Trovan: Package Insert / Prescribing Info

TROVAN Tablets

TROVAN Tablets contain trovafloxacin mesylate, a synthetic broad-spectrum antibacterial agent for oral administration. Chemically, trovafloxacin mesylate, a fluoronaphthyridone related to the fluoroquinolone antibacterials, is (1α, 5α, 6α)-7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, monomethanesulfonate. Trovafloxacin mesylate differs from other quinolone derivatives by having a 1,8-naphthyridine nucleus.

The chemical structure is:

Its empirical formula is C20H15F3N4O3•CH3SO3H and its molecular weight is 512.46.

Trovafloxacin mesylate is a white to off-white powder.

Trovafloxacin mesylate is available in 100 mg and 200 mg (trovafloxacin equivalent) blue, film-coated tablets. TROVAN Tablets contain microcrystalline cellulose, cross-linked sodium carboxymethylcellulose and magnesium stearate. The tablet coating is a mixture of hydroxypropylcellulose, hydroxypropylmethylcellulose, titanium dioxide, polyethylene glycol and FD&C blue #2 aluminum lake.

TROVAN I.V.

TROVAN I.V. contains alatrofloxacin mesylate, the L-alanyl-L-alanyl prodrug of trovafloxacin mesylate. Chemically, alatrofloxacin mesylate is (1α, 5α, 6α)-L-alanyl-N-[3-[6-carboxy-8-(2,4-difluorophenyl)-3-fluoro-5,8-dihydro-5-oxo-1,8-naphthyridine-2-yl]-3-azabicyclo[3.1.0]hex-6-yl]-L-alaninamide, monomethanesulfonate. It is intended for administration by intravenous infusion.

Following intravenous administration, the alanine substituents in alatrofloxacin are rapidly hydrolyzed in vivo to yield trovafloxacin. (See CLINICAL PHARMACOLOGY.)

The chemical structure is:

Its empirical formula is C26H25F3N6O5•CH3SO3H and its molecular weight is 654.62.

Alatrofloxacin mesylate is a white to light yellow powder.

TROVAN I.V. is available in 40 mL and 60 mL single use vials as a sterile, preservative-free aqueous concentrate of 5 mg trovafloxacin/mL as alatrofloxacin mesylate intended for dilution prior to intravenous administration of doses of 200 mg or 300 mg of trovafloxacin, respectively. (See HOW SUPPLIED.)

The formulation contains Water for Injection, and may contain sodium hydroxide or hydrochloric acid for pH adjustment. The pH range for the 5 mg/mL aqueous concentrate is 3.5 to 4.3.

Absorption

Trovafloxacin is well-absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability is approximately 88%. For comparable dosages, no dosage adjustment is necessary when switching from parenteral to oral administration (Figure 1). (See DOSAGE AND ADMINISTRATION.)

Figure 1. Mean trovafloxacin serum concentrations determined following 1 hour intravenous infusions of alatrofloxacin at daily doses of 200 mg (trovafloxacin equivalents) to healthy male volunteers and following daily oral administration of 200 mg trovafloxacin for 7 days to six male and six female healthy young volunteers.

Pharmacokinetics

The mean pharmacokinetic parameters (±SD) of trovafloxacin after single and multiple 100 mg and 200 mg oral doses and 1 hour intravenous infusions of alatrofloxacin in doses of 200 and 300 mg (trovafloxacin equivalents) appear in the chart below.

Serum concentrations of trovafloxacin are dose proportional after oral administration of trovafloxacin in the dose range of 30 to 1000 mg or after intravenous administration of alatrofloxacin in the dose range of 30 to 400 mg (trovafloxacin equivalents). Steady state concentrations are achieved by the third daily oral or intravenous dose of trovafloxacin with an accumulation factor of approximately 1.3 times the single dose concentrations.

Oral absorption of trovafloxacin is not altered by concomitant food intake; therefore, it can be administered without regard to food.

The systemic exposure to trovafloxacin (AUC0–∞) administered as crushed tablets via nasogastric tube into the stomach was identical to that of orally administered intact tablets. Administration of concurrent enteral feeding solutions had no effect on the absorption of trovafloxacin given via nasogastric tube into the stomach. When trovafloxacin was administered as crushed tablets into the duodenum via nasogastric tube, the AUC0–∞ and peak serum concentration (Cmax) were reduced by 30% relative to the orally administered intact tablets. Time to peak serum level (Tmax) was also decreased from 1.7 hrs to 1.1 hrs.

Distribution

The mean plasma protein bound fraction is approximately 76%, and is concentration-independent. Trovafloxacin is widely distributed throughout the body. Rapid distribution of trovafloxacin into tissues results in significantly higher trovafloxacin concentrations in most target tissues than in plasma or serum.

Presence in Breast Milk

Trovafloxacin was found in measurable concentrations in the breast milk of three lactating subjects. The average measurable breast milk concentration was 0.8 µg/mL (range: 0.3–2.1 µg/mL) after single I.V. alatrofloxacin (300 mg trovafloxacin equivalents) and repeated oral trovafloxacin (200 mg) doses.

Metabolism

Trovafloxacin is metabolized by conjugation (the role of cytochrome P450 oxidative metabolism of trovafloxacin is minimal). Thirteen percent of the administered dose appears in the urine in the form of the ester glucuronide and 9% appears in the feces as the N-acetyl metabolite (2.5% of the dose is found in the serum as the active N-acetyl metabolite). Other minor metabolites (diacid, sulfamate, hydroxycarboxylic acid) have been identified in both urine and feces in small amounts (<4% of the administered dose).

Excretion

Approximately 50% of an oral dose is excreted unchanged (43% in the feces and 6% in the urine).

After multiple 200 mg doses, to healthy subjects, mean (±SD) cumulative urinary trovafloxacin concentrations were 12.1±3.4 µg/mL. With these levels of trovafloxacin in urine, crystals of trovafloxacin have not been observed in the urine of human subjects.

Special Populations

Microbiology

Trovafloxacin is a fluoronaphthyridone related to the fluoroquinolones with in vitro activity against a wide range of gram-negative and gram-positive aerobic, and anaerobic microorganisms. The bactericidal action of trovafloxacin results from inhibition of DNA gyrase and topoisomerase IV. DNA gyrase is an essential enzyme that is involved in the replication, transcription and repair of bacterial DNA. Topoisomerase IV is an enzyme known to play a key role in the partitioning of the chromosomal DNA during bacterial cell division. Mechanism of action of fluoroquinolones including trovafloxacin is different from that of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines. Therefore, fluoroquinolones may be active against pathogens that are resistant to these antibiotics. There is no cross-resistance between trovafloxacin and the mentioned classes of antibiotics. The overall results obtained from in vitro synergy studies, testing combinations of trovafloxacin with beta-lactams and aminoglycosides, indicate that synergy is strain specific and not commonly encountered. This agrees with results obtained previously with other fluoroquinolones. Resistance to trovafloxacin in vitro develops slowly via multiple-step mutation in a manner similar to other fluoroquinolones. Resistance to trovafloxacin in vitro occurs at a general frequency of between 1×10-7 to 10-10. Although cross-resistance has been observed between trovafloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to trovafloxacin.

Trovafloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:

Aerobic gram-positive microorganisms
Enterococcus faecalis (many strains are only moderately susceptible)
Staphylococcus aureus (methicillin-susceptible strains)
Streptococcus agalactiae
Streptococcus pneumoniae (penicillin-susceptible strains)
Viridans group streptococci

Aerobic gram-negative microorganisms
Escherichia coli
Gardnerella vaginalis
Haemophilus influenzae
Klebsiella pneumoniae
Moraxella catarrhalis
Proteus mirabilis
Pseudomonas aeruginosa

Anaerobic microorganisms
Bacteroides fragilis
Peptostreptococcus species
Prevotella species

Other microorganisms
Chlamydia pneumoniae
Legionella pneumophila
Mycoplasma pneumoniae

The following in vitro data are available, but their clinical significance is unknown.

Trovafloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of ≤2 µg/mL against most (90%) strains of the following microorganisms; however, the safety and effectiveness of trovafloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-positive microorganisms
Streptococcus pneumoniae (penicillin resistant strains)

Aerobic gram-negative microorganisms
Citrobacter freundii
Enterobacter aerogenes
Morganella morganii
Proteus vulgaris

Anaerobic microorganisms
Bacteroides distasonis
Bacteroides ovatus
Clostridium perfringens

Other microorganisms
Mycoplasma hominis
Ureaplasma urealyticum

NOTE: Mycobacterium tuberculosis and Mycobacterium avium-intracellulare complex organisms are commonly resistant to trovafloxacin.

NOTE: The activity of trovafloxacin against Treponema pallidum has not been evaluated; however, other quinolones are not active against Treponema pallidum. (See WARNINGS.)

Susceptibility Tests

Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on dilution methods1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of trovafloxacin mesylate powder. The MIC values should be interpreted according to the following criteria:

For testing non-fastidious aerobic organisms:

For testing Haemophilus spp.1

For testing Streptococcus spp. including Streptococcus pneumoniae2:

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard trovafloxacin mesylate powder should provide the following MIC values:

Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with trovafloxacin mesylate equivalent to 10 µg trovafloxacin to test the susceptibility of microorganisms to trovafloxacin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a trovafloxacin mesylate disk (equivalent to 10 µg trovafloxacin) should be interpreted according to the following criteria:

The following zone diameter interpretive criteria should be used for testing non-fastidious aerobic organisms:

For testing Haemophilus spp.3:

For testing Streptococcus spp. including Streptococcus pneumoniae4:

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for trovafloxacin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the trovafloxacin mesylate equivalent to 10-µg trovafloxacin disk should provide the following zone diameters in these laboratory quality control strains:

Anaerobic Techniques: For anaerobic bacteria, the susceptibility to trovafloxacin as MICs can be determined by standardized test methods3. The MIC values obtained should be interpreted according to the following criteria:

Interpretation is identical to that stated above for results using dilution techniques.

As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized trovafloxacin mesylate powder should provide the following MIC values:

1

This interpretive standard is applicable only to broth microdilution susceptibility tests with Haemophilus spp. using Haemophilus Test Medium (HTM)1.

2

These interpretive standards are applicable only to broth microdilution susceptibility tests using cation adjusted Mueller-Hinton broth with 2–5% lysed horse blood.

3

This zone diameter standard is applicable only to tests with Haemophilus spp. using HTM2.

4

These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.

General

Moderate to severe phototoxicity reactions have been observed in patients who are exposed to direct sunlight while receiving some drugs in this class. Therapy should be discontinued if phototoxicity (e.g., a skin eruption, etc.) occurs.

The safety and efficacy of TROVAN in patients with severe cirrhosis (Child-Pugh Class C) have not been studied.

Symptomatic pancreatitis has been reported on therapy. Clinicians should monitor pancreatic tests in patients who develop symptoms consistent with pancreatitis as clinically indicated.

Because a rapid or bolus intravenous injection may result in life-threatening hypotension, alatrofloxacin should only be administered by slow intravenous infusion over a period of 60 minutes. Profound hypotension has also been reported in patients receiving alatrofloxacin at the recommended rate of infusion. (See WARNINGS and DOSAGE AND ADMINISTRATION: Intravenous Administration.)

Information For Patients

Patients should be advised:

• to discontinue therapy and to inform their physician immediately if they develop symptoms suggestive of hepatic dysfunction including fatigue, anorexia, vomiting, abdominal pain, jaundice, dark urine or pale stool. (See WARNINGS.)
• to inform their physician if they develop symptoms suggestive of pancreatitis including abdominal pain and/or nausea and vomiting. (See PRECAUTIONS: General.)
• that TROVAN Tablets may be taken without regard to meals;
• that vitamins or minerals containing iron, aluminum- or magnesium-base antacids, antacids containing citric acid buffered with sodium citrate, or sucralfate or Videx®, (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should be taken at least 2 hours before or 2 hours after taking TROVAN tablets. (See PRECAUTIONS: Drug Interactions.);
• that TROVAN may cause lightheadedness and/or dizziness. Dizziness and/or lightheadedness was the most common adverse reaction reported, and for females under 45 years, it was reported significantly more frequently than in other groups. The incidence of dizziness may be substantially reduced if TROVAN Tablets are taken at bedtime or with food. Patients should know how they react to trovafloxacin before they operate an automobile or machinery or engage in activities requiring mental alertness and coordination. (See WARNINGS and ADVERSE REACTIONS.);
• to discontinue treatment and inform their physician if they experience pain, inflammation or rupture of a tendon, and to rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been confidently excluded;
• that TROVAN may be associated with hypersensitivity reactions, even following the first dose, and to discontinue the drug at the first sign of a skin rash, hives or other skin reactions, difficulty in swallowing or breathing, any swelling suggesting angioedema (e.g., swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction. (See WARNINGS and ADVERSE REACTIONS.);
• to avoid excessive sunlight or artificial ultraviolet light (e.g., tanning beds) while taking TROVAN and to discontinue therapy if phototoxicity (e.g., sunburn-like reaction or skin eruption) occurs.
• that convulsions have been reported in patients taking quinolones, including trovafloxacin, and to notify their physician before taking this drug if there is a history of this condition

Drug Interactions

Antacids, Sucralfate, and Iron: The absorption of oral trovafloxacin is significantly reduced by the concomitant administration of some antacids containing magnesium or aluminum, citric acid/sodium citrate (Bicitra®), as well as sucralfate and iron (ferrous ions). These agents as well as formulations containing divalent and trivalent cations such as Videx®, (Didanosine), chewable/buffered tablets or the pediatric powder for oral solution, should be taken at least 2 hours before or 2 hours after oral trovafloxacin administration. (See CLINICAL PHARMACOLOGY.)

Morphine: Co-administration of intravenous morphine significantly reduces the absorption of oral trovafloxacin. Intravenous morphine should be administered at least 2 hours after oral TROVAN dosing in the fasted state and at least 4 hours after oral TROVAN is taken with food. Trovafloxacin administration had no effect on the pharmacokinetics of morphine or its metabolite, morphine-6-β-glucuronide. (See CLINICAL PHARMACOLOGY.)

Warfarin: There have been reports during the post-marketing experience that trovafloxacin/alatrofloxacin enhance the effects of warfarin, including cases of bleeding. The mechanism for this reaction is unknown. Prothrombin time, International Normalized Ratio (INR) or other suitable anticoagulation tests should be closely monitored if trovafloxacin/alatrofloxacin is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding.

Minor pharmacokinetic interactions without clinical significance have been observed with co-administration of TROVAN Tablets with caffeine, omeprazole and calcium carbonate. (See CLINICAL PHARMACOLOGY.)

No significant pharmacokinetic interactions with theophylline, cimetidine, digoxin, warfarin, or cyclosporine have been observed with TROVAN Tablets. (See CLINICAL PHARMACOLOGY.)

Alatrofloxacin should not be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line. (See DOSAGE AND ADMINISTRATION.)

Laboratory Test Interactions

There are no reported laboratory test interactions.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long term studies in animals to determine the carcinogenic potential of trovafloxacin or alatrofloxacin have not been conducted.

TROVAN did not shorten the time to development of UV-induced skin tumors in hairless albino (Skh-1) mice; thus, it was not photo co-carcinogenic in this model. These mice received oral trovafloxacin and concurrent irradiation with simulated sunlight 5 days per week for 40 weeks followed by a 12-week treatment-free observation period. The daily dose of UV radiation used in this study was approximately 30% of the minimal dose of UV radiation that would induce erythema in Caucasian humans. The median time to the development of skin tumors in the hairless mice (42–43 weeks) was similar in the vehicle control group and those given 10 or 30 mg/kg of trovafloxacin daily. At a dose level of 30 mg/kg/day, the mice had skin trovafloxacin concentrations of approximately 7 µg/g. Following multiple 200 mg daily doses of trovafloxacin, the amount in human skin is estimated to be about 3 µg/g, based upon plasma concentrations measured at this dose level.

Trovafloxacin was not mutagenic in the Ames Salmonella reversion assay or CHO/HGPRT mammalian cell gene mutation assay and it was not clastogenic in mitogen-stimulated human lymphocytes or mouse bone marrow cells. A mouse micronucleus test conducted with alatrofloxacin was also negative. The positive response observed in the E. coli bacterial mutagenicity assay may be due to the inhibition of DNA gyrase by trovafloxacin.

Trovafloxacin and alatrofloxacin did not affect the fertility of male or female rats at oral and I.V. doses of 75 mg/kg/day and 50 mg/kg/day, respectively. These doses are 15 and 10 times the recommended maximum human dose based on mg/kg or approximately 2 times based on mg/m2. However, oral doses of trovafloxacin at 200 mg/kg/day (40 times the recommended maximum human dose based on mg/kg or about 6 times based on mg/m2) were associated with increased preimplantation loss in rats.

Pregnancy

Nursing Mothers

Trovafloxacin is excreted in human milk and was found in measurable concentrations in the breast milk of lactating subjects. (See CLINICAL PHARMACOLOGY, Distribution.)

Because of the potential for unknown effects from trovafloxacin in nursing infants from mothers taking trovafloxacin, a decision should be made either to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of trovafloxacin in pediatric patients and adolescents less than 18 years of age have not been established. Quinolones, including trovafloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species. (See WARNINGS.)

Geriatric Use

In multiple-dose clinical trials of trovafloxacin, 27% of patients were ≥65 years of age and 12% of patients were ≥75 years of age. The overall incidence of drug-related adverse reactions, including central nervous system and gastrointestinal side effects, was less in the ≥65 year group than the other age groups.

POST-MARKETING EXPERIENCE

Adverse reactions reported with TROVAN during the post-marketing period include:

GASTROINTESTINAL: symptomatic pancreatitis.

GENERAL/OTHER: anaphylaxis, Stevens-Johnson Syndrome.

HEMATOPOIETIC: agranulocytosis, aplastic anemia, pancytopenia.

LIVER/BILIARY: symptomatic hepatitis (some patients experienced an associated peripheral eosinophilia), liver failure (including acute hepatic necrosis with eosinophilic infiltration). TROVAN-associated liver enzyme abnormalities and/or symptomatic hepatitis have occurred during short-term or long-term therapy. (See WARNINGS.)

INTRAVENOUS ADMINISTRATION

AFTER DILUTION WITH AN APPROPRIATE DILUENT, TROVAN I.V. SHOULD BE ADMINISTERED BY INTRAVENOUS INFUSION OVER A PERIOD OF 60 MINUTES. CAUTION: RAPID OR BOLUS INTRAVENOUS INFUSION SHOULD BE AVOIDED. (See PRECAUTIONS.)

TROVAN I.V. is supplied in single-use vials containing a concentrated solution of alatrofloxacin mesylate in Water for Injection (equivalent of 200 mg or 300 mg as trovafloxacin). Each mL contains alatrofloxacin mesylate equivalent to 5 mg trovafloxacin. (See HOW SUPPLIED for container sizes.) THESE TROVAN I.V. SINGLE-USE VIALS MUST BE FURTHER DILUTED WITH AN APPROPRIATE SOLUTION PRIOR TO INTRAVENOUS ADMINISTRATION. This parenteral drug product should be inspected visually for discoloration and particulate matter prior to dilution and administration. Since no preservative or bacteriostatic agent is present in this product, aseptic technique must be used in preparation of the final parenteral solution.

Tablets

TROVAN (trovafloxacin mesylate) Tablets are available as blue, film-coated tablets. The 100 mg tablets are round and contain trovafloxacin mesylate equivalent to 100 mg trovafloxacin. The 200 mg tablets are modified oval-shaped and contain trovafloxacin mesylate equivalent to 200 mg trovafloxacin.

TROVAN Tablets are packaged and in unit dose blister strips in the following configurations:

100-mg tablets: color: blue; shape: round; debossing: "PFIZER" on one side and "378" on the other
Bottles of 30 (NDC 0049-3780-30)
Unit Dose/40 tablets (NDC 0049-3780-43)

200-mg tablets: color: blue; shape: modified oval; debossing: "PFIZER" on one side and "379" on the other
Bottles of 30 (NDC 0049-3790-30)
Unit Dose/40 tablets (NDC 0049-3790-43)

Injection

TROVAN is also available for intravenous administration as the prodrug, TROVAN I.V. (alatrofloxacin mesylate injection), in the following configurations:

Single-use vials containing a clear, colorless to pale-yellow concentrated solution of alatrofloxacin mesylate equivalent to 5 mg trovafloxacin/mL.

5 mg/mL, 40 mL, 200 mg
Unit dose package (NDC 0049-3890-28)

5 mg/mL, 60 mL, 300 mg
Unit dose package (NDC 0049-3900-28)

Hospitalized Community Acquired Pneumonia

Adult patients with clinically and radiologically documented community acquired pneumonia, requiring hospitalization and initial intravenous therapy, participated in two randomized, multicenter, double-blind, double-dummy trials. The first trial compared intravenous alatrofloxacin (200 mg once daily for 2 to 7 days) followed by oral trovafloxacin (200 mg once daily) for a total of 7 to 14 days of therapy to intravenous ciprofloxacin (400 mg BID) plus ampicillin (500 mg QID) for 2 to 7 days followed by oral ciprofloxacin (500 mg BID) plus amoxicillin (500 mg TID) for a total of 7 to 14 days of therapy. The second study compared intravenous alatrofloxacin (200 mg once daily for 2 to 7 days) followed by oral trovafloxacin (200 mg once daily) for a total of 7 to 14 days of therapy to intravenous ceftriaxone (1000 mg once daily for 2 to 7 days) followed by oral cefpodoxime (400 mg BID) for 7 to 14 days of total therapy with optional blinded erythromycin added to the ceftriaxone/cefpodoxime arm if an atypical pneumonia was suspected.

The clinical success rate (cure + improvement with no need for further antibiotic therapy) at the End of Treatment was 90% (311/346) and 90% (325/363) for TROVAN and the comparator agents, respectively. The clinical success rate at the End of Study (Day 30) was 86% (256/299) and 85% (283/334) for TROVAN and the comparator agents, respectively. All cause mortality (Day 1–35) was 2.45% (10/408) on TROVAN and 5.45% (23/422) on the comparator agents.

The following outcomes are the clinical success rates for the clinically evaluable patient groups by pathogen in these two studies:

Of the above patients with clinical failure at end of treatment or study, only one alatrofloxacin patient (H. influenzae + S. pneumoniae) and one ceftriaxone + erythromycin patient (Legionella) had a microbiologically confirmed persistent pathogen at the time of failure with no emergence of resistance in either study.

Nosocomial Pneumonia

Adult patients with clinically and radiologically documented nosocomial pneumonia participated in a randomized, multicenter, double-blind, double-dummy trial comparing intravenous alatrofloxacin (300 mg once daily for 2 to 7 days) followed by oral trovafloxacin (200 mg once daily) for a total of 7 to 14 days of therapy to intravenous ciprofloxacin (400 mg BID) for 2 to 7 days followed by oral ciprofloxacin (750 mg BID) for a total of 7 to 14 days of therapy with optional blinded clindamycin or metronidazole added to the ciprofloxacin arm if an anaerobic pneumonia was suspected. In subjects with documented Pseudomonas infection or methicillin-resistant S. aureus, aztreonam or vancomycin, respectively, could have been added to either treatment regimen.

The clinical success rate (cure + improvement with no need for further antibiotic therapy) at the End of Treatment was 77% (68/88) and 78% (79/101) for TROVAN and ciprofloxacin, respectively. The clinical success rate at the End of Study (Day 30) was 69% (50/72) and 68% (54/79) for TROVAN and ciprofloxacin, respectively.

The following outcomes are the clinical success rates for the clinically evaluable patient groups by pathogen:

Of the above patients with clinical failure at end of treatment or study, 2 alatrofloxacin patients (S. aureus, P. aeruginosa) and 4 ciprofloxacin patients (all P. aeruginosa) had a microbiologically confirmed persistent pathogen at the time of failure. Three of the 4 ciprofloxacin patients with clinical failure and persistence had emergence of resistance with none on alatrofloxacin.

Complicated Intra-Abdominal Infections

Patients hospitalized with clinically documented, complicated intra-abdominal infections, including post-surgical infections, participated in a randomized, double-blind, multicenter trial comparing intravenous alatrofloxacin (300 mg once daily) followed by oral trovafloxacin (200 mg once daily) to intravenous imipenem/cilastatin (1g q8h) followed by oral amoxicillin/clavulanic acid (500 mg TID) for a maximum of 14 days of therapy. The clinical success rate (cure + improvement) at the End of Treatment was 88% (136/155) and 86% (122/142) for alatrofloxacin→trovafloxacin and imipenem/cilastatin→amoxicillin/clavulanic acid, respectively. The clinical success rate at the End of Study (Day 30) was 83% (129/156) and 84% (127/152) for alatrofloxacin→trovafloxacin and imipenem/cilastatin→amoxicillin/clavulanic acid, respectively.

The following are the clinical success rates for the clinically evaluable patient groups by pathogen:

Of patients with a baseline pathogen and a clinical response of failure at the End of Study, 9 of 26 on TROVAN and 10 of 21 on imipenem/cilastatin had microbiologically-confirmed persistence of the baseline pathogen with no emergence of resistance in either group.