Evaluation of Oral Tebipenem as a Step-Down Therapy following Intravenous Ertapenem against Extended-Spectrum ß-Lactamase-Producing Escherichia coli in a Hollow-Fiber In Vitro Infection Model.

Tebipenem is an orally bioavailable carbapenem in development for the treatment of patients with complicated urinary tract infections. Herein, we describe the results of studies designed to evaluate tebipenem's potential as an oral (p.o.) transition therapy from intravenous (i.v.) ertapenem therapy for the most common uropathogen, Escherichia coli. These studies utilized a 7-day hollow-fiber in vitro infection model and 5 extended-spectrum ß-lactamase-producing E. coli challenge isolates. Human free-drug serum concentration-time profiles for tebipenem 600 mg p.o. every 8 h and ertapenem 1 g i.v. every 24 h were simulated in the hollow-fiber in vitro infection model. Samples were collected for bacterial density and drug concentration determination over the 7-day study period. Generally, ertapenem monotherapy resulted in a greater reduction in bacterial density than did tebipenem monotherapy. In the treatment arms in which ertapenem dosing was stopped following dosing for 1 or 3 days, immediate bacterial regrowth occurred and matched that of the growth control. Finally, in the treatment arms in which ertapenem dosing was stopped following dosing for 1 or 3 days and tebipenem dosing was initiated for the remainder of the 7-day study, the intravenous-to-oral transition regimen reduced bacterial burdens and prevented regrowth. Given that transition from intravenous to oral antibiotic therapy has been shown to reduce hospital length of stay, nosocomial infection risk, and cost, and improve patient satisfaction, these data demonstrate tebipenem's potential role as an oral transition agent from intravenous antibiotic regimens within the antibiotic stewardship paradigm.

Development of Modernized Acinetobacter baumannii Susceptibility Test Interpretive Criteria for Recommended Antimicrobial Agents Using Pharmacometric Approaches.

Acinetobacter baumannii-Acinetobacter calcoaceticus complex (referred to herein as A. baumannii) treatment guidelines contain numerous older antimicrobial agents with susceptibility test interpretive criteria (STIC, also known as susceptibility breakpoints) set using only epidemiological data. We utilized a combination of in vitro surveillance data, preclinical murine thigh and lung infection models, population pharmacokinetics, simulation, and pharmacokinetic/pharmacodynamic (PK/PD) target attainment analyses to evaluate A. baumannii STIC for four commonly recommended antimicrobials from different classes (amikacin, ceftazidime, ciprofloxacin, and minocycline). Antimicrobial in vitro surveillance data were based on 1,647 clinical A. baumannii isolates obtained from 109 centers in the United States and Europe. Among these isolates, 5 were selected for evaluation in murine infection models based on fitness and MIC variability. PK and dose-ranging studies were conducted using neutropenic murine thigh and lung infection models The MIC ranges for the 5 isolates evaluated were as follows: amikacin, 2 to 32 µg/mL; ceftazidime, 4 to 16 µg/mL; ciprofloxacin, 0.12 to 2 µg/mL; minocycline, 0.25 to 4 µg/mL. All organisms grew ≥1.5 log10 CFU in both models in untreated controls. Plasma and epithelial lining fluid (ELF) pharmacokinetics for all drugs were determined in mice using liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. For each isolate, 5 dose levels of each drug were tested individually in the thigh and lung infection model. The inoculum ranged from 7.9 to 8.4 and 6.8 to 7.7 log10 CFU/mL for the lung and thigh models, respectively. PK/PD targets associated with net bacterial stasis and 1- and 2-log10 CFU reductions from baseline were identified for each organism/infection model using Hill-type models. Population pharmacokinetic models for each agent were identified from the literature. Using demographic variables for simulated patients with hospital-acquired or ventilator-associated bacterial pneumonia or urinary tract infections (including acute pyelonephritis) who were administered maximal dosing regimens of each agent, estimates of protein binding, and ELF penetration ratios based on data from the literature, free-drug plasma and total-drug concentration-time profiles were generated, and PK/PD indices by MIC were calculated. Percent probabilities of attaining median and randomly assigned PK/PD targets associated with the above-described endpoints were determined. Recommended susceptible breakpoints for each agent were those representing the highest MIC at which the percent probabilities of achieving PK/PD targets associated with a 1-log10 CFU reduction from baseline approached or were ≥90%. The following susceptible breakpoints for A. baumannii were identified: amikacin, ≤8 µg/mL for pneumonia; ceftazidime, ≤32 and ≤8 µg/mL for pneumonia; ciprofloxacin, ≤1 µg/mL; and minocycline, ≤0.5/≤1 µg/mL which correspond to the standard and high minocycline dosing regimens of 200 mg per day and 200 mg every 12 h, respectively. Implementation of appropriate STIC will help clinicians optimally use the above-described agents and improve the likelihood of successful patient outcomes.

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses as Support for Meropenem-Vaborbactam Dosing Regimens and Susceptibility Breakpoints.

Meropenem-vaborbactam is a fixed-dose beta-lactam/beta-lactamase inhibitor with potent in vitro and in vivo activity against Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales. Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken using population pharmacokinetic models, nonclinical PK-PD targets for efficacy, in vitro surveillance data, and simulation to provide support for 2 g meropenem-2 g vaborbactam every 8 h (q8h) administered as a 3-h intravenous (i.v.) infusion, and dosing regimens adjusted for patients with renal impairment. Simulated patients varying by renal function measure (estimated glomerular filtration rate [eGFR], mL/min/1.73 m2 and absolute eGFR, mL/min) and resembling the clinical trial population (complicated urinary tract infection, including acute pyelonephritis) were generated. The PK-PD targets for meropenem, the percentage of time on day 1 that free-drug plasma concentrations were above the MIC (%T>MIC), and vaborbactam, the ratio of free-drug plasma area under the concentration-time curve (AUC) on day 1 to the MIC (AUC:MIC ratio), were calculated. Percent probabilities of achieving meropenem free-drug plasma %T>MIC and vaborbactam free-drug plasma AUC:MIC ratio targets were assessed. MIC distributions for Enterobacterales, KPC-producing Enterobacterales, and Pseudomonas aeruginosa were considered as part of an algorithm to assess PK-PD target attainment. For assessments of free-drug plasma PK-PD targets associated with a 1-log10 CFU reduction from baseline, percent probabilities of PK-PD target attainment ranged from 81.3 to 100% at meropenem-vaborbactam MIC values of 4 or 8 µg/mL among simulated patients. The results of these PK-PD target attainment analyses provide support for a dosing regimen of 2 g meropenem-2 g vaborbactam q8h administered as a 3-h i.v. infusion, with dosing regimens adjusted for patients with renal impairment and a meropenem-vaborbactam susceptibility breakpoint of ≤8 µg/mL (tested with a fixed vaborbactam concentration of 8 µg/mL) for Enterobacterales and P. aeruginosa based on these dosing regimens.

Population Pharmacokinetics of Meropenem and Vaborbactam Based on Data from Noninfected Subjects and Infected Patients.

Meropenem-vaborbactam is a broad-spectrum carbapenem-beta-lactamase inhibitor combination approved in the United States and Europe to treat patients with complicated urinary tract infections and in Europe for other serious bacterial infections, including hospital-acquired and ventilator-associated pneumonia. Population pharmacokinetic (PK) models were developed to characterize the time course of meropenem and vaborbactam using pooled data from two phase 1 and two phase 3 studies. Multicompartment disposition model structures with linear elimination processes were fit to the data using NONMEM 7.2. Since both drugs are cleared primarily by the kidneys, estimated glomerular filtration rate (eGFR) was evaluated as part of the base structural models. For both agents, a two-compartment model with zero-order input and first-order elimination best described the pharmacokinetic PK data, and a sigmoidal Hill-type equation best described the relationship between renal clearance and eGFR. For meropenem, the following significant covariate relationships were identified: clearance (CL) decreased with increasing age, CL was systematically different in subjects with end-stage renal disease, and all PK parameters increased with increasing weight. For vaborbactam, the following significant covariate relationships were identified: CL increased with increasing height, volume of the central compartment (Vc) increased with increasing body surface area, and CL, Vc, and volume of the peripheral compartment were systematically different between phase 1 noninfected subjects and phase 3 infected patients. Visual predictive checks demonstrated minimal bias, supporting the robustness of the final models. These models were useful for generating individual PK exposures for pharmacokinetic-pharmacodynamic (PK-PD) analyses for efficacy and Monte Carlo simulations to evaluate PK-PD target attainment.

Pharmacokinetic-Pharmacodynamic Evaluation of Ertapenem for Patients with Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia.

Ertapenem provides activity against many pathogens commonly associated with hospital-acquired and ventilator-associated bacterial pneumoniae (HABP and VABP, respectively), including methicillin-susceptible Staphylococcus aureus and numerous Gram-negative pathogens with one major gap in coverage, Pseudomonas aeruginosa Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were conducted to evaluate ertapenem against the most prevalent Enterobacteriaceae causing HABP/VABP. The objective of these analyses was to provide dose selection support for and demonstrate the appropriateness of ertapenem to empirically treat patients with HABP/VABP when administered with murepavadin, a novel targeted antimicrobial exhibiting a highly specific spectrum of activity against P. aeruginosa A previously developed population pharmacokinetic model, a total-drug epithelial lining fluid (ELF) to free-drug serum penetration ratio, contemporary in vitro surveillance data for ertapenem against Enterobacteriaceae, and percentage of the dosing interval for which drug concentrations exceed the MIC value (%T>MIC) targets associated with efficacy were used to conduct Monte Carlo simulations for five ertapenem regimens administered over short or prolonged durations of infusion. Overall total-drug ELF percent probabilities of PK-PD target attainment based on a %T>MIC target of 35% among simulated patients with HABP/VABP arising from Enterobacteriaceae based on pathogen prevalence data for nosocomial pneumonia ranged from 89.1 to 92.7% for all five ertapenem regimens evaluated. Total-drug ELF percent probabilities of PK-PD target attainment ranged from 99.8 to 100%, 97.9 to 100%, 10.6 to 74.1%, and 0 to 1.50% at MIC values of 0.06, 0.12, 1, and 4 µg/ml, respectively (MIC90 values for Escherichia coli, Serratia marcescens, Enterobacter species, and Klebsiella pneumoniae, respectively). Results of these analyses provide support for the evaluation of ertapenem in combination with murepavadin for the treatment of patients with HABP/VABP.

Population pharmacokinetic analysis for a single 1,200-milligram dose of oritavancin using data from two pivotal phase 3 clinical trials.

Oritavancin is a lipoglycopeptide antibiotic with activity against Gram-positive bacteria. Here we describe oritavancin population pharmacokinetics and the impact of patient-specific covariates on drug exposure variability. Concentration-time data were analyzed from two phase 3 clinical trials, SOLO I and SOLO II, in which oritavancin was administered as a single 1,200-mg dose to patients with acute bacterial skin and skin structure infections. A total of 1,337 drug concentrations from 297 patients (90% of whom had 4 or 5 pharmacokinetic samples) were available for analysis. A previously derived population model based on data from 12 phase 1, 2, and 3 oritavancin studies was applied to the SOLO data set. Alterations to the structural model were made, as necessary, based on model fit. Analyses utilized Monte Carlo parametric expectation maximization (S-ADAPT 1.5.6). The previous population pharmacokinetic model fit the data well (r(2) = 0.972), and population pharmacokinetic parameters were estimated with acceptable precision and lack of bias. Covariate evaluations revealed statistically significant relationships between central compartment volume and age and between clearance and height; however, these relationships did not indicate a clinically relevant impact on oritavancin exposure over the range of age and height observed in the SOLO studies. The mean (coefficient of variation [CV]) area under the plasma concentration-time curve from time zero to 72 h (AUC0-72) and maximum plasma concentration (Cmax) were 1,530 (36.9%) µg · h/ml and 138 (23%) µg/ml, respectively. The mean (CV) half-life at alpha phase (t1/2α), t1/2ß, and t1/2γ were 2.29 (49.8%), 13.4 (10.5%), and 245 (14.9%) hours, respectively. These analyses are the first to describe oritavancin pharmacokinetics following a single 1,200-mg dose. Covariate analyses suggested that no dose adjustments are required for renal impairment (creatinine clearance, >29 ml/min), mild or moderate hepatic impairment, age, weight, gender, or diabetes status.

Population pharmacokinetic analyses for BC-3781 using phase 2 data from patients with acute bacterial skin and skin structure infections.

BC-3781, a pleuromutilin antimicrobial agent, is being developed for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia. Data from a phase 2 study of patients with ABSSSI were used to refine a previous population pharmacokinetic (PK) model and explore potential predictors of PK variability. The previously derived population PK model based on data from three phase 1 studies was applied to sparse sampling data from a phase 2 ABSSSI study and modified as necessary. Covariate analyses were conducted to identify descriptors (e.g., body size, renal function, age) associated with interindividual variability in PK. All population PK analyses were conducted by using Monte Carlo parametric expectation maximization implemented in S-ADAPT 1.5.6. The population PK data set contained 1,167 concentrations from 129 patients; 95% of the patients had 5 or more PK samples (median, 11). The previous population PK model (three-compartment model with first-order elimination and nonlinear protein binding) provided an acceptable and unbiased fit to the data from the 129 patients. Population PK parameters were estimated with acceptable precision; individual clearance values were particularly well estimated (median individual precision of 9.15%). Graphical covariate evaluations showed no relationships between PK and age or renal function but modest relationships between body size and clearance and volume of distribution, which were not statistically significant when included in the population PK model. This population PK model will be useful for subsequent PK-pharmacodynamic analyses and simulations conducted to support phase 3 dose selection. (This study has been registered at ClinicalTrials.gov under registration no. NCT01119105.).

Pharmacokinetic-pharmacodynamic determinants of oseltamivir efficacy using data from phase 2 inoculation studies.

Given the limited understanding about pharmacokinetic-pharmacodynamic (PK-PD) determinants of oseltamivir efficacy, data from two phase 2 influenza virus inoculation studies were evaluated. Healthy volunteers in studies 1 and 2 were experimentally infected with influenza A/Texas (the concentration of neuraminidase inhibitor which reduced neuraminidase activity by 50% [IC(50)] = 0.18 nM) or B/Yamagata (IC(50) = 16.76 nM), respectively. In study 1, 80 subjects received 20, 100, or 200 mg of oral oseltamivir twice daily (BID), 200 mg oseltamivir once daily, or placebo for 5 days. In study 2, 60 subjects received 75 or 150 mg of oral oseltamivir BID or placebo for 5 days. Oseltamivir carboxylate (OC) (active metabolite) PK was evaluated using individual PK data and a population PK model to derive individual values for area under the concentration-time curve from 0 to 24 h (AUC(0-24)), minimum concentration of OC in plasma (C(min)), and maximum concentration of OC in plasma (C(max)). Exposure-response relationships were evaluated for continuous (area under composite symptom score curve [AUCSC], area under the viral titer curve, and peak viral titer) and time-to-event (alleviation of composite symptom scores and cessation of viral shedding) efficacy endpoints. Univariable analyses suggested the existence of intuitive and highly statistically significant relationships between OC AUC(0-24 )evaluated as a 3-group variable and AUCSC, time to alleviation of composite symptom scores, and time to cessation of viral shedding. The upper OC AUC(0-24) threshold (~14,000 ng · h/ml) was similar among these endpoints. Multivariable analyses failed to demonstrate the influence of study/strain on efficacy endpoints. These results provide the first demonstration of exposure-response relationships for efficacy for oseltamivir against influenza and suggest that OC exposures beyond those achieved with the approved oseltamivir dosing regimen will provide enhanced efficacy. The clinical applicability of these observations requires further investigation.

Impact of different factors on the probability of clinical response in tigecycline-treated patients with intra-abdominal infections.

Patients with intra-abdominal infections differ with regard to the type of infection and the severity of illness. However, the impact of these factors, together with differences in drug exposure, on clinical response is not well understood. Using phase 2 and 3 data for patients with complicated intra-abdominal infections, the relative importance of tigecycline exposure, host factors, and disease factors, alone or in combination, for the probability of clinical response was examined. Patients with complicated intra-abdominal infections who received tigecycline intravenously as a 100-mg loading dose followed by 50 mg every 12 h for 5 to 14 days and who had adequate clinical, pharmacokinetic, and response data were evaluated. Multivariable logistic regression was used to identify factors associated with clinical response. A final multivariable logistic regression model demonstrated six factors based on 123 patients to be predictive of clinical success: a weight of <94 kg (P = 0.026), the absence of Pseudomonas aeruginosa in baseline cultures (P = 0.021), an APACHE II score of <13 (P = 0.029), non-Hispanic race (P = 0.005), complicated appendicitis or cholecystitis (P = 0.004), and a ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) of > or =3.1 (P = 0.003). The average model-predicted probability of clinical success when one unfavorable factor was present was 0.940. This probability was lower (0.855) when the AUC/MIC ratio was < 3.1 and the remaining five factors were set to the favorable condition. The average model-predicted probability of clinical success in the presence of two unfavorable factors was 0.594. These findings demonstrated the impact of individual and multiple factors on clinical response in the context of drug exposure.

Cost-Effectiveness of daptomycin versus vancomycin and gentamicin for patients with methicillin-resistant Staphylococcus aureus bacteremia and/or endocarditis.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is an increasingly common cause of bacteremia and endocarditis. The cost-effectiveness (CE) of daptomycin was compared with that of vancomycin-gentamicin in patients with MRSA bacteremia with or without endocarditis. METHODS: With use of data from an open-label, randomized study comparing daptomycin with vancomycin-gentamicin in the aforementioned patient population, 3 cost strata were considered: (1) study drug acquisition (daptomycin, $0.37/mg; vancomycin, $7/g; and gentamicin, $0.12/mg); (2) stratum 1 plus the cost of therapy for treatment failures and adverse events, therapeutic drug monitoring, and preparation and administration of all medications; and (3) stratum 2 plus hospital bed costs. Drug costs were based on mean wholesale price, with other costs based on those for a typical community hospital. Cost-effectiveness ratios were calculated as cost divided by proportion of successes. Sensitivity analyses were performed by varying the study drug cost. RESULTS: Forty-five (20 successes) and 44 (14 successes) patients received daptomycin and vancomycin-gentamicin, respectively. The respective median cost-effectiveness ratios for daptomycin and vancomycin-gentamicin for each cost stratum were as follows: $4082 (range, $1062-$13,893) and $560 (range, $66-$1649) for stratum 1 (P < .001); $4582 (range, $1109-$21,882) and $1635 (range, $163-$33,444) for stratum 2 (P = .026); $23,639 (range, $6225-$141,132) and $26,073 (range, $5349-$187,287) for stratum 3 (P = .82). Sensitivity analyses indicated that if the cost of vancomycin was $0, strata 3 cost-effectiveness ratios did not differ ($23,639 and $25,668, respectively; P = .85). Similar results between groups were seen among patients with bacteremia. CONCLUSIONS: When all costs of therapy were considered, the cost-effectiveness of daptomycin and vancomycin-gentamicin was similar, even if the cost of vancomycin was $0.

Effect of food and antacids on the pharmacokinetics of pirfenidone in older healthy adults.

Pirfenidone is a small, synthetic molecule under investigation for treatment of idiopathic pulmonary fibrosis. In an open-label, single-dose crossover study, the pharmacokinetics (PK) of pirfenidone were investigated with or without food and antacids in healthy adult volunteers. Concentrations of pirfenidone and its metabolites in plasma and urine were determined by liquid chromatography with tandem mass spectrometry, and candidate pharmacokinetic models were fit to plasma data using weighted, non-linear regression. The effect of food and antacids on pirfenidone exposure was evaluated by determining 'equivalence' using FDA guidelines. Adverse events were recorded by site personnel and classified by investigators on the basis of severity and relationship to study drug. Sixteen subjects yielded 64 pharmacokinetic profiles. The best fit was achieved using a five-compartment, linear model with an allowance for direct conversion to the primary metabolite (5-carboxy-pirfenidone). Coadministration with food decreased the rate and, to a lesser degree, the extent of pirfenidone absorption of absorption. Analysis of adverse events revealed a correlation between pirfenidone C(max) and the risk of gastrointestinal (GI) adverse events, suggesting that food may reduce the risk of certain adverse events associated with pirfenidone. Administration of pirfenidone with food has a modest effect on overall exposure but results in lower peak concentrations, which may improve tolerability.

A long journey from minimum inhibitory concentration testing to clinically predictive breakpoints: deterministic and probabilistic approaches in deriving breakpoints.

Since the origin of an "'International Collaborative Study on Antibiotic Sensitivity Testing'" in 1971, considerable advancement has been made to standardize clinical susceptibility testing procedures of antimicrobial agents. However, a consensus on the methods to be used and interpretive criteria was not reached, so the results of susceptibility testing were discrepant. Recently, the European Committee on Antimicrobial Susceptibility Testing achieved a harmonization of existing methods for susceptibility testing and now co-ordinates the process for setting breakpoints. Previously, breakpoints were set by adjusting the mean pharmacokinetic parameters derived from healthy volunteers to the susceptibilities of a population of potential pathogens expressed as the mean minimum inhibitory concentration (MIC) or MIC90%. Breakpoints derived by the deterministic approach tend to be too high, since this procedure does not take the variabilities of drug exposure and the susceptibility patterns into account. Therefore, first-step mutants or borderline susceptible bacteria may be considered as fully susceptible. As the drug exposure of such sub-populations is inadequate, resistance development will increase and eradication rates will decrease, resulting in clinical failure. The science of pharmacokinetics/pharmacodynamics integrates all possible drug exposures for standard dosage regimens and all MIC values likely to be found for the clinical isolates into the breakpoint definitions. Ideally, the data sets used originate from patients suffering from the disease to be treated. Probability density functions for both the pharmacokinetic and microbiological variables are determined, and a large number of MIC/drug exposure scenarios are calculated. Therefore, this method is defined as the probabilistic approach. The breakpoints thus derived are lower than the ones defined deterministically, as the entire range of probable drug exposures from low to high is modeled. Therefore, the amplification of drug-resistant sub-populations will be reduced. It has been a long journey since the first attempts in 1971 to define breakpoints. Clearly, this implies that none of the various approaches is right or wrong, and that the different approaches reflect different philosophies and mirror the tremendous progress made in the understanding of the pharmacodynamic properties of different classes of antimicrobials.

Re-evaluation of the role of broad-spectrum cephalosporins against staphylococci by applying contemporary in-vitro results and pharmacokinetic-pharmacodynamic principles.

The potency of cefepime, ceftriaxone, and ceftazidime was assessed by CLSI broth microdilution methods against 41,644 S. aureus (63.2% oxacillin-susceptible) and 14,266 coagulase-negative staphylococci (CoNS; 22.2% oxacillin-susceptible) through the SENTRY Antimicrobial Surveillance Program database (1998-2004). Using normal volunteer pharmacokinetic data and a linear intermittent intravenous infusion model, and an animal-derived pharmacokinetic/pharmacodynamic (PK-PD) target of > or = 40% time above MIC, expected probabilities of target attainment (PTA) for cephems were evaluated using Monte Carlo simulation. Current CLSI breakpoints would rank the tested agents cefepime > or = ceftriaxone > ceftazidime and by PK-PD PTA cefepime > ceftazidime > ceftriaxone. Cefepime has a potency advantage over ceftazidime (four- to eight-fold) and superiority at the usual dosing over ceftriaxone (22.7-66.1%) for oxacillin-susceptible staphylococci. Ceftazidime pharmacokinetic overcomes by-weight activity disadvantages, while a low proportion (<5%) of active free-drug penalizes ceftriaxone in the PTA calculations. PTA remained at > or = 0.9 to a breakpoint of 8 mg/L for cefepime (1 g q8 or 12 hours) and ceftazidime and to a breakpoint of 2 mg/L for ceftriaxone. Regardless of applied breakpoint (CLSI or PKPD), cefepime has the widest and most potent anti-staphylococcal activity among commonly used "third- or fourth-generation" cephems. When used at doses > or = 3 g/day, cefepime assures maximal coverage of oxacillin-susceptible staphylococci whether using existing (CLSI) or modified (PK-PD) breakpoints. Ceftriaxone should be used with caution.

Pharmacodynamics in the study of drug resistance and establishing in vitro susceptibility breakpoints: ready for prime time.

Considerable advancements have been made in providing informative, relevant interpretations of the results of antimicrobial susceptibility tests to clinicians, clinical microbiologists, epidemiologists, and researchers. At the same time, the science of pharmacokinetics has flourished, and the importance of drug exposure in vivo on outcome is now recognized by researchers and clinicians alike. More recently, pharmacokinetic and quantitative measures of antimicrobial susceptibility have been integrated using pharmacokinetic-pharmacodynamic (PK-PD) models to forecast clinical and microbiological outcomes. Stochastic methods utilizing patient population pharmacokinetics, target organism minimum inhibitory concentration (MIC) distributions, and PK-PD targets from non-clinical models of infection or clinical data have established a new paradigm for determining in vitro susceptibility breakpoints and selection of empirical therapy in clinical practice. Given the increasing problem of antimicrobial resistance, these new tools are valuable additions for clinicians, researchers, and regulatory authorities.

Pharmacodynamic profiling of levofloxacin and gatifloxacin using Monte Carlo simulation for community-acquired isolates of Streptococcus pneumoniae.

In vitro and in vivo models of infection suggest that the area under the concentration-time curve (AUC): minimum inhibitory concentration (MIC) ratio is the pharmacodynamic parameter that is most predictive of bactericidal activity for the fluoroquinolones. Additionally, this parameter has also been correlated with clinical outcomes in humans with respiratory tract infection. Despite these defined relationships, broad-scale application of these principles in the section of optimal therapy in the clinical arena has been restricted by the imprecise estimates of drug exposures (ie, AUC:MIC ratio) in the infected population. In an effort to best describe the known variability in the pharmacokinetic and susceptibility profile of agents of interest, Monte Carlo simulation has been employed to assess the probability of attaining the desired AUC:MIC ratio. In this report Monte Carlo simulation was used to estimate the probability of attaining various target AUC:MIC ratios using AUC values from patients treated with either gatifloxacin or levofloxacin and the in vitro potency of the compounds as assessed in 881 clinical isolates of Streptococcus pneumoniae isolated from outpatients. Using a simulated patient population of 5,000, the median AUC:MIC ratios were 144 and 50 for gatifloxacin and levofloxacin, respectively. The probability of attaining AUC:MIC ratios of 30, 40, 65, 100, and 125 for gatifloxacin were 99%, 95%, 85%, 68%, and 60%, respectively. For levofloxacin, similar dynamic hit rates were 82%, 61%, 35%, 17%, and 12% over the range of target values. Regardless of the optimal ratio selected, gatifloxacin had a higher probability of achieving the AUC:MIC target than did levofloxacin. Simulations of this type can assist in the decision process surrounding the choice of optimal therapies based on our current understanding of antimicrobial pharmacodynamic principles.

The use of Monte Carlo simulation to examine pharmacodynamic variance of drugs: fluoroquinolone pharmacodynamics against Streptococcus pneumoniae.

BACKGROUND: For fluoroquinolones, AUC:MIC ratios correlate with maximal bacterial eradication in in vitro models of infection and favorable cure rates in humans with respiratory tract infection. Inter-subject pharmacokinetic and MIC variability may impact the probability of attaining optimal AUC:MIC ratios and hence favorable clinical outcome. METHODS: Monte Carlo simulation was utilized to estimate the probability of attaining AUC:MIC ratios of 30, 40, 50, 60, 70, 80, 90, 100, 110 and 120 using AUC values from patients treated with either gatifloxacin or levofloxacin and microbiologic activity against S. pneumoniae observed in 1997 SENTRY Antimicrobial Surveillance Program. RESULTS: The probability curves for 5000 patient simulations were plotted. The median AUC:MIC ratios were 120 for gatifloxacin and 50.5 for levofloxacin. The probability of attaining AUC:MIC ratios of 30, 50, 70 and 100 for gatifloxacin were 94%, 86%, 78% and 62%, and for levofloxacin were 80%, 51%, 31% and 17%, respectively. CONCLUSION: Gatifloxacin has a higher probability of achieving target AUC:MIC ratios than levofloxacin. Monte Carlo simulation, using patient-based AUC and MIC distributions, may have implications for selection of optimal antibiotics for the empiric treatment of infections. Moreover, Monte Carlo simulation may have utility in the determination of MIC breakpoints.

Closure of a bronchopleural fistula using decalcified human spongiosa and a fibrin sealant.

Bronchopleural fistulas associated with empyema can occur as a life-threatening sequelae after pulmonary resection, most frequently occurring after pneumonectomy. With the use of the flexible bronchoscope, the bronchopleural fistula of a 62-year-old critically ill woman was permanently sealed with a fibrin sealant and a small section of demineralized human spongiosa. Closure of bronchopleural fistulas with the application of fibrin sealant plus human spongiosa may offer a valuable addition to the armament of therapeutic alternatives.

Pharmacodynamics of ceftriaxone and cefixime against community-acquired respiratory tract pathogens.

Over the last decade or so there has been a growing interest in routes of antimicrobial administration other than by the conventional intravenous route for institutionalized patients and for some outpatients. Both oral (PO) and intramuscular (IM) routes of administration are less costly than giving antimicrobial agents by vein (IV). In addition, fewer complications such as catheter-related sepsis and phlebitis are associated with non-IV routes of administration. Furthermore, a reduced-dosage, reduced-volume IM administration of ceftriaxone may provide a tolerable route of administration and equivalent bactericidal activities compared with higher dose IV ceftriaxone. The purpose of this study was to determine the time that the drug concentration remained in excess of the minimum inhibitory concentration (MIC) (T > MIC) and the duration of bactericidal activities of ceftriaxone one gram administered IV, ceftriaxone 250 mg given IM and cefixime 400 mg given orally against clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in adult volunteers. Single doses of each agent were administered and serum concentrations were collected over the standard dosing period of 24 h for all study regimens. Ceftriaxone, regardless of route of administration and dose, resulted in bactericidal activities and T > MIC for 100% of the dosing period for S. pneumoniae, H. influenzae, and M. catarrhalis. Cefixime maintained at least 50% T > MIC and bactericidal activity against both isolates each of H. influenzae and M. catarrhalis. Against both isolates of S. pneumoniae, cefixime achieved T > MIC for at least 50% of the dosing period, but did not maintain bactericidal activity. Reduced dose ceftriaxone given IM seems to be a viable alternative to ceftriaxone IV if the pathogen, susceptibility and infection site are known. Based on T > MIC exceeding 50% of the dosing interval, cefixime would be considered an effective alternative to IV therapy against common respiratory tract pathogens. Clinical studies need to be conducted to confirm these findings.

Clinical use of the fluoroquinolones.

The appetite for modification to the basic quinolone nucleus has grown logarithmically since the first quinolone was employed in clinical practice. Important structural refinements have led to expanded microbiologic activity, optimal pharmacokinetics, and increased safety profiles. The practicing clinician and researcher may glean considerable information from the quinolone structure with regard to microbiologic spectra and safety before administering these agents to patients. Although some toxicities can be ominously predictable, such as with the so-called high-risk quinolones (e.g., double-halogenated and trifluorinated quinolones), clinicians must rely on animal models of toxicity and clinical trial data to discern other toxicities (e.g., Q-Tc interval prolongation). A few quinolones enjoy a relatively clean safety profile and are well tolerated (e.g., gatifloxacin, levofloxacin, ciprofloxacin). Other quinolones may be associated with significant collateral system toxicity during therapy; however, under certain conditions, albeit rare, their potential for benefit may outweigh the existing risk. Clinafloxacin, for use in the management of lung infections caused by multiply resistant B. cepacia in cystic fibrosis patients, is an example of a risk that may be outweighed by its therapeutic benefit. Because there are many treatment alternatives within the clinician's armamentarium, the obligation is to select the safest, most therapeutically effective, and most cost-effective agent that is available. In addition to increasing mortality and morbidity, the development of toxicity or an adverse event during therapy may compromise the immediate effectiveness of treatment as well as affect the cost of the patient's care significantly. With the immediate abundance of quinolones available for use, the safest, most effective, and best-tolerated agents will likely emerge as the most appropriate therapeutic choices when a quinolone is indicated.

Antimicrobial pharmacodynamics.

The ultimate goal of antimicrobial therapy is to provide the best possible outcomes for patients. For this to occur, the clinician should be cognizant of many clinical, microbiologic, pharmacologic, and epidemiologic data as well as fundamental pharmacodynamic concepts. An understanding of pharmacodynamic principles is essential; it forms the scientific basis for the design of dosing strategies that maximize clinical efficacy and minimize toxicity. In the 1990s, data accumulated from in vitro models of infection, animal models of infection, healthy volunteer studies, and clinical trials that have expanded knowledge on how drugs best kill microorganisms. This knowledge has enabled clinicians to establish the best modes of antibiotic administration to maximize the killing of microorganisms and to optimize clinical outcomes.