic uveitis or other ocular manifestations (e.g., neuroretinitis, optic neuritis) can occur at any stage of syphilis and can be isolated abnormalities or associated with neurosyphilis. Patients with ocular symptoms should receive full ophthalmic examinations, including cranial nerve evaluation; if cranial nerve dysfunction is present, CSF examinations are needed. If ocular syphilis is suspected, immediate referral to and management in collaboration with an ophthalmologist is crucial. Ocular syphilis should be treated with a regimen recommended for neurosyphilis, even if CSF examinations are normal.

Hearing loss and other otologic symptoms can occur at any stage of syphilis and can be isolated abnormalities or associated with neurosyphilis. Patients with isolated auditory symptoms and normal neurologic examinations do not need CSF examinations before initiation of treatment. Otosyphilis should be managed in collaboration with an otolaryngologist and treated with a regimen recommended for neurosyphilis.

CDC and others state that neurosyphilis, ocular syphilis, or otosyphilis in adults should be treated with IV penicillin G potassium or sodium (18–24 million units daily by continuous IV infusion or given as 3–4 million units every 4 hours for 10–14 days). Alternatively, if compliance can be ensured, a regimen of IM penicillin G procaine (2.4 million units once daily for 10–14 days and 500 mg of oral probenecid 4 times daily for 10–14 days) may be considered. Because these regimens recommended for neurosyphilis are shorter than those recommended for the treatment of late latent syphilis, some clinicians suggest that a regimen of IM penicillin G benzathine (2.4 million units once weekly for up to 3 weeks) be considered after completion of the IV penicillin G or IM penicillin G procaine regimen.

CDC states that limited data suggest that IM or IV ceftriaxone (1–2 g daily for 10–14 days) can be used as an alternative for the treatment of neurosyphilis in patients hypersensitive to penicillin; although cross-allergenicity between penicillins and ceftriaxone can occur, the risk of cross-reactivity between penicillin and third generation cephalosporins is lower than with some other cephalosporins. (See Patients at Risk for Penicillin Hypersensitivity Reactions under Cautions.) Because other nonpenicillin regimens have not been adequately studied for the treatment of neurosyphilis, if safety of ceftriaxone is a concern in a patient hypersensitive to penicillin, appropriate testing should be done to confirm penicillin allergy and, if necessary, the patient should be desensitized and managed in consultation with an expert.

Syphilis in HIV-infected Individuals

HIV-infected individuals with primary or secondary syphilis, latent syphilis, tertiary syphilis, or neurosyphilis should receive the same treatment regimens recommended for those without HIV infection. Neurosyphilis, ocular syphilis, and otosyphilis should be considered in the differential diagnosis of neurologic, ocular, and other signs and symptoms among HIV-infected individuals. All HIV-infected individuals with syphilis should receive careful clinical and serologic follow-up after treatment.

Syphilis During Pregnancy

Syphilis during pregnancy can result in stillbirth, hydrops fetalis, or preterm birth; the infant may be born with congenital syphilis, including asymptomatic infection. The reported rate of maternal-fetal transmission of the infection is 60–100% in pregnant women with primary or secondary syphilis, 40% in those with early latent syphilis, and less than 8% in those with late latent syphilis. The risk of transmission to the infant increases directly with gestational age at the time of maternal infection.

Penicillin G is the drug of choice for the treatment of syphilis during pregnancy and use of an appropriate treatment regimen in the mother can effectively prevent maternal transmission of T. pallidum and treat infection in the fetus. If a pregnant woman has clinical or serologic evidence of syphilis or if the diagnosis of syphilis cannot be excluded, the pregnant woman should receive the usual penicillin G regimen appropriate for the stage of syphilis. In addition, some experts recommend that pregnant women with primary, secondary, or early latent syphilis who are treated with IM penicillin G benzathine should receive a second dose of IM penicillin G benzathine 1 week after the first dose. If a pregnant patient with late latent syphilis misses a dose of the recommended multiple-dose regimen of IM penicillin G benzathine, the full course of treatment must be repeated.

There are no proven alternatives to penicillin G for the treatment of syphilis during pregnancy, and pregnant women with any stage of syphilis who have a history of penicillin allergy should be desensitized and treated with the appropriate penicillin G regimen. Tetracyclines should be avoided during the second and third trimesters. Erythromycin and azithromycin should not be used for the treatment of syphilis during pregnancy since these macrolides do not reliably cure syphilis in the woman and do not treat the infection in the fetus. In addition, data are insufficient to recommend ceftriaxone or other cephalosporins for the treatment of syphilis in pregnant women.

Congenital Syphilis

There has been a substantial increase in the incidence of congenital syphilis reported in the US during recent years that reflects the increased incidence of primary and secondary syphilis among women of reproductive potential. Data indicate that the case rate of congenital syphilis in the US increased from 9.2 cases per 100,000 live births in 2013 to 33.1 cases per 100,000 live births in 2018. Data for 2019 indicate 48.5 cases of congenital syphilis per 100,000 live births in the US. Regardless of the stage of syphilis in the pregnant woman, congenital syphilis can occur as the result of placental transmission at any time during pregnancy or via contact with maternal lesions at the time of delivery.

Neonates born to women who have had syphilis during pregnancy should be examined carefully and tested at birth for evidence of congenital syphilis. Infected infants can have hepatosplenomegaly; snuffles (copious nasal secretions); lymphadenopathy; mucocutaneous lesions; pneumonia, osteochondritis, periostitis, and pseudoparalysis; edema; rash (maculopapular consisting of small dark red-copper spots) that is most severe on the hands and feet; hemolytic anemia; or thrombocytopenia at birth or within the first 4–8 weeks after birth. Untreated infants, including those asymptomatic at birth, may develop late manifestations that usually appear when the child is older than 2 years of age and may involve the CNS, bones and joints, teeth, eyes, and skin. Late manifestations can be prevented by treatment of congenital syphilis. The diagnosis of congenital syphilis is complicated by transplacental transfer of maternal nontreponemal and treponemal immunoglobulin G (IgG) antibodies to the fetus that make interpretation of reactive serologic tests for syphilis difficult in infants. Treatment decisions for neonates usually are made based on diagnosis of syphilis in the mother; adequacy of maternal syphilis treatment; clinical, laboratory, or radiologic evidence of syphilis in the neonate; and comparison of maternal nontreponemal serologic titers (at delivery) and titers in the neonate (using the same test and, if possible, the same laboratory).

For neonates with confirmed proven or highly probable congenital syphilis (those with abnormal physical examination consistent with congenital syphilis, serum quantitative nontreponemal serologic titer that is 4 or more times the mother’s titer [at delivery], or positive darkfield or polymerase chain reaction [PCR] test of placenta, cord, lesions, or body fluids or a positive silver stain of the placenta or cord), CDC and AAP recommend IV penicillin G potassium or sodium (50,000 units/kg every 12 hours during the first 7 days of life and 50,000 units/kg every 8 hours thereafter for a total duration of 10 days) or, alternatively, IM penicillin G procaine (50,000 units/kg once daily for 10 days). If more than 1 day of treatment is missed, the entire 10-day course of treatment should be restarted. There are insufficient data on use of other anti-infectives (e.g., ampicillin) for the treatment of congenital syphilis, and a 10-day regimen of penicillin G potassium or sodium or penicillin G procaine should be administered even if the neonate received ampicillin for another indication (e.g., empiric treatment for possible sepsis).

For neonates with possible congenital syphilis (those with normal physical examination and serum quantitative nontreponemal serologic titer the same as or less than 4 times the mother’s titer [at delivery] and the mother was not treated, inadequately treated, has no documentation of receiving treatment, was treated with a nonpenicillin regimen, or treatment was initiated less than 30 days before delivery), CDC and AAP recommend IV penicillin G potassium or sodium (50,000 units/kg every 12 hours during the first 7 days of life and 50,000 units/kg every 8 hours thereafter for a total duration of 10 days) or, alternatively, IM penicillin G procaine (50,000 units/kg once daily for 10 days). Some experts state that a single dose of IM penicillin G benzathine (50,000 units/kg) can be used as an alternative if follow-up can be ensured; however, others prefer the 10-day regimens if the mother had untreated early syphilis at the time of delivery since such neonates are at increased risk for congenital syphilis.

For neonates less likely to have congenital syphilis (those with normal physical examination and serum nontreponemal serologic titer the same as or less than 4 times the mother’s titer [at delivery] and the mother received adequate treatment during pregnancy with a regimen appropriate for the stage of syphilis and treatment was initiated at least 30 days prior to delivery and the mother has no evidence of reinfection or relapse), CDC and AAP recommend a single dose of IM penicillin G benzathine (50,000 units/kg).

Although no treatment is required for neonates unlikely to have congenital syphilis (those with normal physical examination and serum nontreponemal serologic titer the same as or less than 4 times the mother’s titer [at delivery] and the mother received adequate treatment before pregnancy and the mother had nontreponemal serologic titers that remained low and stable before and during pregnancy and at delivery), some experts would consider treating the neonate with a single dose of IM penicillin G benzathine (50,000 units/kg), especially if adequate follow-up of the neonate cannot be ensured and the neonate has a reactive nontreponemal test.

There are no proven alternatives to penicillin G for the treatment of congenital syphilis, and infants who are allergic to penicillin or develop presumed penicillin allergy during treatment should be desensitized, if possible, and treated with the appropriate penicillin G regimen. Data are insufficient to date regarding use of other anti-infectives (e.g., ceftriaxone) for the treatment of congenital syphilis.

Syphilis in Older Infants and Children

Infants and children 1 month of age or older diagnosed with syphilis should have CSF examinations to rule out neurosyphilis and birth and maternal medical records should be reviewed to determine whether the child has acquired or congenital syphilis. Such infants and children should be managed in consultation with a pediatric infectious disease specialist.

Any infant older than 1 month of age with known or suspected congenital syphilis and children older than 2 years of age who have late and previously untreated congenital syphilis should be treated with IV penicillin G potassium or sodium (50,000 units/kg every 4–6 hours for 10 days); some experts suggest that these infants and children also receive a single dose of IM penicillin G benzathine (50,000 units/kg [up to 2.4 million units]) after the penicillin G potassium or sodium regimen. If the infant or child has no clinical manifestations of congenital syphilis and evaluations (including CSF examinations) are normal, some experts state that treatment with IM penicillin G benzathine (50,000 units/kg [up to 2.4 million units] once weekly for less than 3 weeks) can be considered.

For the treatment of acquired syphilis in infants and children, CDC and AAP state that those with primary or secondary syphilis should receive a single dose of IM penicillin G benzathine (50,000 units/kg [up to 2.4 million units]). AAP states that those with early latent syphilis should receive a single dose of IM penicillin G benzathine (50,000 units/kg [up to 2.4 million units]), and those with late latent syphilis should receive IM penicillin G benzathine (50,000 units/kg [up to 2.4 million units] once weekly for 3 successive weeks).

There are no proven alternatives to penicillin G for the treatment of syphilis in infants and children, and those who have a history of penicillin allergy or develop presumed penicillin allergy during treatment should be desensitized and treated with the appropriate penicillin G regimen. Data are insufficient regarding use of other anti-infectives (e.g., ceftriaxone) for the treatment of syphilis in infants and children hypersensitive to penicillin.

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

Yaws, Pinta, and Bejel

Penicillin G (IM penicillin G benzathine, IM penicillin G procaine) is used in the treatment of yaws (T. pallidum subsp pertenue), pinta (T. carateum), and bejel (T. pallidum subsp endemicum). A single dose of IM penicillin G benzathine has historically been the treatment of choice for these endemic treponematoses; however, a single dose of oral azithromycin has been recommended as the preferred regimen for the treatment of yaws in areas where the disease is endemic. The fixed combinations of penicillin G benzathine and penicillin G procaine should not be used for the treatment of yaws, pinta, or bejel.

Staphylococcal Infections

Although natural penicillins have been used in the treatment of upper and lower respiratory tract infections, skin and skin structure infections, bone and joint infections, septicemia, meningitis, endocarditis, or other infections caused by susceptible nonpenicillinase-producing S. aureus or S. epidermidis, natural penicillins are inactivated by staphylococcal penicillinases and are ineffective for the treatment of infections caused by penicillinase-producing S. aureus and S. epidermidis. Because penicillin susceptibility cannot be assumed, in vitro susceptibility testing is indicated if use of a natural penicillin is being considered for the treatment of a staphylococcal infection.

Streptococcal Infections

S. agalactiae Infections

IV penicillin G potassium or sodium has been used for the treatment of infections caused by S. agalactiae ^† (group B streptococci; GBS), including bacteremia, pneumonia, endocarditis, and meningitis. If penicillin G potassium or sodium is used for the treatment of serious infections caused by S. agalactiae, concomitant use of an aminoglycoside usually is recommended.

IV penicillin G potassium or sodium is used for intrapartum prophylaxis in pregnant women for prevention of perinatal GBS disease^†. (See Prevention of Perinatal Group B Streptococcal Disease under Uses.)

S. pneumoniae Infections

Natural penicillins are used for the treatment of infections caused by susceptible S. pneumoniae, including upper and lower respiratory tract infections (e.g., pneumonia, empyema, otitis media, sinusitis), arthritis, pericarditis, endocarditis, septicemia, and meningitis. Although many strains of S. pneumoniae are susceptible to natural penicillins, strains that have intermediate resistance or are completely resistant to the drugs have been reported with increasing frequency and treatment failures have been reported. Because penicillin susceptibility cannot be assumed, in vitro susceptibility testing is indicated if use of a natural penicillin is being considered for the treatment of infections caused by S. pneumoniae. (See Meningitis and other CNS Infections under Uses.)

Oral penicillin V is used for prevention of S. pneumoniae infections^† in children and adults at risk for invasive disease caused by the organism. (See Prevention of Invasive Pneumococcal Disease in Asplenic Individuals under Uses.)

Streptococcus pyogenes Infections

Natural penicillins are used for the treatment of infections caused by S. pyogenes (group A β-hemolytic streptococci; GAS) including upper and lower respiratory tract infections (e.g., pharyngitis, tonsillitis, otitis media, sinusitis), skin and skin structure infections (e.g., erysipelas, cellulitis, and pyoderma), and severe infections (e.g., bacteremia, septic or toxic scarlet fever, streptococcal toxic shock syndrome, streptococcal myositis, necrotizing fasciitis).

Because S. pyogenes has remained uniformly susceptible to natural penicillins, they are considered drugs of choice for the treatment of a variety of S. pyogenes infections, including pharyngitis and tonsillitis (see Pharyngitis and Tonsillitis under Uses), streptococcal bacteremia, septic or toxic scarlet fever, streptococcal toxic shock syndrome, cellulitis, erysipelas, necrotizing fasciitis, and streptococcal myositis. However, efficacy for the treatment of some severe infections may be compromised because of various factors (e.g., inadequate dosage, delay in treatment, penicillin tolerance, overwhelming infection, irreversible effects of streptococcal pyrogenic exotoxins) and concomitant use of other anti-infectives has been recommended when a natural penicillin is used for the treatment of serious S. pyogenes infections. Because strains of β-hemolytic streptococci resistant to natural penicillins are extremely rare and strains of S. pyogenes resistant to penicillin G and penicillin V have not been reported, routine vitro susceptibility testing is not usually required when considering a natural penicillin for the treatment of such infections.

IM penicillin G benzathine and oral penicillin V are used for secondary prophylaxis to prevent recurrence of rheumatic fever. (See Prevention of Rheumatic Fever Recurrence under Uses.)

Other Streptococcal Infections

Natural penicillins are used for the treatment of infections caused by other β-hemolytic streptococci, including groups C, F, G, H, K, L, and M streptococci. IV penicillin G potassium or sodium is labeled for use in the treatment of septicemia, empyema, pneumonia, pericarditis, endocarditis, or meningitis caused by susceptible groups C, H, G, L, and M streptococci,

IM penicillin G benzathine is labeled for use in the treatment of mild to moderate upper respiratory tract infections caused by susceptible streptococci, IM fixed combinations of penicillin G benzathine and penicillin G procaine are labeled for use in the treatment of moderately severe to severe infections of the upper respiratory tract infection and skin and skin structure infections caused by susceptible streptococci, and oral penicillin V potassium is labeled for the treatment mild to moderate infections of the upper respiratory tract caused by susceptible streptococci.

Whipple’s Disease

Penicillin G has been used in the treatment of Whipple’s disease^† caused by Tropheryma whipplei. The optimal anti-infective regimen for the treatment of Whipple’s disease has not been identified, in part because of difficulties in identifying and cultivating the causative agent and because relapses may occur, even after adequate and long-term treatment. Some clinicians recommend an initial parenteral regimen (e.g., ceftriaxone, penicillin G with or without streptomycin) followed by a long-term regimen of oral co-trimoxazole.

Prevention of Invasive Pneumococcal Disease in Asplenic Individuals

Oral penicillin V is used for prevention of invasive pneumococcal infections in children with anatomic or functional asplenia^† (e.g., congenital asplenia or polysplenia, splenectomy, sickle cell disease, thalassemia). Oral penicillin V also is used for prevention of invasive S. pneumoniae disease in certain asplenic adults^†.

Asplenic infants, children, adolescents, and adults are at increased risk of fulminant septicemia, most commonly caused by S. pneumoniae. In infants with sickle cell anemia, AAP recommends that penicillin V prophylaxis for prevention of invasive pneumococcal infections should be initiated as soon as the diagnosis is established (preferably by 2 months of age) and that discontinuance of prophylaxis can be considered at 5 years of age if the child is receiving regular medical attention, is fully immunized against pneumococcal disease, and has not had a severe pneumococcal infection or surgical splenectomy. In children with asplenia from causes other than sickle cell anemia, the appropriate duration of prophylaxis is unknown; some experts recommend that such children receive prophylaxis throughout childhood and into adulthood. In adults who have undergone splenectomy, some clinicians recommend that prophylaxis for prevention of invasive pneumococcal infections should be continued for at least 1–2 years after the procedure.

Age-appropriate vaccination against pneumococcal disease is recommended in all asplenic individuals. Regardless of vaccination status, AAP states that anti-infective prophylaxis for prevention of invasive pneumococcal disease is recommended for young children with anatomic or functional asplenia.

Prevention of Perinatal Group B Streptococcal Disease

IV penicillin G potassium or sodium is used in pregnant women during labor (intrapartum) for prevention of early-onset neonatal group B streptococcal (GBS) disease^†.

GBS infection is the leading cause of neonatal infections in the US. 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 an invasive neonatal infection that can be associated with substantial morbidity and mortality. GBS infection during pregnancy can cause asymptomatic bacteriuria, urinary tract infection, intra-amniotic infection, or endometritis in the woman and is associated with stillbirths and premature delivery. Neonatal GBS infections are characterized as early-onset GBS disease (usually occurring within the first 24 hours after birth through day 6) or late-onset GBS disease (occurring between 7–90 days of age). GBS disease in neonates usually presents as respiratory distress, apnea, shock, or pneumonia and may involve septicemia or meningitis; other manifestations such as osteomyelitis, septic arthritis, necrotizing fasciitis, adenitis, and cellulitis also can occur. Approximately 20% of survivors of neonatal GBS meningitis have moderate to severe neurodevelopmental impairment.

Major risk factors for early-onset neonatal GBS disease include maternal GBS colonization in the genitourinary and GI tracts, early membrane rupture (18 hours or more before delivery), intra-amniotic infection, premature delivery (before 37 weeks’ gestation), very low birth weight, intrapartum fever (38°C or higher), and previous delivery of an infant who had GBS disease. The most effective strategy for prevention of early-onset neonatal GBS disease is universal prenatal screening for GBS colonization (e.g., vaginal and rectal cultures) and use of intrapartum anti-infective prophylaxis (i.e., prophylaxis administered after onset of labor or membrane rupture but before delivery) in those with positive results. Following implementation of guidelines for targeted GBS intrapartum anti-infective prophylaxis in the US, the incidence of early-onset GBS disease was reduced by more than 80% (1.8 neonates with early-onset GBS disease per 1000 live births in the 1990s to 0.23 neonates per 1000 live births in 2015). Such prophylaxis has no measurable effect on the incidence of late-onset GBS disease.

The American College of Obstetricians and Gynecologists (ACOG), AAP, and other experts recommend routine universal prenatal screening for GBS colonization (e.g., vaginal and rectal cultures) in all pregnant women at 36 through 37 weeks of gestation (i.e., performed within the time period of 36 weeks 0 days to 37 weeks 6 days of gestation), unless intrapartum anti-infective prophylaxis is already planned because the woman had known GBS bacteriuria during any trimester of the current pregnancy or has a history of a previous infant with GBS disease. Anti-infective prophylaxis for prevention of early-onset perinatal GBS is indicated in all women identified as having positive GBS cultures during the routine prenatal GBS screening during the current pregnancy, unless a cesarean delivery is performed before the onset of labor in the setting of intact membranes. Intrapartum anti-infective prophylaxis also is indicated in women with unknown GBS status at the time of onset of labor (cultures not performed or results unknown) who have risk factors for perinatal GBS infection (e.g., preterm birth at less than 37 weeks’ gestation, duration of membrane rupture 18 hours or longer, intrapartum fever 38°C or higher). If a women presents in labor at term with unknown GBS status but has a history of GBS colonization during a previous pregnancy, these experts state that the risk for early-onset GBS disease in the infant is increased and it is reasonable to offer intrapartum anti-infective prophylaxis based on the history of GBS colonization.

When intrapartum anti-infective prophylaxis is indicated in the mother for prevention of early-onset GBS disease in the neonate, ACOG, AAP, and other experts recommend IV penicillin G (loading dose of 5 million units followed by 2.5–3 million units every 4 hours until delivery) as the regimen of choice. IV ampicillin (loading dose of 2 g followed by 1 g every 4 hours until delivery) is the preferred alternative for such prophylaxis when penicillin G is not available. Penicillin G is considered the drug of choice since it has a narrower spectrum of activity than ampicillin and is less likely to induce resistance in other vaginal organisms.

If intrapartum prophylaxis is indicated in a penicillin-allergic woman at low risk for anaphylaxis or severe non-IgE-mediated reactions if a penicillin is used (e.g., history of nonspecific symptoms unlikely to be allergic [GI distress, headaches, vaginal candidiasis]; non-urticarial maculopapular [morbilliform] rash without systemic symptoms; pruritus without rash; family history but no personal history of penicillin allergy; patient reports history of penicillin allergy but has no recollection of symptoms or treatment), ACOG, AAP, and others recommend IV cefazolin (loading dose of 2 g followed by 1 g every 8 hours until delivery). If intrapartum prophylaxis is indicated in a penicillin-allergic woman at high risk for anaphylaxis or severe non-IgE-mediated reactions if a penicillin is used (e.g., history suggestive of an IgE-mediated event such as pruritic rash, urticaria, immediate flushing, hypotension, angioedema, respiratory distress, or anaphylaxis; recurrent reactions to penicillin, reactions to multiple β-lactam anti-infectives, or positive penicillin allergy test; severe delayed-onset cutaneous or systemic reactions such as eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome, Stevens-Johnson syndrome, or toxic epidermal necrolysis), these experts recommend IV clindamycin (900 mg IV every 8 hours until delivery) if the GBS isolate is tested and found to be susceptible to the drug. If the GBS isolate is resistant to clindamycin, IV vancomycin (20 mg/kg [up to 2 g] every 8 hours until delivery) is the recommended alternative in such women.

Routine use of anti-infective prophylaxis (e.g., penicillin G, ampicillin) in neonates born to women who received adequate GBS intrapartum prophylaxis is not recommended. Regardless of whether intrapartum GBS prophylaxis was administered to the mother, appropriate diagnostic evaluations and anti-infective treatment should be initiated in the neonate if signs or symptoms of active infection develop. Ampicillin in conjunction with an aminoglycoside is the initial regimen of choice for empiric treatment of presumptive neonatal sepsis, including presumptive GBS infection, since it is likely to be active against GBS and other possible causative agents (e.g., other streptococci, enterococci, L. monocytogenes, Escherichia coli).

For additional information regarding the prevention of neonatal early-onset GBS disease, the current ACOG guidelines available at [Web] should be consulted.

Prevention of Rheumatic Fever Recurrence

Natural penicillins (IM penicillin G benzathine, oral penicillin V potassium) are used for prevention of recurrent attacks of rheumatic fever (secondary prophylaxis) in individuals who have had a previous attack of rheumatic fever.

Individuals who have had a previous attack of rheumatic fever are at high risk for a recurrent attack of rheumatic fever if they develop asymptomatic or symptomatic S. pyogenes pharyngitis. A recurrent attack can be associated with worsening severity of rheumatic heart disease that developed after the first attack or, less frequently, may be associated with new-onset rheumatic heart disease in those who did not develop cardiac manifestations during the first attack. Secondary anti-infective prophylaxis to prevent recurrent episodes of S. pyogenes pharyngitis is the most effective method to prevent development of severe rheumatic heart disease.

AHA and AAP recommend secondary anti-infective prophylaxis of rheumatic fever in all patients who have a well-documented history of rheumatic fever (even if manifested solely by Sydenham’s chorea) and in those with definite evidence of rheumatic heart disease (even after prosthetic valve replacement). Such prophylaxis should be initiated as soon as the diagnosis of rheumatic fever or rheumatic heart disease is made, although patients with acute rheumatic fever should first receive the usually recommended anti-infective treatment for S. pyogenes pharyngitis and tonsillitis (see Pharyngitis and Tonsillitis under Uses).

In general, prevention of recurrent rheumatic fever requires long-term, continuous anti-infective prophylaxis. Some clinicians recommend that secondary prophylaxis be continued indefinitely; however, the risk of rheumatic fever recurrence depends on several factors. The risk increases with multiple previous attacks and decreases with increasing age and as the interval since the most recent attack increases. Patients who have had rheumatic carditis, with or without valvular disease, are at relatively high risk for recurrences of carditis and are likely to sustain increasingly severe cardiac involvement with each recurrence. Patients who have never developed rheumatic carditis are at lower risk of cardiac involvement if they have a recurrence of rheumatic fever. Therefore, decisions to discontinue secondary anti-infective prophylaxis for prevention of recurrent attacks of rheumatic fever must be weighed carefully, taking into account epidemiologic risk factors such as the patient’s risk of exposure to streptococcal infections (e.g., those at high risk of exposure include children and adolescents, parents of young children, teachers, health-care personnel, military recruits, others living in crowded conditions, economically disadvantaged populations) and the consequences of recurrence. The clinician and patient should discuss the potential risks and benefits whenever discontinuance of such prophylaxis is being considered.

AHA and AAP recommend that secondary anti-infective prophylaxis in patients who have had rheumatic fever without carditis should be continued for 5 years since the last episode of rheumatic fever or until 21 years of age, whichever is longer. In those who have had rheumatic fever with carditis but have no residual heart disease (no valvular disease), secondary prophylaxis should be continued for 10 years since the last episode or until 21 years of age, whichever is longer. In those who have had rheumatic fever with carditis and have residual heart disease (persistent valvular disease), AHA and AAP recommend that secondary prophylaxis should be continued for 10 years since the last episode or until 40 years of age, whichever is longer, but life-long prophylaxis may be indicated in some high-risk patients.

IM penicillin G benzathine (given once every 3–4 weeks) is considered the drug of choice for secondary prophylaxis of recurrent rheumatic fever. A 4-week regimen is recommended by AHA and AAP for most patients in the US at risk of rheumatic fever recurrences, but a 3-week dosing interval may be warranted and is recommended when there is a particularly high risk of rheumatic fever (e.g., recurrent acute rheumatic fever despite adherence to a 4-week regimen). There is some evidence that serum penicillin concentrations may decline to subtherapeutic concentrations before the fourth week in some patients and there is limited evidence of an increased frequency of prophylactic failure with a 4-week interval compared with a 3-week interval in areas with a high risk of rheumatic fever.

If patient compliance is not a problem, an oral regimen of penicillin V or sulfadiazine can be used as an alternative for secondary prophylaxis of rheumatic fever recurrence. However, because the risk of recurrence appears to be higher with oral prophylaxis than with IM penicillin G benzathine (even with optimal patient adherence), oral anti-infectives are most appropriate in patients at lower risk for rheumatic fever recurrence. Some clinicians use IM penicillin G benzathine initially and change to oral prophylaxis (usually with oral penicillin V) when the patient reaches late adolescence or young adulthood and has remained free of rheumatic attacks for at least 5 years. A regimen of oral sulfadiazine is recommended in patients with penicillin hypersensitivity; however, a macrolide (azithromycin, clarithromycin, erythromycin) should be used in patients allergic to penicillins and sulfonamides.

Natural Penicillins General Statement Dosage and Administration

Administration

Penicillin V potassium is administered orally. Although the manufacturers state that penicillin V potassium may be given with meals, maximum oral absorption is achieved when the drug is administered at least 1 hour before or 2 hours after meals. Oral penicillin V potassium should not be used for initial treatment of severe infections and should not be relied on in patients with nausea, vomiting, gastric dilatation, esophageal achalasia, or intestinal hypermotility.

Penicillin G benzathine, penicillin G procaine, and fixed combinations containing penicillin G benzathine and penicillin G procaine are administered only by deep IM injection and should not be administered IV. Special precaution must be taken with these preparations to avoid inadvertent intravascular or intra-arterial administration or injection into or near major peripheral nerves or blood vessels since such injections may result in severe and/or permanent neurovascular damage. IM injections of these long-acting, depot, or repository forms of penicillin G should be made at a slow, steady rate to prevent blockage of the needle.

Penicillin G potassium and penicillin G sodium are administered by IM injection, intermittent IV injection or infusion, or continuous IV infusion. Large IV doses of penicillin G potassium or sodium (more than 10 million penicillin G units) should be administered slowly because of the potential for serious electrolyte disturbances from the potassium and/or sodium content of these preparations.

Dosage

For specific information on dosage of the natural penicillins, see the individual monographs in 8::12.16.04.

Cautions for Natural Penicillins General Statement

Hypersensitivity Reactions

Hypersensitivity reactions, including serious and occasionally fatal reactions, have been reported in patients receiving penicillins and may range in severity from mild rash to anaphylaxis. Although the most serious hypersensitivity reactions tend to occur following parenteral administration of penicillins, anaphylaxis has occurred following oral administration of the drugs.

Manifestations of Penicillin Hypersensitivity

Hypersensitivity reactions to penicillins can be divided into 4 different types. Type I reactions are mediated by IgE and usually are immediate reactions (occurring within 1 hour or up to 6 hours after administration of the penicillin), but may be accelerated reactions (occurring 2–72 hours after administration of the drug); these reactions can be life-threatening and include anaphylaxis, angioedema, bronchospasm, laryngospasm, urticaria, and pruritus. Type II reactions are cytotoxic reactions that may be mediated by IgM or IgG antibodies and usually are delayed reactions occurring 5–72 hours or longer after administration of a penicillin; cytotoxic reactions include adverse hematologic effects such as hemolytic anemia, agranulocytosis, leukopenia, neutropenia, and thrombocytopenia. Type III reactions involve the formation of immune complexes consisting of the penicillin or derivatives and IgG or IgM antibodies and usually are delayed reactions occurring 24 hours or longer after administration of a penicillin; these reactions include serum sickness-like reactions, allergic vasculitis, and Arthus phenomenon. Type IV reactions are mediated by T cells and are delayed or late reactions that usually occur 48 hours or longer after administration of a penicillin; these reactions generally include dermatologic reactions ranging from less severe, benign skin reactions to severe cutaneous adverse reactions (SCAR).

Dermatologic reactions are some of the most common hypersensitivity reactions to penicillins. Urticarial, erythematous, or morbilliform (maculopapular or exanthematic) rash and pruritus occur most frequently. However, severe dermatologic reactions, including erythema nodosum, erythema multiforme, fixed drug eruptions, Stevens-Johnson syndrome, exfoliative dermatitis, acute generalized exanthematous pustulosis, toxic epidermal necrolysis, or drug reactions with eosinophilia and systemic symptoms (DRESS) have been reported rarely. Contact dermatitis can occur as a result of occupational exposure in individuals involved in the manufacture of penicillins and in pharmacists, nurses, or other health-care personnel involved in preparing penicillins for administration. Rash has been reported more frequently with ampicillin and amoxicillin than with other currently available penicillins; however, most cases of rash reported with these aminopenicillins appear to be nonimmunologic.

Serum sickness-like reactions has been reported to occur in about 2% of patients receiving penicillin G. The serum sickness-like reaction is characterized by fever, malaise, urticarial rash, arthralgia, myalgia, and lymphadenopathy; angioedema also occurs occasionally and erythema nodosum occurs rarely. The serum sickness-like reaction may occur within days to weeks (may be evident 6–10 days) after initiation of penicillin therapy. In most cases, the reaction is mild and resolves within a few days or weeks following discontinuance of the penicillin; however, the reaction can be severe.

The most serious hypersensitivity reaction to penicillins is anaphylaxis. Anaphylaxis has been reported to occur in up to 0.05% of patients receiving penicillin G, and has been estimated to be fatal in up to 5–10% of reported cases. Although anaphylaxis has been reported most frequently with parenteral penicillin G, such reactions have been reported rarely after oral administration of penicillin G (no longer commercially available in the US) or oral penicillin V. Anaphylactic reactions to penicillins can occur within minutes (usually within the first 30 minutes) after administration and are manifested by nausea, vomiting, abdominal pain, pallor, tachycardia, generalized pruritus, angioneurotic edema (which may affect the larynx), severe dyspnea (caused by bronchospasms), cyanosis, diaphoresis, dizziness, rigors, loss of consciousness, and peripheral circulatory failure (caused by vasodilation and loss of plasma volume).

Mechanisms of Penicillin Hypersensitivity

Sensitization to penicillins usually results from previous exposure to one of the drugs or its degradation products. However, immediate hypersensitivity reactions have been reported in some patients the first time they received a penicillin. In these cases, prior exposure to the drugs may have been the result of normal environmental sources of penicillium molds or penicillin, trace amounts present in milk or foods derived from penicillin-treated animals, prior penicillin allergy testing, or occupational exposures.

Penicillin itself does not appear to be highly immunogenic since it does not readily combine with protein to produce an antigen; however, many penicillin metabolites or degradation products are haptens and can form antigenic complexes with proteins and polypeptides. These antigenic degradation products of penicillin include penicilloyl, penicilloic acid, and penicillin polymer conjugation products. In addition, high molecular weight protein impurities that also can act as haptens may be present in some penicillin preparations (especially less purified preparations previously available). Most penicillins, including penicillin G, become more allergenic after a period of time in solution. This occurs because antigenic degradation products and polymer conjugation products form during in vitro storage, especially when penicillin G solutions are exposed to high temperatures or are stored in high concentrations at room temperature. (See Stability under Chemistry and Stability.)

The antigenic determinants of penicillin hypersensitivity have been classified as major and minor determinants, depending on how frequently they are involved in hypersensitivity reactions to the drugs rather than on how severe the reactions are. The major determinant (which is responsible for the greatest number of penicillin hypersensitivity reactions) is the penicilloyl derivative that is formed when the β-lactam ring is opened as the result of metabolism or degradation and allows amide linkage to body proteins. The minor determinants include the intact penicillin molecule, penicilloic acid, and other penicillin degradation products. The major determinant elicits IgE antibodies which mediate type I immediate and accelerated reactions such as anaphylaxis and some maculopapular and erythematous hypersensitivity reactions. Minor determinants also can elicit IgE antibodies.

Patients at Risk for Penicillin Hypersensitivity Reactions

Prior to initiation of penicillin therapy, the patient should be questioned in detail regarding a previous history of hypersensitivity reactions to penicillins, cephalosporins, or other drugs. There is clinical and laboratory evidence of partial cross-allergenicity among β-lactam antibiotics, including penicillins, cephalosporins, and cephamycins.

Individuals with a history of immediate hypersensitivity reaction (e.g., anaphylaxis) to a penicillin are at increased risk for developing a severe reaction if they receive one of the drugs. It generally has been recommended that a patient who has had a hypersensitivity reaction to one penicillin should be considered hypersensitive to all currently available penicillins, unless specific allergy testing is performed. However, cross-allergenicity among the penicillins (e.g., between natural penicillins and aminopenicillins) is not absolute and some patients who have had a reaction to one penicillin have subsequently tolerated a different penicillin.

The true incidence of cross-allergenicity between penicillins and other β-lactam antibiotics has not been definitely established. In several studies when a cephalosporin was administered to patients with a history of penicillin hypersensitivity, 4.4–10% of these patients also had hypersensitivity reactions to the cephalosporin. Cross-allergenicity is more likely with cephalosporins that share an R1 side chain with penicillins (e.g., cephalexin, cephalothin [no longer available in the US], cefadroxil) and less likely with second and third generation cephalosporins that do not share this side chain (e.g., cefazolin, cefuroxime, ceftazidime, ceftriaxone). Although some cephalosporins that do not share side chains with penicillins (e.g., cefazolin, ceftriaxone) have been administered safely to individuals with a history of penicillin allergy, specific allergy testing may be indicated if use of a cephalosporin is being considered in an individual with penicillin allergy and vice versa. The risk of cross-allergenicity between penicillins and carbapenems (e.g., imipenem) is low and the risk of cross-allergenicity between penicillins and monobactams (e.g., aztreonam) is even lower.

Appropriate assessment of patients with a history of penicillin allergy is important to guide decisions regarding continued or future use of penicillins, especially when one of the drugs is indicated for the treatment or prevention of an infection when there are no adequate alternatives or when possible alternatives are associated with an increased risk of adverse effects or have a spectrum of activity broader than that required for treatment of the causative organism and would increase the risk of inducing bacterial resistance. It has been estimated that about 10% of US patients report having had an allergic reaction to a penicillin in the past. However, many of these patients may actually have had a nonimmune-mediated adverse reaction. In addition, although penicillin allergy persists in some individuals, possibly for life, it wanes over time in a high percentage of patients.

Comprehensive initial screening that may include a review of medical records and/or a patient interview is important to identify details about reported prior allergic reactions to penicillins (e.g., specific drug involved, manifestations, time to onset and symptom resolution, other indicators of non-IgE- versus IgE-mediated reactions, treatment received to manage the reaction, documentation of the reaction in a medical record, time elapsed since the reported reaction, history of treatment with other anti-infectives, history of skin testing and other drug allergy testing) that could be used for risk stratification and to make informed decisions regarding the need for penicillin allergy testing. A variety of screening algorithms have been suggested that could be useful in certain situations to designate patients as being at high, moderate, or low risk for experiencing a severe reaction (e.g, anaphylaxis) or a reaction that is more severe than the initially reported reaction if they receive a penicillin and/or to identify those who should receive penicillin allergy testing. Specialized references should be consulted for more specific information regarding such algorithms.

Penicillin Allergy Testing and Penicillin Desensitization

Administration of penicillins to patients with a history of IgE-mediated penicillin hypersensitivity reactions can result in severe, immediate reactions. However, many individuals with a reported history of penicillin allergy are likely to have had other types of adverse drug reactions that were not hypersensitivity reactions or their penicillin sensitivity has waned over time. Because a reported history of penicillin hypersensitivity may not accurately differentiate between allergic and non-allergic reactions to penicillins or accurately predict the risk of a future hypersensitivity reaction, diagnostic tests may be indicated. Use of appropriate screening and penicillin allergy testing to confirm or refute a history of penicillin allergy can optimize selection of anti-infectives in patients who may have been misdiagnosed or mislabeled as penicillin allergic and supports the goals of antimicrobial stewardship.

For patients who report a history of penicillin allergy, appropriate sensitivity testing (e.g., skin testing, patch testing, drug provocation or challenge, in vitro immunoassays) may be indicated to confirm penicillin hypersensitivity and assess the risk of a subsequent hypersensitivity reaction if the individual receives a penicillin. For safety reasons, certain patients with a history of penicillin hypersensitivity who are considered high risk may not be appropriate candidates for penicillin allergy testing or specific types of allergy tests. Some experts recommend that penicillins be avoided in individuals with a history of severe hypersensitivity reactions to the drugs (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, acute interstitial nephritis, hemolytic anemia, drug reaction with eosinophilia and systemic symptoms [DRESS]) and state that such individuals are not candidates for allergy testing.

The proportion of patients with a history of penicillin hypersensitivity who continue to produce IgE antipenicillin antibodies decreases as the time after the patient’s last exposure to penicillin increases. Therefore, penicillin allergy tests may be negative in some patients with a history of hypersensitivity to penicillins, especially if the reported reaction occurred decades ago. In several studies when skin tests with benzylpenicilloyl polylysine were administered to patients with a history of hypersensitivity reactions to penicillins, 67–93% of these patients had positive reactions to benzylpenicilloyl polylysine when the tests were given within 1 year after the reaction, 50–60% had positive reactions to the skin tests when the tests were given 1–10 years after a reaction, and only 20–25% had positive reactions when the tests were given 10 years or more after the reaction. However, negative test results for penicillin allergy do not completely ensure that a hypersensitivity reaction to penicillin will not occur. Although skin tests may detect the presence of IgE antipenicillin antibodies directed against the skin test antigens and are useful to predict future occurrence of most type I IgE-mediated hypersensitivity reactions, additional testing (e.g., drug challenge) may be recommended in some individuals with negative skin test results to further assess the risk of an IgE-mediated hypersensitivity reaction.

Desensitization to penicillins has been used and is recommended to enable a penicillin to be administered to certain patients who are hypersensitive to the drugs and have life-threatening infections for which other effective anti-infectives are not available (e.g., endocarditis, neurosyphilis, congenital syphilis). In general, desensitization is performed by administering increasing doses of a penicillin preparation at relatively short intervals and is based on the premise that small, incremental doses of the penicillin will allow gradual binding of penicillin to IgE antibodies which should result in a gradual, rather than massive, release of histamine and other mediators of hypersensitivity reactions and result in short-term suppression of antigen-specific mast-cell responses. However, desensitization can be hazardous since it may cause anaphylaxis and is rarely justified when other anti-infectives are available that can be used in patients who are hypersensitive to penicillins. If desensitization to a penicillin is deemed necessary, the procedure usually is performed in a hospital setting; the patient should be monitored continuously during the procedure and all necessary emergency equipment should be readily available to treat a hypersensitivity reaction should it occur. The results of desensitization procedures that allow administration of a penicillin are only temporary. It has been recommended that desensitization procedures need to be repeated if additional therapeutic doses of a penicillin are indicated and the time elapsed since the last dose is longer than 4 half-lives of the drug.

Specialized references should be consulted for specific information on penicillin allergy evaluation and testing, including protocols for various test types and timing and interpretation of the tests, and for specific information on desensitization procedures.

Hematologic Effects

Adverse hematologic effects reported rarely in patients receiving penicillin G or penicillin V include transient neutropenia, leukopenia, and thrombocytopenia. These adverse hematologic effects occur most frequently when high doses of penicillin G are administered IV and generally are reversible following discontinuance of the drugs. Eosinophilia and hemolytic anemia also have been reported. Although most adverse hematologic effects reported in patients receiving a penicillin are considered to be hypersensitivity reactions, penicillin G appeared to have a direct toxic effect on granulocyte maturation in some reported cases. Pancytopenia, presumably resulting from impaired release of mature cells from the bone marrow, has been reported rarely with high doses of IV penicillin G.

Positive direct antiglobulin (Coombs’) test results have been reported in patients receiving high doses of penicillin G; this reaction usually results from the presence of antipenicillin antibodies which bind to penicillin-coated erythrocytes. A small percentage of patients with positive direct antiglobulin test results develop hemolytic anemia during or following penicillin therapy. Hemolytic anemia has been reported most frequently with large doses of IV penicillin G; however, this adverse effect has occurred with usual doses of penicillin G and has also been reported rarely with usual doses of oral penicillin V. Following discontinuance of penicillin therapy, hemoglobin concentrations and reticulocyte counts return to pretreatment values, but hemolysis may persist for weeks and the direct antiglobulin test may not revert to negative for 1–3 months or longer since penicillin-coated erythrocytes and specific antibodies remain in the circulation for this period of time.

Coagulation disorders have been reported rarely with high doses of IV penicillin G (e.g., 6 million units or more in uremic patients or 24 million units or more in individuals with normal renal function). In some patients, the coagulation disorder was characterized by prolonged bleeding time, abnormal platelet aggregation, an increase in antithrombin III activity, and interference with conversion of fibrinogen to fibrin.

GI Effects

Some of the most frequent adverse reactions to oral penicillin V are GI effects, including nausea, vomiting, epigastric distress, and diarrhea. Black hairy tongue also has been reported.

Clostridioides difficile-associated Diarrhea and Colitis

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridioides difficile (formerly known as Clostridium difficile).

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 in patients receiving nearly all anti-infectives, including penicillin G and penicillin V, and may range in severity from mild diarrhea to fatal colitis. C. difficile produces toxins A and B which contribute to development of CDAD; 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. (See Clostridioides difficile-associated Diarrhea and Colitis under Cautions.)

Renal and Metabolic Effects

Renal tubular damage and interstitial nephritis have been reported in patients receiving high doses of IV penicillin G. Manifestations may include fever, rash, eosinophilia, proteinuria, eosinophiluria, hematuria, and increased BUN concentrations, and usually resolve following discontinuance of penicillin G therapy.

Because of their potassium and sodium content, penicillin G potassium and penicillin G sodium preparations can cause serious and potentially fatal electrolyte disturbances. High doses of penicillin G sodium may result in congestive heart failure.

Nervous System and Neurovascular Effects

Neurotoxic reactions, including hyperreflexia, myoclonic twitches, seizures, and coma, have been reported following administration of massive doses of IV penicillin G potassium or penicillin G sodium, especially in patients with impaired renal function.

Repeated IM injection of penicillin G preparations into the anterolateral thigh has resulted in quadriceps femoris fibrosis and atrophy.

Inadvertent intravascular administration of penicillin G benzathine and/or penicillin G procaine, including inadvertent direct intra-arterial injection or injection immediately adjacent to an artery, has resulted in severe neurovascular damage, especially in neonates and children. Transverse myelitis with permanent paralysis, gangrene requiring amputation of digits and more proximal portions of extremities, and necrosis and sloughing at and surrounding the injection site have occurred following inadvertent injection of penicillin G benzathine and/or penicillin G procaine, including in the buttock, thigh, and deltoid areas. Other serious complications of suspected intravascular administration of penicillin G benzathine and/or penicillin G procaine include immediate pallor, mottling, or cyanosis of the extremity both distal and proximal to the injection site, followed by bleb formation, or severe edema requiring anterior and/or posterior compartment fasciotomy in the lower extremity.

Local Effects

Pain, phlebitis, and thrombophlebitis have been reported following IV administration of penicillin G.

Pain, inflammation, lump, abscess, necrosis, edema, hemorrhage, cellulitis, atrophy, ecchymosis, and skin ulcer have been reported at IM injection sites of penicillin G benzathine or fixed combinations of penicillin G benzathine and penicillin G procaine.

Jarisch-Herxheimer Reaction

A Jarisch-Herxheimer reaction may occur when penicillin G is used for the treatment of syphilis. The reaction reportedly occurs in 50% of patients treated for primary syphilis, 75% of those treated for secondary syphilis, and 30% of those treated for neurosyphilis. Jarisch-Herxheimer reactions may also occur when penicillin G is used to treat other spirochetal infections (e.g., yaws, leptospirosis^†, Lyme disease^†, relapsing fever^†) or certain bacterial infections (anthrax, brucellosis, tularemia, rat-bite fever).

Jarisch-Herxheimer reactions usually begin 1–2 hours after initiation of penicillin G therapy (within the first 24 hours after initiation for treatment of syphilis) and consist of headache, fever, chills, sweating, sore throat, myalgia, malaise, tachycardia, hyperventilation, and vasodilation with flushing and mild hypotension. The reaction has been presumed to be caused by the release of pyrogen and/or endotoxins from phagocytized organisms and may be mediated by cytokines.

Although some clinicians have suggested that concomitant administration of corticosteroids may reduce the incidence and severity of the Jarisch-Herxheimer reaction, other clinicians state that the use of corticosteroids has a minimal effect and should be considered only in patients in whom there is a serious risk of increased local damage resulting from exacerbation of existing lesions (e.g., patients with syphilitic optic atrophy).

Antipyretics can be used to manage symptoms of the Jarisch-Herxheimer reaction, but have not been proven to prevent the reaction.

Precautions and Contraindications

Penicillin G and penicillin V are contraindicated in patients with a history of previous hypersensitivity to any penicillin.

Penicillin G procaine and the fixed combinations of penicillin G benzathine and penicillin G procaine also are contraindicated in patients with a history of hypersensitivity to procaine.

The commercially available frozen premixed penicillin G potassium injection in dextrose may be contraindicated in patients with known allergy to corn or corn products.

Precautions Related to Hypersensitivity

Prior to initiation of penicillin therapy, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other drugs. The manufacturers state that serious hypersensitivity reactions to penicillins are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. The manufacturers also state that penicillins should be used with caution in patients with a history of clinically important allergies or asthma.

If a hypersensitivity reaction occurs, penicillin G or penicillin V should be discontinued and appropriate therapy initiated as indicated (e.g., epinephrine, corticosteroids, antihistamines, bronchodilators, maintenance of an adequate airway and oxygen).

To enable informed decisions regarding continued or future use of penicillins in patients who have had a hypersensitivity reaction or report a history of penicillin allergy, appropriate screening and penicillin allergy testing may be indicated. (See Hypersensitivity Reactions under Cautions.)

Procaine Sensitivity

A small percentage of the population is hypersensitive to procaine, and the manufacturers recommend that patients with a history of procaine sensitivity should receive a test dose of procaine prior to administration of penicillin G procaine.

Administration Precautions

Special precaution should be taken to avoid IV, intravascular, or intra-arterial administration or injection of penicillin G benzathine and/or penicillin G procaine into or near major peripheral nerves or blood vessels since such injections may produce severe and/or permanent neurovascular damage. Prompt consultation with an appropriate specialist is indicated if any evidence of compromise of the blood supply occurs at, proximal to, or distal to the site of injection. (See Nervous System and Neurovascular Effects under Cautions.)

Large IV doses of penicillin G potassium or sodium should be administered slowly because of the potential for serious electrolyte disturbances. (See Renal and Metabolic Effects under Cautions.)

Laboratory Monitoring

Renal, hepatic, and hematologic systems should be evaluated periodically during prolonged therapy with penicillin G, particularly if high dosage is used. In addition, electrolyte balance and cardiovascular status should be evaluated periodically during prolonged therapy with high dosage of IV penicillin G potassium or sodium.

Superinfection/C. difficile-associated Diarrhea and Colitis

As with other anti-infectives, prolonged use of penicillin G or penicillin V may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be instituted.

Because CDAD has been reported with the use of nearly all anti-infectives, including natural penicillins, it should be considered in the differential diagnosis in patients who develop diarrhea during or after penicillin G or penicillin V therapy. 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.

If CDAD is suspected or confirmed, anti-infective therapy not directed against C. difficile should be discontinued as soon as possible. Patients should be managed with appropriate anti-infective therapy directed against C. difficile (e.g., fidaxomicin, vancomycin, metronidazole), supportive therapy (e.g., fluid and electrolyte management, protein supplementation), and surgical evaluation as clinically indicated.

Patients should be advised that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued; however, it is important to 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.

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of natural penicillins and other antibacterials, penicillin G and penicillin V should be used only for the treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria. Prescribing penicillin G or penicillin V in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of development of drug-resistant bacteria.

Patients should be advised that antibacterials (including penicillin G and penicillin V) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold). 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 natural penicillins or other antibacterials in the future.

When selecting or modifying anti-infective therapy, results of culture and in vitro susceptibility testing should be used. In the absence of such data, local epidemiology and susceptibility patterns should be considered when selecting anti-infectives for empiric therapy.

Because penicillin susceptibility can no longer be assumed, staphylococcal and S. pneumoniae isolates should routinely be tested for in vitro susceptibility.

Information on test methods and quality control standards for in vitro susceptibility testing of antibacterial agents and specific interpretive criteria for such testing recognized by FDA is available at [Web]. For most antibacterial agents, including natural penicillins, FDA recognizes the standards published by the Clinical and Laboratory Standards Institute (CLSI). (See In Vitro Susceptibility Testing under Spectrum.)

Mutagenicity and Carcinogenicity

Long-term animal studies have not been performed to evaluate the mutagenic or carcinogenic potential of penicillin G.

Pregnancy and Lactation

Pregnancy

Although available data regarding use of penicillin G or penicillin V in pregnant women, including first-trimester exposures, have not shown evidence of adverse effects on the fetus, there are no adequate or controlled studies using natural penicillins in pregnant women.

Reproduction studies evaluating penicillin G in mice, rats, and rabbits have not revealed evidence of impaired fertility or harm to the fetus.

The manufacturers state that penicillin G should be used during pregnancy only when clearly needed. Some clinicians state that penicillin G and penicillin V are considered low risk and safe for use during pregnancy.

Penicillin G is included in CDC recommendations for the treatment of syphilis in pregnant women and penicillin G and penicillin V are included in CDC recommendations for the treatment or prophylaxis of anthrax in pregnant women. In addition, penicillin G is included in ACOG recommendations for intrapartum anti-infective prophylaxis in pregnant women for prevention of early-onset neonatal GBS disease.

Fertility

Data are not available regarding the effect of penicillin G on fertility.

Lactation

Penicillin G and penicillin V are distributed into human milk.

The manufacturers state that penicillin G should be used with caution in nursing women.

Some clinicians state that penicillin G and penicillin V usually are considered compatible with breast-feeding; others state that the drugs should be used with caution in nursing women.

Drug Interactions

Although drug interactions reported with natural penicillins have generally involved penicillin G, the possibility that some of these interactions could occur with penicillin V should be considered. In addition, the possibility that drug interactions reported with other penicillins could also occur with natural penicillins should be considered.

Drug Eliminated by Renal Secretion

Concomitant use of drugs that compete with penicillin G for renal tubular secretion (e.g., aspirin, indomethacin, phenylbutazone, probenecid, sulfonamides, thiazide diuretics, furosemide, ethacrynic acid) may prolong the serum half-life of penicillin G. (See Probenecid under Drug Interactions.)

Aminoglycosides

The antibacterial activity of aminoglycosides and penicillins may be additive or synergistic in vitro against some organisms. Although the exact mechanism of this synergistic effect has not been determined, it appears that, by inhibiting bacterial cell wall synthesis, the penicillin allows more effective ingress of the aminoglycoside to the ribosomal binding site.

In vitro and animal studies indicate that a synergistic bactericidal effect can occur against some strains of enterococci when penicillin G is used in conjunction with amikacin, gentamicin, streptomycin, or tobramycin. The synergistic effect between penicillin G and aminoglycosides is used to therapeutic advantage in the treatment of endocarditis or other severe infections caused by enterococci. In vitro synergism between penicillins and aminoglycosides against enterococci does not generally occur if the strain is resistant to the aminoglycoside. Strains of enterococci resistant to streptomycin have been reported with increasing frequency, but strains of the organism resistant to gentamicin have been reported less frequently. The combination of penicillin G and streptomycin has been synergistic in vitro against 20–60% of clinical isolates of enterococci, but the combination of penicillin G and gentamicin is reportedly synergistic in vitro against most clinical isolates of the organism.

A synergistic bactericidal effect also generally occurs in vitro against viridans streptococci when penicillin G is used in conjunction with gentamicin or streptomycin and against group G streptococci when the drug is used in conjunction with gentamicin.

Bacteriostatic Anti-infectives

Bacteriostatic anti-infectives (chloramphenicol, erythromycin, sulfonamides, tetracyclines) have been reported to antagonize the bactericidal activity of penicillins in vitro, and some manufacturers recommend that such antibacterials should not be used concomitantly with penicillins. However, in vitro additive or synergistic effects between penicillins and bacteriostatic anti-infectives against some organisms have been demonstrated and in vivo antagonism has not been convincingly documented clinically.

Methotrexate

Concomitant use of methotrexate and penicillins may reduce the renal clearance of methotrexate, resulting in increased serum concentrations of methotrexate and increased hematologic and GI toxicity. Patients should be carefully monitored if methotrexate and penicillins are used concomitantly.

Colestipol

Concomitant administration of colestipol and oral penicillin G (no longer commercially available in the US) resulted in decreased serum concentrations of penicillin G. This may occur since colestipol is an anion-exchange resin and is capable of binding certain drugs and inhibiting their GI absorption. The manufacturer of colestipol recommends that other drugs be administered at least 1 hour before or 4 hours after colestipol.

Probenecid

Oral probenecid administered shortly before or simultaneously with a penicillin generally produces higher and prolonged serum concentrations of the penicillin. This effect occurs mainly because probenecid competitively inhibits renal tubular secretion of penicillins. Concomitant administration of oral probenecid also reportedly increases CSF concentrations of penicillin G by interfering with the active transport mechanism centered in the choroid plexus that transports drugs out of CSF.

The effect of oral probenecid on the pharmacokinetics of IM penicillin G procaine is used to therapeutic advantage when penicillin G procaine is used for the treatment of neurosyphilis.

Proton-pump Inhibitors

Concomitant use of a proton-pump inhibitor and an oral penicillin may alter absorption of the penicillin because of increased gastric pH.

Laboratory Test Interferences

Although published reports of laboratory test interferences with natural penicillins generally involve penicillin G, the possibility that interferences reported with penicillin G and other penicillins could also occur with penicillin V should be considered.

Tests for CSF, Serum, or Urinary Proteins

Penicillins interfere with or cause false-positive results in a variety of test methods used to determine CSF, serum, or urinary proteins.

Studies using penicillin G, oxacillin, or nafcillin indicate that penicillins cause false-positive and falsely elevated results in qualitative and quantitative turbidimetric methods for CSF, serum, or urinary, serum proteins that use sulfosalicylic acid or trichloroacetic acid.

Penicillin G reportedly causes false-positive results in the Folin-Ciocalteau method for CSF protein.

Penicillins interfere with the binding of albumin to dyes used to determine serum albumin concentrations. Penicillin G, in high concentrations, competitively competes with 4′-hydroxyazobenzene-2-carboxylic acid (HABA) dye for albumin-binding sites. Although this could theoretically cause falsely decreased serum albumin concentrations when HABA dye methods are used, serum concentrations of penicillin G attained with usual dosages of the drug probably will not interfere with this method.

The binding of penicillin G to albumin in patients receiving high doses of IV penicillin G reportedly may result in a double peak for serum albumin on electrophoretic scans that could be misinterpreted as bisalbuminemia; however, this effect should not alter the results of quantitation of albumin by electrophoresis.

Studies using penicillin G or nafcillin indicate that penicillins also interfere with tests for urinary protein that use the biuret reagent and can cause false-positive results or an atypical color reaction which cannot be interpreted. Studies using nafcillin or ampicillin indicate that penicillins can also cause slightly increased urinary protein concentrations when the Coomassie brilliant blue method is used. Penicillins do not appear to interfere with tests for urinary protein that use bromphenol-blue (Albustix).

Tests for Glucose

Studies using penicillin G or ampicillin indicate that penicillins can interfere with urinary glucose determinations using cupric sulfate (e.g., Benedict’s solution, Clinitest). In high concentrations, penicillins can cause false-positive results in these tests for urinary glucose. Glucose oxidase tests for urinary glucose (Clinistix, Tes-Tape) are reportedly unaffected by the presence of penicillins.

Tests for Uric Acid

Studies using penicillin G and ampicillin indicate that penicillins can cause falsely increased serum uric acid concentrations when the copper-chelate method is used; however, phosphotungstate and uricase methods for serum uric acid appear to be unaffected by the drugs.

Tests that Use Bacteria

Results of the Guthrie test for phenylketonuria (PKU) are unreliable in neonates receiving a penicillin because the drugs are active against Bacillus subtilis, the organism used in the test. The addition of sodium hydroxide and hydrochloric acid to blood samples prior to the Guthrie test reportedly inactivates penicillins and permits interpretation of the test.

Penicillins also are active against Lactobacillus casei, the organism used in microbiologic assays of folic acid; therefore, this method should not be used to determine serum folic acid concentrations in patients receiving a penicillin.

Tests for Urinary Steroids

Penicillin G acts as a ketogenic chromogen and has caused falsely increased concentrations of urinary 17-ketogenic steroids and 17-ketosteroids by interfering with the Norymberski method and the Zimmerman color reaction, respectively. The Glenn-Nelson technique for determining 17-hydroxycorticosteroids is reportedly unaffected by the presence of penicillin G.

Immunohematology Tests

Positive direct antiglobulin (Coombs’) test results have bee reported in patients receiving large doses of penicillin G. This reaction usually results from the presence of antipenicillin antibodies which bind to penicillin-coated erythrocytes and may interfere with hematologic studies or transfusion cross-matching procedures.

Other Laboratory Tests

Penicillins may decrease urinary excretion of aminohippurate sodium (PAH) and phenolsulfonphthalein (PSP) by competing for renal tubular secretion with these diagnostic agents. Therefore, the PAH and PSP excretion tests should not be performed in patients receiving a penicillin.

Penicillin G interferes with the Mauzerall and Granick method for determining urinary concentrations of δ-aminolevulinic acid (ALA) resulting in falsely increased concentrations of the compound. Because an increased urinary concentration of ALA generally indicates lead intoxication, the Mauzerall and Granick procedure should not be used to evaluate lead intoxication in patients who are receiving a penicillin unless a separation procedure is first used to remove ALA from the urine specimen.

Mechanism of Action

Penicillins usually are bactericidal in action. Like most other β-lactam antibiotics, the antibacterial activity of the drugs results from inhibition of mucopeptide synthesis in the bacterial cell wall.

Although the exact mechanism(s) of action of penicillins has not been fully elucidated, β-lactam antibiotics reversibly 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 structural 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 variants of the organisms. Cell death following exposure to β-lactam antibiotics usually results from lysis, which is mediated by endogenous bacterial autolysins such as peptidoglycan hydrolases. Penicillins are most active against susceptible bacteria while they are in the logarithmic phase of growth; bacteria must generally be actively dividing to be affected by the drugs.

The target enzymes of β-lactam antibiotics have been classified as penicillin-binding proteins (PBPs) and appear to vary substantially among bacterial species. Differences in the affinity of various β-lactam antibiotics for PBPs contribute to differences in morphology that occur in susceptible organisms following exposure to these antibiotics and may also explain some differences in spectra of activity of β-lactam antibiotics that do not result from the presence or absence of β-lactamase production in the organisms.

Although the clinical importance is unclear, β-lactam antibiotics (including penicillins) vary in their rate of bactericidal action and in the completeness of this effect. This appears to result partly from differences in drug-induced morphologic effects on susceptible bacteria and subsequent formation of bacterial variants with varying degrees of osmotic stability. Most penicillins, including natural penicillins, cause the formation of spheroplasts which are unstable and usually lyse rapidly. Although amoxicillin and ampicillin have similar chemical structures and similar spectra of activity, amoxicillin appears to cause rapid formation of spheroplasts and lysis in susceptible bacteria whereas ampicillin produces abnormally elongated or filamentous forms which are more stable and lyse at a slower rate. It has been suggested that the differences in morphologic response to different penicillins may have clinical importance. Since the organisms would have less opportunity for renewed growth, penicillin derivatives that cause rapid spheroplast formation and lysis theoretically could be more effective compared with derivatives that cause delayed lysis; however, this has not been proven clinically.

The antibacterial activity of penicillins depends partly on their ability to gain access and bind to the target enzymes. The cell walls of gram-positive bacteria are relatively permeable to most penicillins, especially natural penicillins; however, gram-negative bacteria have an outer membrane around the cell wall that decreases accessibility to the PBPs. Penicillins vary in their ability to penetrate the outer membrane of gram-negative bacteria. Natural penicillins are unable to penetrate the outer membranes of many gram-negative bacteria. The bulky side chains of penicillinase-resistant penicillins, which help to protect them from hydrolysis by staphylococcal penicillinases, also prevent these derivatives from penetrating the outer membrane of most gram-negative bacteria. Aminopenicillins and extended-spectrum penicillins can more readily penetrate the outer membranes of gram-negative bacteria, and it has been suggested that the greater ability of these derivatives to gain access to the PBPs may be related to the fact that they have polar groups on the side chain at R on the penicillin nucleus.

Spectrum

Natural penicillins are active in vitro against many gram-positive and gram-negative aerobic cocci (except penicillinase-producing strains), some gram-positive aerobic and anaerobic bacilli, and many spirochetes. The drugs generally are inactive against gram-negative aerobic and anaerobic bacilli and also are inactive against mycobacteria, Mycoplasma, Rickettsia, fungi, and viruses.

Penicillin G and penicillin V have similar spectra of activity; however, penicillin V is slightly less active than penicillin G in vitro on a weight basis against many susceptible organisms.

In Vitro Susceptibility Testing

When in vitro susceptibility testing is performed according to the standards of the Clinical and Laboratory Standards Institute (CLSI), clinical isolates identified as susceptible are inhibited by drug concentrations usually achievable when the recommended dosage is used for the site of infection, resulting in likely clinical efficacy. Clinical isolates identified as intermediate have MICs or zone diameters that approach usually attainable blood and tissue concentrations and/or for which response rates may be lower than response rates for isolates identified as susceptible. The intermediate category also includes a buffer zone for inherent variability in test methods that should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins. If results of in vitro susceptibility testing indicate that a clinical isolate is resistant, the strain is not inhibited by drug concentrations generally achievable with usual dosage schedules and/or MICs or zone diameters 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.

Strains of staphylococci resistant to penicillinase-resistant penicillins also should be considered resistant to natural penicillins, although results of in vitro susceptibility tests may indicate that the organisms are susceptible to the drugs.

Strains of enterococci identified as susceptible to penicillin G by in vitro susceptibility tests may be susceptible only if high dosage is used for the treatment of serious enterococcal infections; concomitant use of an aminoglycoside usually is indicated for the treatment of serious infections (e.g., endocarditis) caused by penicillin-susceptible enterococci. Synergy between penicillin G and an aminoglycoside is best predicted for enterococci using a high-level aminoglycoside screening test.

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test in vitro susceptibility to natural penicillins, a disk containing 10 penicillin G units should be used for most organisms (except S. pneumoniae) and results can be applied to both penicillin G and penicillin V and, in some cases, results also can be applied to certain other penicillin classes.

When the penicillin G disk is used to test susceptibility of staphylococci and the test is performed according to CSLI standardized procedures, results can be applied to natural penicillins, aminopenicillins, and extended-spectrum penicillins. Staphylococci with growth inhibition zones of 29 mm or greater are considered susceptible to natural penicillins, aminopenicillins, and extended-spectrum penicillins and those with zones of 28 mm or less are considered resistant to these penicillins.

When the penicillin G disk is used to test susceptibility of enterococci to natural penicillins, enterococci with growth inhibition zones of 15 mm or greater are considered susceptible to natural penicillins and those with zones of 14 mm or less are considered resistant to the drugs.

When the penicillin G disk is used to test susceptibility of β-hemolytic streptococci (streptococcal groups A [S. pyogenes], B [S. agalactiae], C, G), strains with growth inhibition zones of 24 mm or more are considered susceptible to natural penicillins and aminopenicillins.

Because penicillin G-resistant strains of S. pneumoniae may not be detected in the disk-diffusion procedure if the penicillin G disk is used, a disk containing 1 mcg of oxacillin should be used to test susceptibility of S. pneumoniae to natural penicillins. When the oxacillin disk is used and the test is performed according to CLSI standardized procedures, S. pneumoniae (nonmeningeal isolates) with growth inhibition zones of 20 mm or greater are considered susceptible to natural penicillins and aminopenicillins. The disk-diffusion test does not distinguish between strains that have intermediate resistance (relatively resistant) and those that are highly resistant, and a dilution susceptibility test should be used to determine susceptibility of S. pneumoniae (nonmeningeal isolates) that have growth inhibition zones of 19 mm or less in the disk-diffusion test using the oxacillin disk. A dilution susceptibility test also should be used to test susceptibility of all S. pneumoniae isolates from patients with meningitis.

When the penicillin G disk is used to test susceptibility of N. gonorrhoeae to natural penicillins, N. gonorrhoeae with growth inhibition zones of 47 mm or greater are considered susceptible to natural penicillins, those with zones of 27–46 mm are considered to have intermediate susceptibility, and those with zones of 26 mm or less are considered resistant to the drugs. N. gonorrhoeae with growth inhibition zones of 19 mm or less are likely to be penicillinase-producing strains (PPNG); the β-lactamase test should be used for rapid, accurate recognition of this form of resistance.

Dilution Susceptibility Tests

When dilution susceptibility testing is performed according to CLSI standardized procedures to determine in vitro susceptibility of staphylococci to natural penicillins, those with a penicillin G MIC of 0.12 mcg/mL or less are considered susceptible and those with a penicillin G MIC of 0.25 mcg/mL or greater are considered resistant.

When dilution susceptibility testing of S. pneumoniae (nonmeningeal isolates) is performed according to CLSI standardized procedures, those with an MIC of 2 mcg/mL or less are considered susceptible to natural penicillins, those with an MIC of 4 mcg/mL are considered to have intermediate susceptibility, and those with an MIC of 8 mcg/mL are considered resistant. When S. pneumoniae from patients with meningitis are tested, those with an MIC of 0.06 mcg/mL or less are considered susceptible to penicillin G and those with an MIC of 0.12 mcg/mL or greater are considered resistant.

When dilution susceptibility testing of β-hemolytic streptococci (streptococcal groups A [S. pyogenes], B [S. agalactiae], C, G) is performed, those with a penicillin G MIC of 0.12 mcg/mL or less are considered susceptible to natural penicillins and aminopenicillins.

Viridans group streptococci (S. mutans, S. salivarius, S. bovis, S. anginosus, and S. mitis groups) with a penicillin G MIC of 0.12 mcg/mL or less are considered susceptible to natural penicillins, those with an MIC of 0.25–2 mcg/mL are considered to have intermediate susceptibility, and those with an MIC of 4 mcg/mL or greater are considered resistant. Those with intermediate susceptibility may require concomitant use of an aminoglycoside for effective bactericidal activity.

When dilution susceptibility testing of enterococci is performed according to CLSI standardized procedures, those with a penicillin G MIC of 8 mcg/mL or less are considered susceptible to natural penicillins and those with a penicillin G MIC of 16 mcg/mL or greater are considered resistant.

When testing susceptibility of N. gonorrhoeae using dilution susceptibility testing according to CLSI standardized procedures, those with a penicillin G MIC of 0.06 mcg/mL or less are considered susceptible to natural penicillins, those with an MIC of 0.12–1 mcg/mL are considered to have intermediate susceptibility, and those with an MIC of 2 mcg/mL or greater are considered resistant.

N. meningitidis with a penicillin G MIC of 0.06 mcg/mL or less in dilution susceptibility testing are considered susceptible to penicillin G, those with an MIC of 0.12–0.25 mcg/mL are considered to have intermediate susceptibility, and those with an MIC of 0.5 mcg/mL are considered resistant.

Gram-positive Aerobic Bacteria

Natural penicillins are active in vitro against many gram-positive aerobic cocci including non-penicillinase-producing Staphylococcus aureus and S. epidermidis; Streptococcus pneumoniae; S. pyogenes (group A β-hemolytic streptococci; GAS); S. agalactiae (group B streptococci; GBS); other β-hemolytic streptococci (e.g., groups C, G, H, L, M, R); viridans streptococci; and nonenterococcal group D streptococci. Although some strains of enterococci are susceptible to penicillin G in vitro, many strains are resistant and penicillin tolerance has been reported. Penicillinase-producing strains of S. aureus and S. epidermidis are resistant to penicillin G and penicillin V.

Natural penicillins also are active in vitro against some gram-positive aerobic bacilli, including Bacillus anthracis, Corynebacterium diphtheriae, Erysipelothrix rhusiopathiae, and Listeria monocytogenes.

Gram-negative Aerobic Bacteria

Haemophilus

Natural penicillins are active in vitro against some strains of Haemophilus influenzae and H. parainfluenzae. Although most strains of H. ducreyi are β-lactamase producers and are resistant to natural penicillins, some strains of the organism are inhibited in vitro by penicillin G concentrations of 4 mcg/mL.

Neisseria

Natural penicillins usually are active in vitro against N. meningitidis. Strains of N. meningitidis resistant to natural penicillins appear to be rare in the US, and the organism generally is inhibited in vitro by penicillin G concentrations of 0.03 mcg/mL.

Although natural penicillins may be active in vitro against strains of non-penicillinase-producing N. gonorrhoeae, penicillinase-producing strains of N. gonorrhoeae (PPNG) are resistant.

Other Gram-Negative Aerobic Bacteria

Natural penicillins are active against Bordetella pertussis and Eikenella corrodens.

Penicillin G has some activity in vitro against Legionella, although the drug may not be effective clinically. In vitro, some strains of L. pneumophila, L. gormanii, and L. dumoffii may be inhibited by penicillin G concentrations of 1–16 mcg/mL. Penicillin G concentrations of 0.04–1 mcg/mL inhibit some strains of L. micdadei (the Pittsburgh pneumonia agent) and L. bozemanii in vitro.

Pasteurella multocida, an organism that can be aerobic or facultatively anaerobic, is usually inhibited in vitro by penicillin G concentrations of 0.2–0.8 mcg/mL or penicillin V concentrations of 0.4–16 mcg/mL. Natural penicillins also are active in vitro against Streptobacillus moniliformis and Spirillum minus.

Although some strains of Moraxella catarrhalis are inhibited in vitro by penicillin V, many strains of the organism are β-lactamase producers and are therefore resistant to penicillin G and penicillin V.

Natural penicillins are inactive against Enterobacteriaceae and Pseudomonas.

Anaerobic Bacteria

Natural penicillins are active in vitro against many gram-positive anaerobic bacteria, including Actinomyces, Arachnia, Bifidobacterium, Clostridium (including C. botulinum, C. perfringens, and C. tetani), Cutibacterium acnes (formerly Propionibacterium acnes), Eubacterium, Lactobacillus, Peptococcus, and Peptostreptococcus.

Gram-negative anaerobic bacteria vary in their susceptibility to natural penicillins. Penicillin G may be active in vitro against some strains of Fusobacterium and Veillonella. Although penicillin G may be active in vitro against some strains of Bacteroides melaninogenica or B. oralis, the B. fragilis group (e.g., B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus) require high penicillin G concentrations for in vitro inhibition and usually are resistant.

Spirochetes

Penicillin G and penicillin V are active against spirochetes including Treponema pallidum subsp pallidum, T. pallidum subsp pertenue, T. carateum, Borrelia burgdorferi, B. hermsii, B. recurrentis, and Leptospira.

Resistance

Mechanisms of Penicillin Resistance

The major mechanisms of resistance to β-lactam antibiotics, including penicillins, are the production of β-lactamases and/or intrinsic resistance. β-Lactamases can inactivate the drugs by hydrolyzing the β-lactam ring. Intrinsic resistance can result from the presence of a permeability barrier in the outer membrane of the organism or alterations in the properties of the target enzymes (PBPs).

The production of β-lactamases is considered the principal cause of bacterial resistance to β-lactam antibiotics. However, the presence or absence of β-lactamases, especially in gram-negative bacteria, does not entirely dictate susceptibility or resistance to penicillins. β-Lactamases produced by different bacterial species differ in physical, chemical, and functional properties. Staphylococcal β-lactamases are usually inducible, plasmid-mediated extracellular penicillinases. A variety of β-lactamases are produced by gram-negative bacteria and these are usually secreted in the periplasmic space between the inner and outer membranes of the organisms.

Tolerance

Tolerance to the bactericidal effects of penicillins has been reported in many strains of gram-positive cocci including S. aureus, groups A, B, and G streptococci, S. pneumoniae, E. faecalis (formerly S. faecalis), S. milleri, S. mutans, and S. sanguis. Most susceptible bacteria have penicillin MBCs that are 1–4 times greater than the MICs of the drugs. However, bacteria that are tolerant to penicillins generally have an MBC of the drugs 16 or more times greater than the MIC, and these organisms may be inhibited but are either not killed or are killed at a slower rate than bacteria that are not tolerant. Tolerance appears to result from decreased autolytic activity in the tolerant organism which may be caused by defective enzymes or the presence of an unidentified inhibitor of autolysis.

Infections caused by organisms tolerant to penicillins may persist during penicillin therapy although in vitro susceptibility tests indicate that the organisms are susceptible. The presence of penicillin-tolerant organisms in some serious infections where a rapid and complete bactericidal activity is important (e.g., endocarditis, bacteremia) or in infections in immunocompromised patients may result in a less favorable response to penicillin therapy in terms of mortality and length of positive cultures.

Resistance in Gram-positive Bacteria

Penicillinase-producing S. aureus and S. epidermidis are resistant to natural penicillins because these penicillins are readily inactivated by staphylococcal penicillinases. The appearance of penicillin G-resistant staphylococci in patients treated for infections caused by organisms that were initially susceptible to the drug usually results from selection of penicillinase-producing staphylococci that were present prior to therapy or, particularly in hospitalized patients, superinfection by penicillinase-producing strains.

Strains of S. pneumoniae that are relatively resistant and strains that are completely resistant to penicillins have been reported with increasing frequency. Penicillin resistance in S. pneumoniae is intrinsic and appears to be caused by altered PBPs. Strains of S. pneumoniae completely resistant to penicillin G also are generally resistant to penicillin V, penicillinase-resistant penicillins, aminopenicillins, and cephalosporins. Some strains of S. pneumoniae resistant to penicillins may also be resistant to cephalosporins, tetracyclines, chloramphenicol, erythromycin, clindamycin, and co-trimoxazole, but may be susceptible to rifampin or vancomycin. There is considerable geographic variability in the susceptibility of S. pneumoniae, and the reported incidence of penicillin G-resistant S. pneumoniae may be high in some areas.

Strains of α-hemolytic streptococci resistant to penicillin G have been isolated from the oral flora of patients who have received prolonged treatment with the drug. Resistance to penicillin G has been reported rarely in various streptococci in the viridans group.

Although resistance to penicillin G has been induced in vitro in S. pyogenes (group A β-hemolytic streptococci; GAS), clinical isolates resistant to penicillin have not been documented to date.

Resistance in Gram-negative Bacteria

Strains of H. influenzae or other Haemophilus that produce β-lactamases are generally resistant to natural penicillins, aminopenicillins, and extended-spectrum penicillins.

Penicillinase-producing strains of N. gonorrhoeae (PPNG) are completely resistant to natural penicillins and also usually resistant to aminopenicillins, but may be inhibited by spectinomycin.

Many gram-negative aerobic bacilli are intrinsically resistant to natural penicillins because the drugs are unable to penetrate the outer membrane of these organisms. However, β-lactamase production is also involved in resistance of some gram-negative bacilli (e.g., E. coli, Ps. aeruginosa) and is the principal mechanism for penicillin resistance in many anaerobic bacteria (e.g., Bacteroides). Although B. melaninogenicus was generally susceptible to penicillin G in the past, β-lactamase-producing strains of the organism that are resistant to the drug have been reported with increasing frequency.

Natural Penicillins General Statement Pharmacokinetics

For more specific information on the pharmacokinetics of penicillin G and penicillin V, see Pharmacokinetics in the individual monographs in 8:12.16.04.

Absorption

Oral Administration

Following oral administration, absorption of penicillins occurs mainly in the duodenum and upper jejunum, although a small amount of the drugs may be absorbed in the stomach and large intestine. The extent of absorption of oral penicillins is variable and depends on several factors, including the particular penicillin derivative, dosage form administered, gastric and intestinal pH, and presence of food in the GI tract.

Because natural penicillins are hydrolyzed in the presence of acid, acidic gastric secretions may inactivate the drugs following oral administration. Penicillin G potassium is very susceptible to acid-catalyzed hydrolysis (only about 15–30% of an orally administered dose of the drug is absorbed in healthy, fasting adults) and an oral formulation of penicillin G is no longer commercially available in US. Penicillin V is more resistant to acid-catalyzed inactivation than penicillin G and, therefore, is better absorbed following oral administration. Approximately 60–73% of an oral dose of penicillin V (no longer commercially available in the US) or penicillin V potassium is absorbed from the GI tract in healthy, fasting adults.

Following oral administration of a single dose of penicillin V or penicillin V potassium in fasting children or adults, peak serum concentrations of penicillin V generally are attained within 30–60 minutes and serum concentrations are low or undetectable 6 hours after the dose.

Because natural penicillins are acid-labile, patients with achlorhydria or other individuals with decreased gastric acid production (e.g., neonates, adults 60 years of age or older) absorb orally administered penicillin V to a greater extent than do children older than 1 month of age or adults younger than 60 years of age. GI absorption of penicillins generally is reduced in patients with malabsorption syndromes.

Variable results have been obtained in studies evaluating the effect of food on GI absorption of penicillin V and penicillin V potassium. In most studies, presence of food in the GI tract resulted in lower and delayed peak serum concentrations of penicillin V. If penicillin V is administered 1 hour before a meal, peak serum concentrations may be threefold higher and the total amount absorbed may be twofold higher compared with administration with food.

Parenteral Administration

The rate of absorption of penicillin G after IM injection depends on many factors including dose, concentration, and solubility of the particular preparation administered.

Penicillin G potassium and penicillin G sodium are rapidly absorbed following IM administration, and serum concentrations of penicillin G generally are the same following IM administration of equivalent doses of either salt. Following IM administration in adults of a single dose of penicillin G potassium or sodium, peak serum concentrations of penicillin G generally are attained within 15–30 minutes; serum concentrations of the drug decline rapidly and generally are low or undetectable 3–6 hours later.

Because penicillin G benzathine and penicillin G procaine are relatively insoluble, IM administration of preparations containing these salts provides a tissue depot from which the drugs are slowly absorbed and hydrolyzed to penicillin G. IM administration of penicillin G benzathine results in serum concentrations of penicillin G that are more prolonged, but lower, than those attained with an equivalent IM dose of penicillin G procaine or penicillin G potassium or sodium. IM administration of penicillin G procaine results in serum concentrations of penicillin G that generally are more prolonged, but lower, than those attained with an equivalent IM dose of penicillin G potassium or sodium.

Following IM administration of a single dose of penicillin G benzathine in adults, children, or neonates, peak serum concentrations of penicillin G are attained in 13–24 hours and usually are detectable for 1–4 weeks depending on the dose.

Following IM administration of a single dose of penicillin G procaine in adults or neonates, peak serum concentrations of penicillin G generally are attained in 1–4 hours and the drug usually is detectable in serum for 1–2 days; however, penicillin G may be detectable in serum for up to 5 days (depending on the dose). In general, increasing the dose of penicillin G procaine to more than 600,000 units tends to prolong the duration of penicillin G serum concentrations rather than increase peak serum concentrations.

Following IV infusion of penicillin G potassium or sodium, peak serum concentrations are attained immediately after completion of the infusion. In a study in 10 patients who received 5 million units of penicillin G given IV over 3–5 minutes, mean serum concentrations were 400, 273, and 3 mcg/mL at 5–6 minutes, 10 minutes, and 4 hours after administration, respectively. In a study in 5 healthy adults who received 1 million units of penicillin G given IV over 4 or 60 minutes, mean serum concentrations at 8 minutes after administration were 45 or 14.4 mcg/mL, respectively.

Penicillin G potassium or sodium is absorbed from the peritoneal cavity following local instillation. Penicillin G also is absorbed from pleural surfaces, pericardium, and joint cavities.

Distribution

Penicillins are widely distributed following absorption from the GI tract or IM or IV administration sites. The volume of distribution of penicillin G is reportedly 0.53–0.67 L/kg in adults with normal renal function.

Penicillin G and penicillin V are readily distributed into ascitic, synovial, pleural, pericardial, peritoneal, and interstitial fluids. Following oral, IM, or IV administration, concentrations of the drugs in ascitic fluid and synovial fluid may be equal to or greater than concurrent serum concentrations. Penicillin V is distributed into bile in low concentrations. Penicillin G concentrations in bile generally are greater than those attained in serum, unless biliary obstruction is present.

Natural penicillins are distributed into body tissues in widely varying amounts. Highest concentrations generally are attained in the kidneys, with lower amounts in the liver, lungs, skin, intestines, and muscle. The drugs also are distributed into erythrocytes, and concentrations of penicillin G within erythrocytes may exceed concurrent serum concentrations of the drug. Low concentrations of penicillin G and penicillin V generally are distributed into tonsils, maxillary sinus secretions, and saliva. Only negligible amounts of natural penicillins may be attained in avascular areas, abscesses, aqueous humor, sweat, tears, or bone.

Minimal concentrations of natural penicillins generally are attained in CSF following oral, IM, or IV administration of the drugs in patients with uninflamed meninges. In addition to being passively transported back into the venous system via the arachnoid villi, penicillins appear to be cleared from CSF by an active transport mechanism centered in the choroid plexus which transports the drugs and other organic acids out of CSF. Slightly higher penicillin concentrations are attained in CSF in patients with inflamed meninges because of increased vascular permeability and partial inhibition of the organic acid transport mechanism. Concurrent administration of oral probenecid with IM or IV administration of penicillin G salts also results in increased CSF concentrations of penicillin G. (See Probenecid under Drug Interactions.) Following IM administration of penicillin G procaine or IV administration of penicillin G sodium, concentrations of penicillin G in CSF reportedly range from 0–10% of concurrent serum concentrations of the drug in patients with normal meninges. The minimum treponemicidal concentration of penicillin G is generally defined as 0.03 penicillin G units/mL or 0.02 mcg/mL. In 2 adults with syphilis who received a daily IV dosage of 5 or 10 million units of penicillin G (as the potassium salt) for at least 10 days, penicillin G concentrations in CSF immediately following completion of therapy were 0.3 or 2.4 mcg/mL, respectively. In one study in children 2 weeks to 11 years of age with meningitis who received penicillin G potassium in a dosage of 250,000 units/kg daily given in 6 divided doses by IV infusion over 15 minutes, penicillin G concentrations in CSF specimens obtained between doses averaged 0.8, 0.7, and 0.3 mcg/mL on the first, fifth, and tenth days of therapy, respectively. IM administration of penicillin G procaine generally results in higher penicillin G concentrations in CSF than IM administration of penicillin G benzathine. In one study in adults who received IM penicillin G benzathine given in a dosage of 3.6 million units once weekly for up to 4 weeks, penicillin G was undetectable in CSF of 12/13 patients in CSF specimens obtained following administration of the last dose. In a study in neonates who received a single IM dose of penicillin G benzathine of 100,000 units/kg, peak CSF penicillin G concentrations occurred 12–24 hours after the dose and ranged from 0.012–0.2 mcg/mL; however, CSF penicillin G concentrations were less than 0.01 mcg/mL 48 hours after the dose.

The degree of protein binding varies considerably among penicillins and is enhanced by hydrophilic side chains at R on the penicillin nucleus and decreased by hydrophilic substitutions on the penicillin nucleus. Penicillin V is more highly protein bound than penicillin G. Penicillin G is approximately 45–68% and penicillin V is approximately 75–89% bound to serum protein. Protein binding of the drugs is lower in neonates than in adults; penicillin G is reportedly 49% bound to serum proteins in neonates. Penicillins also are less protein bound in patients with hyperbilirubinemia or azotemia since the drugs are displaced from protein binding sites by bilirubin and other endogenous compounds.

Penicillin G and penicillin V cross the placenta.

Penicillin G and penicillin V are distributed into milk.

Elimination

In adults with normal renal function, the serum half-life of penicillin G is reportedly 0.4–0.9 hours and the serum half-life of penicillin V is reportedly 0.5 hours. Serum concentrations of natural penicillins may be higher and half-lives prolonged in patients with impaired renal function.

Both penicillin G and penicillin V are metabolized to some extent by hydrolysis of the β-lactam ring to penicilloic acids which are microbiologically inactive. Although it has been suggested that, following oral administration, this hydrolysis occurs partly in the GI tract prior to absorption, the drugs appear to undergo metabolism mainly in the liver. Approximately 16–30% of an IM dose of penicillin G sodium and 35–70% of an oral dose of penicillin V or penicillin V potassium is metabolized to penicilloic acid. Small amounts of 6-aminopenicillanic acid (6-APA), formed by removal of the side chain at R on the penicillin nucleus, have also been identified in urine of patients receiving penicillin G or penicillin V. In addition, the drugs appear to be hydroxylated to a small extent to one or more microbiologically active metabolites which also are eliminated in urine.

Natural penicillins and their metabolites are rapidly excreted in urine mainly by tubular secretion. Small amounts of the drugs also are excreted in feces and bile. In adults with normal renal function, 58–85% of a single IM or IV dose of penicillin G potassium or sodium is excreted in urine as unchanged drug and active metabolites within 6 hours; approximately 10% of this amount is excreted by glomerular filtration and the remaining 90% is excreted by active tubular secretion. Following oral administration of a single dose of penicillin V or penicillin V potassium in adults with normal renal function, 20–65% of the dose is excreted in urine as unchanged drug and metabolites within 6–8 hours; approximately 32% of the dose is excreted in feces. Approximately 20% of an oral dose of penicillin G potassium is excreted in urine in patients with normal renal function.

Following IM administration of penicillin G benzathine or penicillin G procaine, the drugs are slowly absorbed and hydrolyzed to penicillin G and elimination of penicillin G in urine continues over a prolonged period of time. Penicillin G has been detected in urine for up to 12 weeks after a single IM dose of penicillin G benzathine of 1.2 million units.

Renal clearance of penicillins is delayed in neonates and premature or young infants because of an immature mechanism for tubular secretion. The serum half-life of penicillin G in neonates varies inversely with age and appears to be independent of birthweight. As tubular function matures, penicillins are cleared more rapidly and children older than 3 months of age generally excrete the drugs similarly to adults.

Renal clearance of penicillins may be delayed in geriatric patients because of diminished tubular secretion ability.

Renal clearance of penicillin G and penicillin V may be increased in pregnant women during the second and third trimesters.

Concurrent administration of oral probenecid competitively inhibits renal tubular secretion of natural penicillins resulting in higher and more prolonged serum concentrations of the drugs. (See Probenecid under Drug Interactions.)

Penicillin G is removed by hemodialysis and may be removed to a lesser extent by peritoneal dialysis.

Chemistry and Stability

Chemistry

Natural penicillins are produced by fermentation of mutant strains of Penicillium chrysogenum. Natural penicillins with different side chains at R on the penicillin nucleus are produced by altering the culture media of Penicillium. Although various natural penicillins have been produced (e.g., penicillins F, G, N, O, V, X), only penicillin G and penicillin V are used clinically. Penicillin G and penicillin V are produced by adding phenylacetic acid or phenoxyacetic acid, respectively, to the culture media. The phenoxymethyl group on penicillin V imparts more acid stability and slightly less potent antibacterial activity compared with the phenyl group on penicillin G.

Penicillin G is commercially available as benzathine, procaine, potassium, and sodium salts; penicillin V is commercially available as the potassium salt. Penicillin G potassium or sodium and penicillin V potassium frequently are referred to as aqueous, crystalline forms of the drugs and penicillin G benzathine and penicillin G procaine frequently are referred to as long-acting, depot, or repository forms of penicillin G. The potassium and sodium salts of the drugs generally are very soluble in water; however, the benzathine and procaine salts of penicillin G are only slightly or very slightly soluble in water.

Potency of penicillin G and its salts usually is expressed in terms of penicillin G units, but also has been expressed as mg of penicillin G. Although potency of penicillin V potassium usually is expressed in terms of mg of penicillin V, it may be expressed in terms of penicillin V units.

Stability

Penicillins generally are inactivated in the presence of heat, alkaline or acid pH, oxidizing agents, alcohols, glycols, and metal ions such as copper, mercury, or zinc. In currently available penicillins, cleavage at any point in the penicillin nucleus, including the β-lactam ring, results in complete loss of antibacterial activity. The major cause of inactivation of penicillins is hydrolysis of the β-lactam ring. The course of hydrolysis and nature of the degradation products can vary and are generally influenced by pH.

Penicillin G potassium and penicillin G sodium are moderately hygroscopic and dry powders of the drugs should be protected from moisture to prevent hydrolysis. In the dry state, natural penicillins and their salts are generally stable for several years at room temperature; however, the drugs deteriorate more rapidly at higher temperatures.

In solution, penicillins are stable for short periods of time and their stability is temperature and pH dependent. At 25°C, penicillin G potassium and penicillin G sodium are stable in the pH range of 6.5–7.5 (maximum stability at pH 6.8). Commercially available penicillin G potassium or sodium powders for injection contain a sodium citrate and citric acid buffer. At 37°C, penicillin G potassium and penicillin G sodium are unstable in acid and reportedly have a half-life of about 5 minutes in vitro in solutions with a pH of approximately 2. These penicillin G salts may be rapidly inactivated in vivo by acidic gastric secretions following oral administration. Penicillin G benzathine is more stable than other penicillin G salts at the pH of gastric acid secretions. The phenoxymethyl group on penicillin V stabilizes it against acid-catalyzed hydrolysis, and penicillin V reportedly has a half-life of 5 hours in vitro in solutions with a pH of 1. Penicillin V is more resistant than penicillin G to inactivation by acidic gastric secretions following oral administration.

Another major cause of in vivo inactivation of penicillins is hydrolysis by bacterial enzymes including β-lactamases and acylases. β-Lactamases hydrolyze the amide bond of the β-lactam ring of penicillins to produce penicilloic acid which is inactive; penicilloic acid is also formed in vitro in penicillin solutions. Natural penicillins are susceptible to the action of many β-lactamases and this is a major mechanism of bacterial resistance to the drugs. (See Mechanisms of Penicillin Resistance under Resistance.) Acylases, produced by many gram-negative bacteria, can also inactivate penicillins by hydrolyzing the acylamino side chains of the drugs. Although acylases appear to be of minor importance in terms of bacterial resistance, these enzymes are used commercially to produce semisynthetic penicillin derivatives.

Commercially available penicillin G or penicillin V preparations may contain small amounts of high molecular weight protein impurities that originate from the fermentation process used to produce the drugs. In addition, small amounts of polymer conjugation products can form in aqueous penicillin solutions during in vitro storage, especially when high penicillin concentrations are stored at room temperature. When stored at room temperature, in vitro studies indicate that penicillin degradation products may form within a few hours in penicillin G solutions with a concentration of 10 million units/L in sterile water, 0.9% sodium chloride, or glucose. The high molecular weight impurities and degradation products of penicillins (e.g., penicillenic acid, penicilloic acid, penicilloyl) are potential antigens when combined with protein and appear to play a role in allergic sensitization to penicillins. Therefore, although potency of the drugs may not be adversely affected, penicillin solutions for parenteral use generally should be refrigerated or used shortly following preparation. .

Penicillins are potentially physically and/or chemically incompatible with some drug, 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.

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