Pharmacodynamic and immunomodulatory effects of polymyxin B in combination with fosfomycin against KPC-2-producing klebsiella pneumoniae

Abstract Determining the role of the immune response in preventing antimicrobial resistance and optimizing antibiotic regimens against carbapenemase-producing Klebsiella pneumoniae (KPC) is a research gap that exists and needs to be further explored. The objective of this study was to determine the pharmacodynamics and immunomodulatory effects of fosfomycin alone and in combination with polymyxin B against KPC-2-producing K. pneumoniae clinical isolates. Six K. pneumoniae isolates were selected (polymyxin B_MIC: 0.5-64 mg/L; Fosfomycin MIC: 16-128 mg/L) to evaluate the pharmacodynamics of mono- and combination therapies in static time-kill studies. A mechanism based model was used to characterize the joint activity of polymyxin B and fosfomycin. A549 human airway epithelial cells were infected with four isolates to evaluate the immunomodulatory effects of treatment. Our mechanism-based model indicated greater bacterial killing efficacy of fosfomycin with polymyxin B compared to monotherapy. In combination, polymyxin B was assumed to exert an outer membrane effect which resulted in an increase in fosfomycin's ability to reach its target site. The mechanism based model described the data well across all six strains with R2 values ranging from 0.705 to 0.935. The combination reduced K. pneumoniae-induced IL-6 and IL-8 but not TNF-α expression. The reduction in cytokine expression was greater with polymyxin B than fosfomycin alone, and combinations showed significantly greater reductions compared to monotherapies. Our findings suggest that further research is needed to understand immune-mediated killing to identify a strategy which harnesses the power of the immune response against these hard to treat bacteria in an in vivo system.

Pharmacodynamic and immunomodulatory effects of polymyxin B in combination with fosfomycin against KPC-2-producing Klebsiella pneumoniae.

Determining the role of the immune response in preventing antimicrobial resistance and optimising antibiotic regimens against carbapenemase-producing Klebsiella pneumoniae is a research gap that exists and needs to be further explored. The objective of this study was to determine the pharmacodynamic and immunomodulatory effects of fosfomycin alone and in combination with polymyxin B against KPC-2-producing K. pneumoniae clinical isolates. Six K. pneumoniae isolates were selected (polymyxin B MIC, 0.5-64 mg/L; fosfomycin MIC, 16-128 mg/L) to evaluate the pharmacodynamics of monotherapy and combination therapies in static time-kill studies. A mechanism-based model was used to characterise the joint activity of polymyxin B and fosfomycin. A549 human airway epithelial cells were infected with four isolates to evaluate the immunomodulatory effects of treatment. Our mechanism-based model indicated greater bacterial killing efficacy of fosfomycin with polymyxin B compared with monotherapy. In combination, polymyxin B was assumed to exert an outer membrane effect that resulted in an increase in the ability of fosfomycin to reach its target site. The mechanism-based model described the data well across all six strains, with R2 values ranging from 0.705-0.935. Combination therapy reduced K. pneumoniae-induced IL-6 and IL-8 but not TNFα expression. The reduction in cytokine expression was greater with polymyxin B than fosfomycin alone; combination therapy showed significantly greater reduction compared to either monotherapy. Our findings suggest that further research is needed to better understand immune-mediated killing in order to identify a strategy which harnesses the power of the immune response against these hard-to-treat bacteria.

Ceftazidime-Avibactam in Combination With Fosfomycin: A Novel Therapeutic Strategy Against Multidrug-Resistant Pseudomonas aeruginosa.

Previously, by targeting penicillin-binding protein 3, Pseudomonas-derived cephalosporinase (PDC), and MurA with ceftazidime-avibactam-fosfomycin, antimicrobial susceptibility was restored among multidrug-resistant (MDR) Pseudomonas aeruginosa. Herein, ceftazidime-avibactam-fosfomycin combination therapy against MDR P. aeruginosa clinical isolate CL232 was further evaluated. Checkerboard susceptibility analysis revealed synergy between ceftazidime-avibactam and fosfomycin. Accordingly, the resistance elements present and expressed in P. aeruginosa were analyzed using whole-genome sequencing and transcriptome profiling. Mutations in genes that are known to contribute to ß-lactam resistance were identified. Moreover, expression of blaPDC, the mexAB-oprM efflux pump, and murA were upregulated. When fosfomycin was administered alone, the frequency of mutations conferring resistance was high; however, coadministration of fosfomycin with ceftazidime-avibactam yielded a lower frequency of resistance mutations. In a murine infection model using a high bacterial burden, ceftazidime-avibactam-fosfomycin significantly reduced the P. aeruginosa colony-forming units (CFUs), by approximately 2 and 5 logs, compared with stasis and in the vehicle-treated control, respectively. Administration of ceftazidime-avibactam and fosfomycin separately significantly increased CFUs, by approximately 3 logs and 1 log, respectively, compared with the number at stasis, and only reduced CFUs by approximately 1 log and 2 logs, respectively, compared with the number in the vehicle-treated control. Thus, the combination of ceftazidime-avibactam-fosfomycin was superior to either drug alone. By employing a "mechanism-based approach" to combination chemotherapy, we show that ceftazidime-avibactam-fosfomycin has the potential to offer infected patients with high bacterial burdens a therapeutic hope against infection with MDR P. aeruginosa that lack metallo-ß-lactamases.

Fosfomycin for Injection (ZTI-01) Versus Piperacillin-tazobactam for the Treatment of Complicated Urinary Tract Infection Including Acute Pyelonephritis: ZEUS, A Phase 2/3 Randomized Trial.

BACKGROUND: ZTI-01 (fosfomycin for injection) is an epoxide antibiotic with a differentiated mechanism of action (MOA) inhibiting an early step in bacterial cell wall synthesis. ZTI-01 has broad in vitro spectrum of activity, including multidrug-resistant Gram-negative pathogens, and is being developed for treatment of complicated urinary tract infection (cUTI) and acute pyelonephritis (AP) in the United States. METHODS: Hospitalized adults with suspected or microbiologically confirmed cUTI/AP were randomized 1:1 to 6 g ZTI-01 q8h or 4.5 g intravenous (IV) piperacillin-tazobactam (PIP-TAZ) q8h for a fixed 7-day course (no oral switch); patients with concomitant bacteremia could receive up to 14 days. RESULTS: Of 465 randomized patients, 233 and 231 were treated with ZTI-01 and PIP-TAZ, respectively. In the microbiologic modified intent-to-treat (m-MITT) population, ZTI-01 met the primary objective of noninferiority compared with PIP-TAZ with overall success rates of 64.7% (119/184 patients) vs 54.5% (97/178 patients), respectively; treatment difference was 10.2% (95% confidence interval [CI]: -0.4, 20.8). Clinical cure rates at test of cure (TOC, day 19-21) were high and similar between treatments (90.8% [167/184] vs 91.6% [163/178], respectively). In post hoc analysis using unique pathogens typed by pulsed-field gel electrophoresis, overall success rates at TOC in m-MITT were 69.0% (127/184) for ZTI-01 versus 57.3% (102/178) for PIP-TAZ (difference 11.7% 95% CI: 1.3, 22.1). ZTI-01 was well tolerated. Most treatment-emergent adverse events, including hypokalemia and elevated serum aminotransferases, were mild and transient. CONCLUSIONS: ZTI-01 was effective for treatment of cUTI including AP and offers a new IV therapeutic option with a differentiated MOA for patients with serious Gram-negative infections. CLINICAL TRIAL REGISTRATION: NCT02753946.

Activity of fosfomycin when tested against US contemporary bacterial isolates.

Fosfomycin and comparators were susceptibility tested against over 2200 contemporary clinical isolates from US medical centers. Fosfomycin was active against Enterobacterales (MIC50/90, 4/16 µg/mL), including multidrug-resistant isolates. Potent activity was exhibited against gram-positive organisms, including Staphylococcus aureus (MIC50/90, 4/8 µg/mL). Fosfomycin may provide a promising alternative option for treatment of infections where resistant bacteria may occur.

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. Polymyxin B or fosfomycin monotherapy was ineffective and selected for resistance by 24 h. Polymyxin B plus a fosfomycin 1-h infusion demonstrated sustained bactericidal activity by 4 h, with undetectable colony counts beyond 144 h. Polymyxin B plus a fosfomycin 3-h infusion demonstrated bactericidal activity at 4 h, followed by regrowth similar to that of the control by 144 h. PAPs revealed resistant subpopulations by 120 h. The combination of polymyxin B and a fosfomycin 1-h infusion is a promising treatment option for KPC-producing K. pneumoniae and suppresses the emergence of resistance. Further evaluation of novel dosing strategies is warranted to optimize therapy.

Dilution Factor of Quantitative Bacterial Cultures Obtained by Bronchoalveolar Lavage in Patients with Ventilator-Associated Bacterial Pneumonia.

Ventilator-associated bacterial pneumonia (VABP) is a difficult therapeutic problem. Considerable controversy exists regarding the optimal chemotherapy for this entity. The recent guidelines of the Infectious Diseases Society of America and the American Thoracic Society recommend a 7-day therapeutic course for VABP based on the balance of no negative impact on all-cause mortality, less resistance emergence, and fewer antibiotic treatment days, counterbalanced with a higher relapse rate for patients whose pathogen is a nonfermenter. The bacterial burden causing an infection has a substantial impact on treatment outcome and resistance selection. We describe the baseline bronchoalveolar lavage (BAL) fluid burden of organisms in suspected VABP patients screened for inclusion in a clinical trial. We measured the urea concentrations in plasma and BAL fluid to provide an index of the dilution of the bacterial and drug concentrations in the lung epithelial lining fluid introduced by the BAL procedure. We were then able to calculate the true bacterial burden as the diluted colony count times the dilution factor. The median dilution factor was 28.7, with the interquartile range (IQR) being 11.9 to 53.2. Median dilution factor-corrected colony counts were 6.18 log10(CFU/ml) [IQR, 5.43 to 6.46 log10(CFU/ml)]. In a subset of patients, repeat BAL on day 5 showed a good stability of the dilution factor. We previously showed that large bacterial burdens reduce or stop bacterial killing by granulocytes. (This study has been registered at ClinicalTrials.gov under registration no. NCT01570192.).

Relationship between Fosfomycin Exposure and Amplification of Escherichia coli Subpopulations with Reduced Susceptibility in a Hollow-Fiber Infection Model.

Understanding the relationship between antibiotic exposure and amplification of bacterial subpopulations with reduced drug susceptibility over time is important for evaluating the adequacy of dosing regimens. We utilized a hollow-fiber infection model to identify the fosfomycin intravenous dosing regimens that prevented the amplification of Escherichia coli bacterial subpopulations with reduced fosfomycin susceptibility. The challenge isolate was E. coli ATCC 25922 (agar MIC with glucose-6-phosphate, 1 mg/liter; agar MIC without glucose-6-phosphate, 32 mg/liter). The fosfomycin dosing regimens studied were 1 to 12 g every 8 h for 10 days to approximate that planned for clinical use. The studies included a no-treatment control regimen. Two bacterial subpopulations were identified, one with reduced susceptibility with agar MIC values ranging from 32 to 128 mg/liter and the other resistant with agar MIC values of 256 to >1,024 mg/liter on plates containing 5× and 256× the baseline MIC value, respectively. An inverted-U-shaped function best described the relationship between the amplification of the two bacterial subpopulations and drug exposure. The lowest fosfomycin dosing regimen that did not amplify a bacterial subpopulation with reduced susceptibility was 4 g administered every 8 h. Nearly immediate amplification of bacterial subpopulations with reduced susceptibility was observed with fosfomycin dosing regimens consisting of 1 to 2 g every 8 h. These data will be useful to support the selection of fosfomycin dosing regimens that minimize the potential for on-therapy amplification of bacterial subpopulations with reduced susceptibility.

Exploration of the Pharmacokinetic-Pharmacodynamic Relationships for Fosfomycin Efficacy Using an In Vitro Infection Model.

Fosfomycin, a phosphonic class antibiotic with a broad spectrum of antibacterial activity, has been used outside the United States since the early 1970s for the treatment of a variety of infections. In the United States, an oral (tromethamine salt) formulation is used for uncomplicated urinary tract infections. Recently, there has been interest in the use of an intravenous solution (ZTI-01) for the treatment of a broad range of infections associated with multidrug-resistant bacteria. In this era of multidrug-resistant bacteria with few treatment options, it is critical to understand the pharmacokinetic-pharmacodynamic (PK-PD) determinants for fosfomycin efficacy. Since such data are limited, a one-compartment in vitro infection model was used to determine the PK-PD index associated with efficacy and the magnitude of this measure necessary for various levels of effect. One challenge isolate (Escherichia coli ATCC 25922, for which the fosfomycin agar MIC is 0.5 mg/liter and the broth microdilution MIC is 1 mg/liter) was evaluated in the dose fractionation studies, and two additional clinical E. coli isolates were evaluated in the dose-ranging studies. Mutation frequency studies indicated the presence of an inherently fosfomycin resistant E. coli subpopulation (agar MIC = 32 to 64 mg/liter) within the standard starting inoculum of a susceptibility test. Due to the presence of this resistant subpopulation, we identified the percentage of the dosing interval that drug concentrations were above the inherent resistance inhibitory concentration found at baseline to be the PK-PD index associated with efficacy (r(2) = 0.777). The magnitudes of this PK-PD index associated with net bacterial stasis and 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 11.9, 20.9, and 32.8, respectively. These data provide useful information for modernizing and optimizing ZTI-01 dosing regimens for further study.

Frequentist and Bayesian pharmacometric-based approaches to facilitate critically needed new antibiotic development: overcoming lies, damn lies, and statistics.

Antimicrobial drug development has greatly diminished due to regulatory uncertainty about the magnitude of the antibiotic treatment effect. Herein we evaluate the utility of pharmacometric-based analyses for determining the magnitude of the treatment effect. Frequentist and Bayesian pharmacometric-based logistic regression analyses were conducted by using data from a phase 3 clinical trial of tigecycline-treated patients with hospital-acquired pneumonia (HAP) to evaluate relationships between the probability of microbiological or clinical success and the free-drug area under the concentration-time curve from time zero to 24 h (AUC(0-24))/MIC ratio. By using both the frequentist and Bayesian approaches, the magnitude of the treatment effect was determined using three different methods based on the probability of success at free-drug AUC(0-24)/MIC ratios of 0.01 and 25. Differences in point estimates of the treatment effect for microbiological response (method 1) were larger using the frequentist approach than using the Bayesian approach (Bayesian estimate, 0.395; frequentist estimate, 0.637). However, the Bayesian credible intervals were tighter than the frequentist confidence intervals, demonstrating increased certainty with the former approach. The treatment effect determined by taking the difference in the probabilities of success between the upper limit of a 95% interval for the minimal exposure and the lower limit of a 95% interval at the maximal exposure (method 2) was greater for the Bayesian analysis (Bayesian estimate, 0.074; frequentist estimate, 0.004). After utilizing bootstrapping to determine the lower 95% bounds for the treatment effect (method 3), treatment effect estimates were still higher for the Bayesian analysis (Bayesian estimate, 0.301; frequentist estimate, 0.166). These results demonstrate the utility of frequentist and Bayesian pharmacometric-based analyses for the determination of the treatment effect using contemporary trial endpoints. Additionally, as demonstrated by using pharmacokinetic-pharmacodynamic data, the magnitude of the treatment effect for patients with HAP is large.

Pharmacokinetic-pharmacodynamic considerations in the design of hospital-acquired or ventilator-associated bacterial pneumonia studies: look before you leap!

Our thesis is a simple one: although a drug can fail in an individual patient for many reasons, appropriately sized and conducted drug-development programs often fail because of insensitive, uninformative end points, and/or poor a priori regimen decisions. The difficulty in successfully developing antimicrobial agents at present is often exacerbated by company decision-makers who are either uninformed or disregard the difference between empirical-based (ie, akin to playing pin-the-tail on the donkey) and quantitative model-based development plans. Frequently, the focus is on Gantt charts (project event schedules) and the on-time submission of a New Drug Application to a regulatory body, such as the US Food and Drug Administration. Such misplaced focus has led and will continue to lead to a number of problems, including program failure or, even worse, regulatory approval of an inappropriate dosing regimen with associated negative safety and efficacy sequelae. We believe that the goal of drug development is not a New Drug Application submitted on time but, rather, an approved, differentiated, safe, and effective new medicine. Here, we focus on the pharmacokinetic-pharmacodynamic data needed to guide dosing regimen decisions for patients with hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia. Early consideration of these data in development programs will reduce risk not only to sponsors but also, most importantly, to the patients enrolled in the clinical trials.

Exposure-response analyses of tigecycline tolerability in healthy subjects.

Tigecycline exposure (area under the concentration-time curve [AUC((0-infinity))] and maximum serum concentration [C(max)]) and first occurrence of nausea and vomiting were evaluated in 136 healthy subjects after 12.5- to 300-mg single doses. Nausea was more frequent in females (46%, 10/22) compared with males (31%, 11/36) after 100-mg doses. Most nausea (vomiting) events occurred < or =4 h (<6 h) after tigecycline. For doses < or =100 mg, the median duration of nausea and vomiting was approximately 5 h. Based on logistic regression, increased exposure (AUC((0-infinity)) >C(max)) to tigecycline results in an increased rate of nausea (P < or = .0001; = .0022) and vomiting (P < or = .0001; = .0006). At the median AUC((0-infinity)) (C(max)) for the 50-mg dose group, the probability of nausea and vomiting was 0.26 (0.29) and 0.07 (0.11), respectively. Model-predicted rates of nausea and vomiting were comparable with those observed for the tetracycline class of antibiotics, with tolerable rates predicted after 50-mg doses of tigecycline.

Moving goalposts--regulatory oversight of antibacterial drugs.

Is uncertainty concerning the regulation of antimicrobial drug trials stifling investment in infectious disease treatments? Here, experts from a large pharma company and a biotech firm provide their perspectives.

Serum, tissue and body fluid concentrations of tigecycline after a single 100 mg dose.

OBJECTIVES: The purpose of this study was to determine the tissue and corresponding serum concentration of tigecycline at selected time points in gall bladder, bile, colon, bone, synovial fluid (SF), lung and CSF in subjects undergoing surgical or medical procedures. METHODS: One hundred and four adult subjects (aged 24-83 years; 64 women, 40 men) received a single intravenous (i.v.) dose of tigecycline (100 mg infused over 30 min). Subjects were randomly assigned to one of four collection times at 4, 8, 12 and 24 h after the start of the infusion. For CSF, samples were collected at approximately 1.5 and 24 h after the start of the infusion. All subjects had serum samples collected before the administration of tigecycline, at the end of the infusion and at the time corresponding to tissue or body fluid collection. Drug concentrations in serum, tissues and body fluids were determined by LC/MS/MS. The area under the mean concentration-time curve from 0 to 24 h (AUC(0-24)) was determined for the comparison of systemic exposure between tissue or body fluid to serum. RESULTS: The mean serum concentrations of tigecycline were similar to those previously published. Tissue penetration, expressed as the ratio of AUC(0-24) in tissue or body fluid to serum, was 537 for bile, 23 for gall bladder, 2.6 for colon, 2.0 for lung, 0.41 for bone, 0.31 for SF and 0.11 for CSF. CONCLUSIONS: A single 100 mg dose of intravenous tigecycline produced considerably higher tissue/fluid concentrations in bile, gall bladder, colon and lung compared with simultaneous serum concentrations. On average, the systemic exposure of tigecycline in bone, SF and CSF ranged from 11% to 41% of serum concentrations. The results in bone are inconsistent with previous radiolabelled studies in animals and it is unclear if tight binding to bone (versus low bone uptake) or poor extraction of tigecycline for LC/MS/MS detection or both may have contributed to the differences we observed in humans.

Safety and efficacy of tigecycline in treatment of skin and skin structure infections: results of a double-blind phase 3 comparison study with vancomycin-aztreonam.

In a randomized, double-blind, controlled trial, 546 patients with complicated skin and skin structure infections received tigecycline 100 mg/day (a 100-mg initial dose and then 50 mg intravenously twice daily) or the combination of vancomycin 2 g/day (1 g intravenously twice daily) and aztreonam 4 g/day (2 g intravenously twice daily) for up to 14 days. The primary end point was the clinical response in the clinical modified intent-to-treat (c-mITT) and clinically evaluable (CE) populations at the test-of-cure visit 12 to 92 days after the last dose. The microbiologic response at the test-of-cure visit was also assessed. Safety was assessed by physical examination, laboratory results, and adverse event reporting. Five hundred twenty patients were included in the c-mITT population (tigecycline group, n = 261; combination group, n = 259), and 436 were clinically evaluable (tigecycline group, n = 223; combination group, n = 213). The clinical responses in the tigecycline and the combination vancomycin and aztreonam groups were similar in the c-mITT population (84.3% versus 86.9%; difference, -2.6% [95% confidence interval, -9.0, 3.8]; P = 0.4755) and the CE population (89.7% versus 94.4%; difference, -4.7% [95% confidence interval, -10.2, 0.8]; P = 0.1015). Microbiologic eradication (documented or presumed) occurred in 84.8% of the patients receiving tigecycline and 93.2% of the patients receiving vancomycin and aztreonam (difference, -8.5 [95% confidence interval, -16.0, -1.0]; P = 0.0243). The numbers of patients reporting adverse events were similar in the two groups, with increased nausea and vomiting rates in the tigecycline group and an increased incidence of rash and increases in alanine aminotransferase and aspartate aminotransferase levels in the combination vancomycin and aztreonam group. Tigecycline was shown to be safe and effective for the treatment of complicated skin and skin structure infections.

A multicenter trial of the efficacy and safety of tigecycline versus imipenem/cilastatin in patients with complicated intra-abdominal infections [Study ID Numbers: 3074A1-301-WW; ClinicalTrials.gov Identifier: NCT00081744].

BACKGROUND: Complicated intra-abdominal infections (cIAI) remain challenging to treat because of their polymicrobial etiology including multi-drug resistant bacteria. The efficacy and safety of tigecycline, an expanded broad-spectrum glycylcycline antibiotic, was compared with imipenem/cilastatin (IMI/CIS) in patients with cIAI. METHODS: A prospective, double-blind, multinational trial was conducted in which patients with cIAI randomly received intravenous (IV) tigecycline (100 mg initial dose, then 50 mg every 12 hours [q12h]) or IV IMI/CIS (500/500 mg q6h or adjusted for renal dysfunction) for 5 to14 days. Clinical response at the test-of-cure (TOC) visit (14-35 days after therapy) for microbiologically evaluable (ME) and microbiological modified intent-to-treat (m-mITT) populations were the co-primary efficacy endpoint populations. RESULTS: A total of 825 patients received >or= 1 dose of study drug. The primary diagnoses for the ME group were complicated appendicitis (59%), and intestinal (8.8%) and gastric/duodenal perforations (4.6%). For the ME group, clinical cure rates at TOC were 80.6% (199/247) for tigecycline versus 82.4% (210/255) for IMI/CIS (95% CI -8.4, 5.1 for non-inferiority tigecycline versus IMI/CIS). Corresponding clinical cure rates within the m-mITT population were 73.5% (227/309) for tigecycline versus 78.2% (244/312) for IMI/CIS (95% CI -11.0, 2.5). Nausea (31.0% tigecycline, 24.8% IMI/CIS [P = 0.052]), vomiting (25.7% tigecycline, 19.4% IMI/CIS [P = 0.037]), and diarrhea (21.3% tigecycline, 18.9% IMI/CIS [P = 0.435]) were the most frequently reported adverse events. CONCLUSION: This study demonstrates that tigecycline is as efficacious as imipenem/cilastatin in the treatment of patients with cIAI.

The pharmacokinetic and pharmacodynamic profile of tigecycline.

Tigecycline, a first-in-class expanded-spectrum antimicrobial agent, has demonstrated efficacy in the treatment of complicated intra-abdominal and skin and skin-structure infections. This new antibiotic is available as an intravenous formulation and exhibits linear pharmacokinetics. It is rapidly distributed and has a large volume of distribution, indicating extensive tissue penetration. After a 100-milligram loading dose, followed by 50 milligrams every 12 h, the steady-state maximum concentration in serum after a 1-h infusion is approximately 0.6 microg/mL, the 24-h steady-state area under the concentration-time curve is approximately 5-6 microg.h/mL, and the terminal elimination half-life is approximately 40 h. The major route of elimination of tigecycline is through the feces, primarily as unchanged drug. The pharmacokinetic profile is not affected by severe or end-stage renal disease, nor is it significantly altered by hemodialysis. The pharmacokinetics of tigecycline are also not affected by food, although tolerability is increased if the drug is administered following a meal.

Pharmacokinetic/pharmacodynamic profile for tigecycline-a new glycylcycline antimicrobial agent.

Tigecycline is a new first-in-class glycylcycline antimicrobial agent with expanded broad-spectrum activity against both Gram-negative and Gram-positive aerobes and anaerobes, as well as atypical bacterial species. The spectrum of activity extends to clinically relevant susceptible and multidrug-resistant strains of Staphylococcus aureus, Streptococcus pneumoniae, vancomycin-resistant enterococci, and Enterobacteriaceae, including extended-spectrum beta-lactamase-producing strains. Tigecycline is administered as an intravenous formulation and has been studied in the treatment of serious polymicrobial infections, including complicated skin and skin-structure infections and intra-abdominal infections. Pharmacokinetic analysis of data from phase 1 trials of healthy subjects indicate that tigecycline has a large volume of distribution, signifying extensive tissue penetration, and a long terminal elimination half-life (approximately 40 h), easily allowing for twice-daily dose administration. Tigecycline penetrates well into blister fluid, which supports the positive findings of phase 2 and 3 studies of the efficacy of tigecycline in the treatment of serious skin and skin-structure infections. Metabolic studies in humans have revealed that tigecycline undergoes very limited metabolism and the primary route of elimination of unchanged drug is through the feces, with glucuronidation and renal elimination as secondary routes. A preliminary pharmacokinetic (PK)/pharmacodynamic analysis in experimental animal models of infection indicates that the efficacy of tigecycline is probably best predicted by the ratio of the area under the concentration-time curve to the minimum inhibitory concentration. The expanded in vitro activity against a broad range of bacteria, including resistant pathogens, and favorable PK profile of tigecycline suggest that this novel antimicrobial agent should offer clinicians an option for the treatment of patients with serious bacterial infections.

Pharmacodynamic effects of a nonpeptide antidiuretic hormone V2 antagonist in cirrhotic patients with ascites.

Water retention and dilutional hyponatremia, mainly attributable to an impairment of free water excretion and increased vasopressin activity, are well-documented complications in cirrhotic patients with ascites. VPA-985 is a selective, nonpeptide, orally active, vasopressin-2-receptor antagonist. The aim of this study was to determine the pharmacodynamics, safety, and pharmacokinetics of ascending single doses (25, 50, 100, 200, and 300 mg) in cirrhotic patients with ascites in a randomized, double-blind, placebo-controlled trial. Each dose level was studied in 5 patients (4 active and 1 placebo). After an overnight fast and fluid restriction (continued for 4 hours after dose administration), all patients were given placebo on baseline day and an oral suspension of VPA or placebo on the following day. VPA produced a significant dose-related increase in daily urine output (1,454 +/- 858 mL to 4,568 +/- 4,385 mL with VPA 300 mg) and a dose-related decrease in urine osmolality. The free water clearance reached greater than 3 mL/min for doses 100 mg or greater. Simultaneously, significant increases in serum osmolality, sodium, and vasopressin levels were found. There was a significant increase in sodium urine excretion. VPA was rapidly absorbed and maximum serum concentrations were achieved within 1 hour after administration. Elimination half-life ranged from 9.0 hours after 100 mg to 22.6 hours after 200 mg. In conclusion, VPA induced a dose-related aquaretic response, suggesting a therapeutic potential in managing water retention in patients with liver cirrhosis with ascites.