Pornpan Koomanachai

Pharmacodynamic modeling of intravenous antibiotics against gram-negative bacteria collected in the United States.

BACKGROUND In the era of escalating antimicrobial resistance, the choice of effective empiric antimicrobial therapy has become considerably more difficult. In an attempt to improve antimicrobial selection, pharmacodynamic modeling that considers the drug, dose, dosing interval, and duration of infusion is increasingly used as a tool to assist in the clinical decision-making process. OBJECTIVE The aim of the PASSPORT (Probability of target attainment of Antibacterial agents Studied for Susceptibility and Pharmacodynamic Optimization in Regional Trials) study was to compare the probabilities of achieving requisite pharmacodynamic exposure (eg, T>MIC, AUC/MIC) of common intravenous antibiotics against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. METHODS Using a 5000-patient Monte Carlo simulation, pharmacodynamic analyses were conducted for standard and high-dose, prolonged (ie, 3-to 4-hour) infusions of cefepime, ceftazidime, ceftriaxone, ciprofloxacin, doripenem, ertapenem, imipenem, levofloxacin, meropenem, and piperacillin/tazobactam in adult patients with normal renal function (>or=50 mL/min). MIC data were incorporated from the 2008 TRUST (Tracking Resistance in the United States Today)-12 surveillance program, a long-running resistance study in 56 participating US hospitals. The cumulative fraction of response (CFR) was determined for each regimen against each population of E coli, K pneumoniae, A baumannii, and P aeruginosa. Optimal CFR was defined a priori as >or=90%. RESULTS All of the beta-lactam regimens had optimal CFRs against E coli, and all but piperacillin/tazobactam 3.375 g q6h had optimal CFRs against K pneumoniae. The fluoroquinolones had the lowest CFRs against all of the pathogen populations tested (73.2%-88.9% against E coli and K pneumortfae; 44.5 %-61.9 % against A baumannii and P aeruginosa). Optimal CFR against A baumannii was not achieved with any of the regimens. Against P aeruginosa, high-dose, prolonged-infusion doripenem and meropenem had CFRs of 97.2% to 98.8%, followed by high-dose, prolonged-infusion ceftazidime (93.3%) and cefepime (93.2%). High-dose, prolonged-infusion regimens were associated with increased CFRs for all (beta-lactams by approximately 10% over that of standard 0.5-hour infusion regimens against the nonfermenting gram-negative bacilli. CONCLUSIONS Based on this model, standard doses of most intravenous (beta-lactam regimens had high probabilities of achieving optimal exposure against Enterobacteriaceae. For nonfermenting gram-negative bacilli such as A baumannii and P aeruginosa, high-dose, prolonged infusions of cefepime, ceftazidime, doripenem, and meropenem had the highest probabilities of achieving bactericidal exposure.

Pharmacodynamic evaluation of tigecycline against Acinetobacter baumannii in a murine pneumonia model

OBJECTIVES Tigecycline is an extended-spectrum antibiotic with activity against Acinetobacter spp. (ACB), an increasingly common cause of nosocomial pneumonia. Although this compound is under investigation for this indication, supportive pharmacodynamic data are not yet available at this infection site. The objective of this study was to characterize the exposure-response relationship of tigecycline with ACB in an established murine pneumonia model. METHODS The pharmacokinetic profile of tigecycline was evaluated in infected neutropenic mice. Tigecycline 6.25, 12.5, 25, 50, 100, 200, 300 and 400 mg/kg, in single or two to six divided subcutaneous doses, were tested against all ACB isolates. Efficacy, defined as the log(10) change in bacterial cfu/mL, was assessed after a 24 h course of therapy. Tigecycline exposures in serum were corrected for dose-specific protein binding. The relationship between the area under the free concentration-time curve to MIC (fAUC/MIC) and change in bacterial density was determined using the sigmoid E(max) model. RESULTS Tigecycline displayed linear pharmacokinetics with a mean half-life of 11.3 +/- 1.4 h. Efficacy correlated well with fAUC/MIC (R(2) = 0.96). The mean 80%, 50% effective and stasis exposures (fAUC/MIC) were 17, 8 and 6, respectively. Maximal efficacy for the five Acinetobacter baumannii studied was 3.4 log kill. CONCLUSIONS Tigecycline efficacy in this murine ACB pneumonia model was well predicted by fAUC/MIC. Requisite tigecycline exposures for efficacy appear to be higher for ACB pneumonia than for other pathogens reported of non-respiratory infections.

In Vitro Pharmacodynamics of Simulated Pulmonary Exposures of Tigecycline Alone and in Combination against Klebsiella pneumoniae Isolates Producing a KPC Carbapenemase

ABSTRACT Multidrug-resistant Klebsiella pneumoniae strains that produce a serine carbapenemase (KPC) are emerging worldwide, with few therapeutic options that retain consistent susceptibility. The objective of this study was to determine the effect of combination therapy with tigecycline versus tigecycline alone against KPC-producing isolates (KPC isolates). An in vitro pharmacodynamic model was used to simulate adult steady-state epithelial lining fluid concentrations of tigecycline (50 mg every 12 h) given alone and in combination with either meropenem (2 g by 3-hour infusion every 8 h) or rifampin (600 mg every 12 h). Five KPC isolates with various phenotypic profiles were exposed over 48 h. Time-kill curves were constructed, and the areas under the bacterial killing and regrowth curves (AUBCs) were calculated. No regimens tested were able to maintain bactericidal reductions in CFU over 48 h. The AUBCs for tigecycline and meropenem monotherapies at 48 h ranged from 375.37 to 388.11 and from 348.62 to 383.83 (CFU-h/ml), respectively. The combination of tigecycline plus meropenem significantly reduced the AUBCs at 24 and 48 h for isolates with tigecycline MICs of ≤2 μg/ml and meropenem MICs of ≤16 μg/ml (P < 0.001) but added no additional activity when the meropenem MIC was 64 μg/ml (P = 0.5). Rifampin provided no additional reduction in CFU or AUBC over tigecycline alone (P = 0.837). The combination of tigecycline with high-dose, prolonged-infusion meropenem warrants further study as a potential treatment option for these multidrug-resistant organisms.

Pharmacodynamic profile of tigecycline against methicillin-resistant Staphylococcus aureus in an experimental pneumonia model.

ABSTRACT Tigecycline (TGC) is an extended-spectrum antibiotic with activity against Staphylococcus aureus, including methicillin (meticillin)-resistant S. aureus strains, which are well-recognized pathogens in nosocomial pneumonia. The objective of this study was to characterize the exposure-response relationship for TGC against S. aureus in an immunocompromised BALB/c murine pneumonia model. Six S. aureus isolates were studied, and the TGC MICs for those isolates ranged from 0.125 to 0.5 mg/liter. The pharmacokinetics (PK) of TGC in serum and bronchoalveolar lavage (BAL) fluid were evaluated, as was the level of protein binding of the compound in this murine species. Administration of TGC at 1.56 to 150 mg/kg of body weight/day in single or two to three divided doses was used in the efficacy studies. TGC displayed linear PK and had a mean half-life of 10.9 ± 2.5 h. Efficacy was highly correlated with the area under the free concentration-time curve (fAUC)/MIC (r2 = 0.93). The 80% and 50% effective exposure indexes and the stasis exposure index were similar between the isolates (means ± standard deviations, 3.04 ± 1.12, 1.84 ± 1.3, and 1.9 ± 1.5, respectively). Maximal efficacy was predicted at a 2.85-log10-CFU reduction. TGC appeared to accumulate in the interstitial space, as the ratios of the fAUC from 0 to 8 h of epithelial lining fluid to plasma were 7.02, 15.11, and 23.95 for doses of 12.5, 25, and 50 mg/kg, respectively. TGC was highly effective in this murine pneumonia model. In light of current MIC distributions, the fAUC/MIC targets that we defined against S. aureus are readily achievable in humans given conventional doses of TGC.

Pharmacokinetics of Colistin Methanesulfonate and Formed Colistin in End-Stage Renal Disease Patients Receiving Continuous Ambulatory Peritoneal Dialysis

ABSTRACT Colistin, administered intravenously as its inactive prodrug colistin methanesulfonate (CMS), is increasingly used as last-line therapy to combat multidrug-resistant Gram-negative bacteria. CMS dosing needs to be adjusted for renal function. The impact of continuous ambulatory peritoneal dialysis (CAPD) on the pharmacokinetics of both CMS and colistin has not been studied. No CMS dosing recommendations are available for patients receiving CAPD. Eight CAPD patients received a single intravenous CMS dose (150 mg colistin base activity [CBA]) over 30 min. Serial blood and dialysate samples, and cumulative urine where applicable, were collected over 25 h. CMS and colistin concentrations were determined by high-performance liquid chromatography. Population pharmacokinetic modeling and Monte Carlo simulations were conducted. The total body clearance of CMS (excluding CAPD clearance) was 1.77 liters/h (44%) [population mean (between-subject variability)], while CAPD clearance was 0.088 liter/h (64%). The population mean terminal half-life of CMS was 8.4 h. For colistin, the total clearance/fraction of CMS metabolized to colistin (fm) (excluding CAPD clearance) was 2.74 liters/h (50%), the CAPD clearance was 0.101 liter/h (34%), and the mean terminal half-life was 13.2 h. Monte Carlo simulations suggested a loading dose of 300 mg CBA on day 1 and a maintenance dose of either 150 mg or 200 mg CBA daily to achieve a target average steady-state plasma colistin concentration of 2.5 mg/liter. Clearance by CAPD was low for both CMS and formed colistin. Therefore, CMS doses should not be increased during CAPD. Modeling and simulation enabled us to propose the first evidence-based CMS dosage regimen for CAPD patients.

Extracorporeal clearance of colistin methanesulphonate and formed colistin in end-stage renal disease patients receiving intermittent haemodialysis: implications for dosing

OBJECTIVES Colistin, administered intravenously as its inactive prodrug colistin methanesulphonate (CMS), is being increasingly used. However, there is very limited information available on the impact of haemodialysis (HD) on the pharmacokinetics of CMS and formed colistin. PATIENTS AND METHODS A single 30 min intravenous dose of CMS (150 mg of colistin base activity) was administered to 10 patients undergoing HD. HD was performed from 1.5 to 5.5 h after the start of the CMS infusion. Serial blood samples were collected over 50 h, additional blood samples pre- and post-dialysis membrane at three timepoints during HD, dialysate samples at four timepoints during HD, and a cumulative urine sample over 24 h. CMS and colistin were determined by HPLC. Population modelling and determination of HD clearance by multiple methods was conducted. RESULTS The average amount of CMS recovered in the dialysate was 30.6% of the dose administered. The concentrations of CMS and colistin in the plasma and the amounts of CMS recovered in the dialysate were well described by the population disposition model. The clearance of CMS by dialysis as estimated by population analysis based on systemic plasma concentrations and amounts in the dialysate was 4.26 L/h (26% coefficient of variation). The dialysis clearance determined from the pre- and post-membrane plasma concentrations was 5.67 L/h (21%) for CMS and 3.99 L/h (44%) for colistin. Thus, CMS clearance by dialysis from trans-cartridge extraction was ∼30% higher than when calculated based on the amount in dialysate, suggesting adsorption to the membrane. CONCLUSIONS Due to the extensive removal of CMS by dialysis, HD should be conducted at the end of a dosing interval and a supplemental dose should be administered.

Newer developments in the treatment of Gram-positive infections

Gram-positive organisms are continually a major cause of infection. These organisms are ever-evolving and exhibit resistance to nearly all available agents. Historically, vancomycin was crowned the drug of choice for many of these organisms including methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, and penicillin-resistant Enterococcus spp. Many of these organisms have exhibited reduced susceptibility or frank resistance to vancomycin which has resulted in treatment failure. For this reason, new strategies in treating Gram-positive infections are a hot topic. There are two general approaches to waging this war: i) development of new antimicrobial agents; and ii) reinvigorating old antibiotics that still retain appreciable activity against Gram-positives. We review both antibiotic groupings with a focus on S. aureus, S. pneumoniae and Enterococcus spp.

Comparative pharmacodynamics for intravenous antibiotics against Gram-negative bacteria in Europe between 2002 and 2006: a report from the OPTAMA program.

The Optimizing Pharmacodynamic Target Attainment using the MYSTIC Antibiogram (OPTAMA) Program has been used globally to estimate antimicrobial exposures for either targeted pathogens or disease states. Herein, we utilised this methodology to determine antimicrobial exposures of cefepime, ceftazidime, ciprofloxacin, imipenem, meropenem and piperacillin/tazobactam against European-derived isolates of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa obtained in 2006 and compared these with results from 2002. All regimens, except ciprofloxacin, provided optimal pharmacodynamic exposures against E. coli, whereas more regional differences were noted with K. pneumoniae. For K. pneumoniae, the carbapenems provided the highest likelihood of optimal exposures. Ciprofloxacin exposures were also noted to be low for both P. aeruginosa and A. baumannii. Moreover, for these two organisms higher doses and/or prolonged infusion of the studied beta-lactams was necessary to obtain the desired pharmacodynamic targets. These data reveal regional differences in the probability of pharmacodynamic optimisation as well as the potential utility of employing regimens utilising higher doses and/or prolonged infusion techniques when directing therapy against P. aeruginosa and A. baumannii.

Application of Pharmacodynamic Profiling for the Selection of Optimal β-lactam Regimens in a Large University Hospital

BACKGROUND Infections caused by drug-resistant Gram-negative bacteria (GNB) are increasing worldwide and as a result, the selection of appropriate empiric antibiotics (ATBs) has been made increasingly difficult. The present study aimed to identify optimized dosing regimens of intravenous (IV) ATBs, defined by cumulative fraction response (CFR), against E. coli (EC), K. pneumoniae (KP), P. aeruginosa (PA), and A. baumannii (AB) at 2,300-bed University Hospital. MATERIALS AND METHODS The minimum inhibitory concentrations (MIC) of EC, KP, PA, and AB from clinical specimens, 250 each, were determined. Pharmacodynamic profiling using Monte Carlo Simulation was performed for standard, high dosage, and prolonged infusions (PI) of ceftriaxone, cefepime, ceftazidime, imipenem, meropenem, and doripenem. A CFR of ≥90% was targeted as providing a sufficiently high ATB exposure. RESULTS When considering the Enterobacteriaceae, the % susceptible for the cephalosporins ranged from 60% for ceftriaxone to 86% for cefepime, as a result only the 2g q8h regimens of ceftazidime and cefepime provided high CFRs. In contrast, all the carbapenems had % susceptible and CFRs ≥90% for EC and KP. While cefepime and ceftazidime demonstrated higher % susceptibility (82-83%) for PA relative to that of the carbapenems (61-69%) only doripenem 2g q8h (4h PI) achieved an optimal CFR (92%) against this organism. Due to the MIC profiles and dismal susceptibilities of AB (16-22%), none of the regimens studied achieved CFRs > 65%. CONCLUSIONS The pharmacodynamic profiling undertaken in the current study provides insights that allow prescribers to select more appropriate empirical antibiotic regimens for the treatment of infection caused by these common GNB pathogens at this Thai hospital. While higher doses and PI of β-lactams improve exposures against EC, KP and PA, this approach will not sufficiently enhance their potency against AB, thus alternative therapies should be considered for this organism.

Chylous ascites and chylothorax due to constrictive pericarditis in a patient infected with HIV: a case report

IntroductionChylothorax and chylous ascites are uncommon and usually associated with trauma or neoplasms. To the best of our knowledge, constrictive pericarditis leading to chylothorax and chylous ascites in a person infected with HIV has never previously been described.Case presentationA 39-year-old Thai man was referred to our institute with progressive dyspnea, edema and abdominal distension. His medical history included HIV infection and pulmonary tuberculosis that was complicated by tuberculous pericarditis and cardiac tamponade. Upon further investigation, we found constrictive pericarditis, chylothorax and chylous ascites. A pericardiectomy was performed which resulted in gradual resolution of the ascites and chylous effusion.ConclusionsAlthough constrictive pericarditis is an exceptionally rare cause of chylothorax and chylous ascites, it should nonetheless be considered in the differential diagnosis as a potentially reversible cause.