Evaluation of the Bactericidal Activity of Fosfomycin in Combination with Selected Antimicrobial Comparison Agents Tested against Gram-Negative Bacterial Strains by Using Time-Kill Curves.

The effects of combining fosfomycin with various antimicrobial agents were evaluated in vitro by broth microdilution checkerboard and time-kill kinetic studies. Checkerboard analyses were used to evaluate the following 30 Gram-negative isolates: 5 Pseudomonas aeruginosa, 5 Acinetobacter baumannii-Acinetobacter calcoaceticus species complex, and 20 Enterobacteriaceae isolates. No isolate exhibited antagonism when fosfomycin was tested in combination, and synergy was observed in more than 25% of the drug combinations tested. The most frequent instances of synergy occurred when testing fosfomycin with ß-lactams. Two isolates of Pseudomonas aeruginosa, 2 of Klebsiella pneumoniae, and 1 of the A. baumannii-A. calcoaceticus species complex that exhibited synergy when fosfomycin was tested in combination were subjected to time-kill kinetic analyses for confirmation. Time-kill assays confirmed synergistic activity. These data indicated that combination therapy with fosfomycin may be beneficial.

Evaluation of activity and emergence of resistance of Polymyxin B and ZTI-01 (Fosfomycin for Injection) against KPC-Producing Klebsiella pneumoniae

ZTI-01 (fosfomycin for injection) is a broad-spectrum antibiotic with a novel mechanism of action and is currently under development in the United States for treatment of complicated urinary tract infections. Globally, fosfomycin and polymyxin B are increasingly being used to treat multidrug-resistant Gram-negative infections. The objectives were to evaluate the pharmacodynamic activity of polymyxin B and fosfomycin alone and in combination against KPC-producing Klebsiella pneumoniae and to assess the rate and extent of emergence of resistance to different antibiotic regimens. Two clinical isolates, BRKP26 (MIC of polymyxin B[MICPMB], 0.5 mg/liter; MIC of fosfomycin [MICFOF], 32 mg/liter) and BRKP67 (MICPMB, 8 mg/liter; MICFOF, 32 mg/liter) at an initial inoculum of 107 CFU/ml, were evaluated over 168 h in a hollow-fiber infection model simulating clinically relevant polymyxin B (2.5-mg/kg loading dose as a 2 h-infusion followed by 1.5-mg/kg dose every 12 h [q12h] as a 1-h infusion) and fosfomycin (6 g q6h as a 1-h or 3-h infusion) regimens alone and in combination. Population analysis profiles (PAPs) and MIC testing were performed to assess emergence of resistance...

Pharmacokinetics, Safety, and Tolerability of Single-Dose Intravenous (ZTI-01) and Oral Fosfomycin in Healthy Volunteers.

The pharmacokinetics, safety, and tolerability of intravenous (i.v.) fosfomycin disodium (ZTI-01) and oral fosfomycin tromethamine were evaluated after a single dose in 28 healthy adult subjects. Subjects received a single 1-h i.v. infusion of 1 g and 8 g fosfomycin disodium and a single dose of 3 g oral fosfomycin tromethamine in a phase I, randomized, open-label, three-period crossover study. Serial blood and urine samples were collected before and up to 48 h after dosing. The mean pharmacokinetic parameters ± standard deviations of fosfomycin in plasma after 1 g and 8 g i.v., respectively, were the following: maximum clearance of drug in serum (Cmax), 44.3 ± 7.6 and 370 ± 61.9 µg/ml; time to maximum concentration of drug in serum (Tmax), 1.1 ± 0.05 and 1.08 ± 0.01 h; volume of distribution (V), 29.7 ± 5.7 and 31.5 ± 10.4 liters; clearance (CL), 8.7 ± 1.7 and 7.8 ± 1.4 liters/h; renal clearance (CLR), 6.6 ± 1.9 and 6.3 ± 1.6 liters/h; area under the concentration-time curve from 0 to infinity (AUC0-∞), 120 ± 28.5 and 1,060 ± 192 µg·h/ml; and half-life (t1/2), 2.4 ± 0.4 and 2.8 ± 0.6 h. After oral administration, the parameters were the following: Cmax, 26.8 ± 6.4 µg/ml; Tmax, 2.25 ± 0.4 h; V/F, 204 ± 70.7 liters; CL/F, 17 ± 4.7 liters/h; CLR, 6.5 ± 1.8 liters/h; AUC0-∞, 191 ± 57.6 µg · h/ml; and t1/2, 9.04 ± 4.5 h. The percent relative bioavailability of orally administered fosfomycin was 52.8% in relation to the 1-g i.v. dose. Approximately 74% and 80% of the 1-g and 8-g i.v. doses were excreted unchanged in the urine by 48 h compared to 37% after oral administration, with the majority of this excretion occurring by 12 h regardless of dosage form. No new safety concerns were identified during this study. The results of this study support further investigation of i.v. fosfomycin in the target patient population, including patients with complicated urinary tract infections and pyelonephritis.

Efficacy and safety of tigecycline compared with vancomycin or linezolid for treatment of serious infections with methicillin-resistant Staphylococcus aureus or vancomycin-resistant enterococci: a Phase 3, multicentre, double-blind, randomized study.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) are causing serious nosocomial infections. Tigecycline was evaluated in hospitalized patients with MRSA or VRE infection. PATIENTS AND METHODS: A randomized (3:1), double-blind, multicentre, Phase 3 study compared the safety and efficacy of tigecycline with vancomycin or linezolid in hospitalized patients with MRSA or VRE infection, respectively. Patients were treated for 7-28 days and the test-of-cure (TOC) assessment was made 12-37 days after the last dose. The primary efficacy endpoint was the clinical response (cure, failure and indeterminate) in the co-primary, microbiologically evaluable (ME) and microbiologically modified intent-to-treat (m-mITT) populations at the TOC assessment. RESULTS: For MRSA infection, clinical cure rates in the ME population (n = 117) were 81.4% (70 of 86 patients) with tigecycline and 83.9% (26 of 31 patients) with vancomycin. In the m-mITT population (n = 133), clinical cure occurred in 75 of 100 tigecycline-treated patients (75.0%) and in 27 of 33 vancomycin-treated patients (81.8%). In patients with complicated skin and skin structure infections caused by MRSA, cure rates were similar with tigecycline or vancomycin (86.4% versus 86.9% in ME population; and 78.6% versus 87.0% in m-mITT population). In patients with MRSA infection, nausea or vomiting occurred more frequently with tigecycline than with vancomycin (41.0% versus 17.9%); most cases were mild, with only three patients discontinuing treatment. In patients with VRE (total enrollment, 15), 3 of 3 and 3 of 8 patients in the ME and m-mITT populations, respectively, were cured by tigecycline, compared with 2 of 3 patients in the ME and m-mITT populations treated with linezolid. CONCLUSIONS: Tigecycline is safe and effective in hospitalized patients with serious infection caused by MRSA. There were too few cases of VRE to draw any conclusions.

Exposure-response analyses of tigecycline efficacy in patients with complicated intra-abdominal infections.

Exposure-response analyses were performed to test the microbiological and clinical efficacies of tigecycline in complicated intra-abdominal infections where Escherichia coli and Bacteroides fragilis are the predominant pathogens. Data from evaluable patients enrolled in three clinical trials were pooled. Patients received intravenous tigecycline (100-mg loading dose followed by 50 mg every 12 h or 50-mg loading dose followed by 25 mg every 12 h). At the test-of-cure visit, microbiological and clinical responses were evaluated. Patients were prospectively classified into cohorts based on infection with a baseline pathogen(s): E. coli only (cohort 1), other mono- or polymicrobial Enterobacteriaceae (cohort 2), at least one Enterobacteriaceae pathogen plus an anaerobe(s) (cohort 3), at least one Enterobacteriaceae pathogen plus a gram-positive pathogen(s) (cohort 4), and all other pathogens (cohort 5). The cohorts were prospectively combined to increase sample size. Logistic regression was used to evaluate ratio of steady-state 24-hour area under the concentration-time curve (AUC) to MIC as a response predictor, and classification-and-regression-tree (CART) analyses were utilized to determine AUC/MIC breakpoints. Analysis began with cohorts 1, 2, and 3 pooled, which included 71 patients, with 106 pathogens. The small sample size precluded evaluation of cohorts 1 (34 patients, 35 E. coli pathogens) and 2 (16 patients, 24 Enterobacteriaceae). CART analyses identified a significant AUC/MIC breakpoint of 6.96 for microbiological and clinical responses (P values of 0.0004 and 0.399, respectively). The continuous AUC/MIC ratio was also borderline predictive of microbiological response (P = 0.0568). Cohort 4 (21 patients, 50 pathogens) was evaluated separately; however, an exposure-response relationship was not detected; cohort 5 (31 patients, 60 pathogens) was not evaluated. The prospective approach of creating homogenous populations of pathogens was critical for identifying exposure-response relationships in complicated intra-abdominal infections.

Exposure-response analyses of tigecycline efficacy in patients with complicated skin and skin-structure infections.

Exposure-response analyses were performed for the microbiological and clinical efficacy of tigecycline in the treatment of complicated skin and skin-structure infections, where Staphylococcus aureus and streptococci are the predominant pathogens. A prospective method was developed to create homogeneous patient populations for PK-PD analyses. Evaluable patients from three clinical trials were pooled for analysis. Patients received a tigecycline 100-mg loading dose/50 mg every 12 h or a 50-mg loading dose/25 mg every 12 h. At the test-of-cure visit, microbiologic and clinical responses were evaluated. Patients were prospectively evaluated and classified into cohorts based on baseline pathogens: S. aureus only (cohort 1), monomicrobial S. aureus or streptococci (cohort 2), two gram-positive pathogens (cohort 3), polymicrobial (cohort 4), or other monomicrobial infections (cohort 5). A prospective procedure for combining cohorts was used to increase the sample size. Logistic regression evaluated steady-state 24-h area under the concentration-time curve (AUC(24))/MIC ratio as a predictor of response, and classification and regression tree (CART) analyses were utilized to determine AUC/MIC breakpoints. Analysis began with pooled cohorts 2 and 3, the focus of these analyses, and included 35 patients with 40 S. aureus and/or streptococcal pathogens. CART analyses identified a significant AUC/MIC breakpoint of 17.9 (P = 0.0001 for microbiological response and P = 0.0376 for clinical response). The continuous AUC/MIC ratio was predictive of microbiological response based on sample size (P = 0.0563). Analysis of all pathogens combined decreased the ability to detect exposure-response relationships. The prospective approach of creating homogeneous populations based on S. aureus and streptococci pathogens was critical for identifying exposure-response relationships.

The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double-blind phase 3 comparison studies with vancomycin-aztreonam.

Two phase 3, double-blind studies in hospitalized adults with complicated skin and skin-structure infections (cSSSI) determined the safety and efficacy of tigecycline versus that of vancomycin-aztreonam. Patients received tigecycline (100 mg, followed by 50 mg intravenously twice daily) or vancomycin (1 g intravenously twice daily) plus aztreonam (2 g intravenously twice daily) for up to 14 days. Populations were as follows: 1116 patients (566 treated with tigecycline, and 550 treated with vancomycin-aztreonam) constituted the modified intent-to-treat (mITT) population, 1057 patients (538 treated with tigecycline, and 519 treated with vancomycin-aztreonam) constituted the clinical mITT (c-mITT) population, and 833 patients (422 treated with tigecycline, and 411 treated with vancomycin-aztreonam) constituted the clinically evaluable population. Clinical responses to tigecycline and vancomycin-aztreonam at test-of-cure were similar: c-mITT, 79.7% (95% confidence interval [CI], 76.1%-83.1%) versus 81.9% (95% CI, 78.3%-85.1%) (P = .4183); and clinically evaluable, 86.5% (95% CI, 82.9%-89.6%) versus 88.6% (95% CI, 85.1%-91.5%) (P = .4233). Adverse events were similar, with increased nausea and vomiting in the tigecycline group and increased rash and elevated hepatic aminotransferase levels in the vancomycin-aztreonam group. Tigecycline monotherapy is as safe and efficacious as the vancomycin-aztreonam combination in treating patients with cSSSI.

Results of a multicenter, randomized, open-label efficacy and safety study of two doses of tigecycline for complicated skin and skin-structure infections in hospitalized patients.

BACKGROUND: Tigecycline is a broad-spectrum glycylcycline antibiotic being investigated for the treatment of serious infections in hospitalized patients. Tigecycline has been shown to be efficacious against serious infections in animals, and preliminary studies in healthy adults have shown that tigecycline has an acceptable tolerability profile. OBJECTIVE: This study compared the clinical and microbiological efficacy, pharmacokinetic properties, and tolerability of 2 doses of tigecycline in hospitalized patients with a complicated skin and skin-structure infection (cSSSI). METHODS: This Phase II, randomized, open-label study was conducted between September 1999 and March 2001 at 14 investigative centers across the United States. Patients were randomized to receive tigecycline 25 or 50 mg IV q12h for 7 to 14 days. The primary efficacy end point was the clinically observed cure rate among clinically evaluable (CE) patients at the test-of-cure visit. Secondary end points were the clinical cure rate at the end of treatment and bacteriologic response in microbiologically evaluable (ME) patients. Also, in vitro tests of susceptibility to tigecycline were performed for selected pathogens known to cause skin infections, including methicillin-resistant and methicillin-susceptible Streptococcus pyogenes, Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, and Enterococcus faecium. Tolerability assessments also were conducted. RESULTS: A total of 160 patients received > or =1 dose of tigecycline; 109 patients were CE, and 91 were ME. The majority of patients (74%) were men, and the mean (SD) age was 49.0 (14.8) years. At the test-of-cure visit, the clinical cure rate in the 25-mg group was 67% (95% CI, 53.3%-79.3%) and in the 50-mg group was 74% (95% CI, 60.3%-85.0%). In the 25-mg group, 56% of the patients had eradication (95% CI, 40.0%-70.4%) of the pathogens compared with 69% (95% CI, 54.2%-82.3%) in the 50-mg group. Values for the minimum concentration of tigecycline that is inhibitory for 90% of all isolates ranged from 0.06 to 0.50 microg/mL for the selected pathogens. Both tigecycline doses were generally well tolerated. Nausea and vomiting were the most common adverse events. CONCLUSIONS: In this study, tigecycline appeared efficacious and showed a favorable pharmacokinetic profile and an acceptable safety profile in the treatment of hospitalized patients with cSSSI. In patients who received 50-mg doses of tigecycline q12h, the clinical cure rates and microbial eradication rates were 74% and 70%, respectively, and were 67% and 56% in patients who received 25-mg doses.