Population pharmacokinetic/pharmacodynamic target attainment analysis of IV fosfomycin for the treatment of MDR Gram-negative bacterial infections.

BACKGROUND: IV fosfomycin is used against MDR Gram-negative bacilli (GNB) but has dose-limiting side effects, especially in patients with impaired kidney function. OBJECTIVES: To determine the optimal dosage of IV fosfomycin for patients with varying degrees of kidney function. METHODS: Adult patients receiving IV fosfomycin for treatment of GNB were eligible. Five serial blood samples were collected after at least three doses of fosfomycin; plasma was assayed by LC-MS/MS and modelled by population pharmacokinetic analysis. The PTA for AUC24/MIC of 98.9 for Escherichia coli and Klebsiella pneumoniae, and 40.8 for Pseudomonas aeruginosa were computed by Monte Carlo simulations. Cumulative fractions of response (CFR) were analysed for each pathogen using EUCAST MIC distributions. RESULTS: A total of 24 patients were included. Creatinine clearance (CLCR) and gender significantly influenced fosfomycin clearance. The kidney function-adjusted dosing regimens are proposed by using the lowest dose that can achieve ≥90% PTA for AUC24/MIC of 98.9 at an MIC of ≤32 mg/L (EUCAST v.13 susceptibility breakpoint for Enterobacterales). For patients with normal kidney function (CLCR 91-120 mL/min), a dosage of 15 g/day is suggested. This regimen achieved 97.1% CFR against E. coli, whereas CFR was 72.9% for K. pneumoniae and 76.7% for P. aeruginosa. CONCLUSIONS: A fosfomycin dosage of 15 g/day with adjustment according to kidney function provided high PTA and CFR when treating E. coli. This dosage is lower than that used in current practice and may improve tolerability. Higher dosages may be needed for P. aeruginosa; however, safety data are limited.

Development and Implementation of a Mobile Application for Choosing Empirical Antimicrobial Therapy for Bacteremia, Pneumonia, Urinary Tract Infection, and Skin and Soft Tissue Infection among Hospitalized Patients.

Clinical practice guidelines (CPGs) and computerized clinical decision support programs are effective antimicrobial stewardship strategies. The DigitalAMS™, a mobile-based application for choosing empirical antimicrobial therapy under the hospital's CPGs, was implemented at Siriraj Hospital and evaluated. From January to June 2018, a cross-sectional study was conducted among 401 hospitalized adults who received ≥1 dose of antimicrobials and had ≥1 documented site-specific infection. The antimicrobial regimen prescribed by the ward physician (WARD regimen), recommended by the DigitalAMS™ (APP regimen), and recommended by two independent infectious disease (ID) physicians before (Emp-ID regimen) and after (Def-ID regimen) the final microbiological results became available were compared in a pairwise fashion. The percent agreement of antimicrobial prescribing between the APP and Emp-ID regimens was 85.7% in the bacteremia group, 59.1% in the pneumonia group, 78.6% in the UTI group, and 85.2% in the SSTI group. The percent agreement between the APP and Emp-ID regimens was significantly higher than that between the WARD and Emp-ID regimens in three site-specific infection groups: the bacteremia group (85.7% vs. 47.9%, p < 0.001), the UTI group (78.6% vs. 37.8%, p < 0.001), and the SSTI group (85.2% vs. 40.2%, p < 0.001). Furthermore, the percent agreement between the APP and Def-ID regimens was similar to that between the Emp-ID and Def-ID regimens in all sites of infection. In conclusions, the implementation of DigitalAMS™ seems useful but needs some revisions. The dissemination of this ready-to-use application with customized clinical practice guidelines to other hospital settings may be beneficial.

Implementation of Clinical Practice Guidelines for Empirical Antibiotic Therapy of Bacteremia, Urinary Tract Infection, and Pneumonia: A Multi-Center Quasi-Experimental Study.

A quasi-experimental study was conducted on the implementation of locally developed clinical practice guidelines (CPGs) for empirical antibiotic (ATB) therapy of common infections (bacteremia, urinary tract infection (UTI), pneumonia) in the hospitals from January 2019 to December 2020. The CPGs were developed using data from patients with these infections at individual hospitals. Relevant CPG data pre- and post-implementation were collected and compared. Of the 1644 patients enrolled in the study, 808 and 836 were in the pre- and post-implementation periods, respectively, and patient outcomes were compared. Significant reductions in the mean durations of intensive care unit stay (3.44 ± 9.08 vs. 2.55 ± 7.89 days; p = 0.035), ventilator use (5.73 ± 12.14 vs. 4.22 ± 10.23 days; p = 0.007), piperacillin/tazobactam administration (0.954 ± 3.159 vs. 0.660 ± 2.217 days, p = 0.029), and cefoperazone/sulbactam administration (0.058 ± 0.737 vs. 0.331 ± 1.803 days, p = 0.0001) occurred. Multivariate analysis demonstrated that CPG-implementation was associated with favorable clinical outcomes (adjusted odds ratio 1.286, 95% confidence interval: 1.004-1.647, p = 0.046). Among patients who provided follow-up cultures (n = 284), favorable microbiological responses were significantly less frequent during the pre-implementation period than the post-implementation period (80.35% vs. 91.89%; p = 0.01). In conclusion, the locally developed CPG implementation is feasible and effective in improving patient outcomes and reducing ATB consumption. Hospital antimicrobial stewardship teams should be able to facilitate CPG development and implementation for antimicrobial therapy for common infections.

Safety and Efficacy of Ivermectin for the Prevention and Treatment of COVID-19: A Double-Blinded Randomized Placebo-Controlled Study.

The safety and efficacy of ivermectin for the prevention and treatment of COVID-19 are still controversial topics. From August to November 2021, we conducted a double-blinded, randomized controlled trial at Siriraj Hospital, Thailand. Eligible participants were adults ≥ 18 years with suspected COVID-19 who underwent a SARS-CoV-2 RT-PCR test. After enrollment, the participants were randomized to receive either ivermectin (400−600 µg/kg/d) or placebo once daily for 3 days. Among 983 participants, 536 (54.5%) with a negative RT-PCR result were enrolled in the prevention study, and 447 (45.5%) with a positive RT-PCR result were enrolled in the treatment study. In the prevention study, the incidence of COVID-19 on Day 14 was similar between the ivermectin and the placebo group (4.7% vs. 5.2%; p = 0.844; Δ = −0.4%; 95% CI; −4.3−3.5%). In the treatment study, there was no significant difference between the ivermectin and placebo group for any Day 14 treatment outcome: proportion with oxygen desaturation (2.7% vs. 1.9%; p = 0.75), change in WHO score from baseline (1 [−5, 1] vs. 1 [−5, 1]; p = 0.50), and symptom resolution (76% vs. 82.2%; p = 0.13). The ivermectin group had a significantly higher proportion of transient blurred vision (5.6% vs. 0.6%; p < 0.001). Our study failed to demonstrate the efficacy of a 3-day once daily of ivermectin for the prevention and treatment of COVID-19. The given regimen of ivermectin should not be used for either prevention or treatment of COVID-19 in populations with a high rate of COVID-19 vaccination.

Feasibility, Challenges, and Benefits of Global Antimicrobial Resistance Surveillance System Implementation: Results from a Multicenter Quasi-Experimental Study.

The Global Antimicrobial Resistance Surveillance System (GLASS) is one of the pillars of the global action plan on antimicrobial resistance launched by the World Health Organization in 2015. This study was conducted to determine the feasibility and benefits of GLASS as a component of antimicrobial stewardship strategies in three provincial hospitals in Thailand. Data on the types of bacteria isolated and their antibiotic susceptibility during January-December 2019 and January-April 2020 were retrieved from the microbiology laboratory of each participating hospital. Laboratory-based antibiograms from 2019 and GLASS-based antibiograms from 2020 were created and compared. A total of 14,877 and 3580 bacterial isolates were obtained during January-December 2019 and January-April 2020, respectively. The common bacteria isolated in both periods were Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Staphylococcus aureus. Hospital-acquired infection (HAI)-related bacteria were observed in 59.0%, whereas community-acquired infection (CAI)-related bacteria were observed in 41.0% of isolates. Antibiotic resistance in CAIs was high and may have been related to the misclassification of colonized bacteria as true pathogens and HAIs as CAIs. The results of this study on AMR surveillance using GLASS methodology may not be valid owing to several inadequate data collections and the problem of specimen contamination. Given these considerations, related personnel should receive additional training on the best practices in specimen collection and the management of AMR surveillance data using the GLASS approach.

Impact of Antibiotic Authorisation at Three Provincial Hospitals in Thailand: Results from a Quasi-Experimental Study.

Implementing antimicrobial stewardship (AMS) at non-university hospitals is challenging. A quasi-experimental study was conducted to determine the impact of customised antibiotic authorisation implementation on antimicrobial consumption and clinical outcomes at three provincial hospitals in Thailand. Customised pre-authorisation of selected restricted antibiotics and post-authorisation of selected controlled antibiotics were undertaken and implemented at each hospital by the local AMS team with guidance from the AMS team at the university hospital. From January 2019−December 2020, there were 1802 selected patients (901 patients during the pre-implementation period and 901 patients during the post-implementation period). The most commonly used targeted antimicrobial was meropenem (49.61%), followed by piperacillin/tazobactam (36.46%). Comparison of the outcomes of the patients during the pre- and post-implementation periods revealed that the mean day of therapy of the targeted antimicrobials was significantly shorter during the post-implementation period (6.24 vs. 7.64 days; p < 0.001), the favourable clinical response (the improvement in all clinical and laboratory parameters at the end of antibiotic therapy) was significantly higher during the post-implementation period (72.70% vs. 68.04%; p = 0.03) and the mean length of hospital stay was significantly shorter during the post-implementation period (15.78 vs. 18.90 days; p < 0.001). In conclusion, implementation of antibiotic authorisation at provincial hospitals under experienced AMS team's guidance was feasible and useful. The study results could be a good model for the implementation of customised AMS strategies at other hospitals with limited resources.

Epidemiology, clinical characteristics, and treatment outcomes of patients with COVID-19 at Thailand's university-based referral hospital.

BACKGROUND: The epidemiology and outcomes of COVID-19 patients in Thailand are scarce. METHODS: This retrospective cohort study included adult hospitalized patients who were diagnosed with COVID-19 at Siriraj Hospital during February 2020 to April 2020. RESULTS: The prevalence of COVID-19 was 7.5% (107 COVID-19 patients) among 1409 patients who underwent RT-PCR for SARS-CoV-2 detection at our hospital during the outbreak period. Patients with COVID-19 presented with symptoms in 94.4%. Among the 104 patients who were treated with antiviral medications, 78 (75%) received 2-drug regimen (lopinavir/ritonavir or darunavir/ritonavir plus chloroquine or hydroxychloroquine), and 26 (25%) received a 3-drug regimen with favipiravir added to the 2-drug regimen. Disease progression was observed in 18 patients (16.8%). All patients with COVID-19 were discharged alive. CONCLUSIONS: The prevalence of COVID-19 was 7.5% among patients who underwent RT-PCR testing, and 10% among those having risk factors for COVID-19 acquisition. Combination antiviral therapies for COVID-19 patients were well-tolerated and produced a favorable outcome.

The safety and efficacy of high versus low vancomycin trough levels in the treatment of patients with infections caused by methicillin-resistant Staphylococcus aureus: a meta-analysis.

BACKGROUND: Recent guidelines have recommended vancomycin trough levels of 15-20 mg/L for treatment of serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA). However, high trough levels may increase risk of nephrotoxicity and mortality, and high vancomycin trough levels have not been well studied. This study was designed to combine safety and efficacy results from independent studies and to compare between high and low vancomycin trough levels in the treatment of MRSA-infected patients using meta-analysis. METHODS: From 19 eligible studies, 9 studies were included in meta-analysis to compare clinical success between high and low vancomycin trough levels, while 10 and 11 studies met criteria for comparing trough levels and nephrotoxicity and trough levels and mortality, respectively. The PubMed/Medline, Web of Science, and Scopus databases, and hand searching were used to identify eligible studies dated up to March 2016. Of 2344 subjects with MRSA infection, 1036 were assigned to trough levels ≥15 mg/L and 1308 to trough levels <15 mg/L. RESULTS: High vancomycin trough levels were found to be associated with risk of nephrotoxicity (odds ratio [OR] 2.14, 95 % confidence interval [CI] 1.42-3.23 and adjusted OR 3.33, 95 % CI 1.91-5.79). There was no evidence of difference between high and low vancomycin trough levels for mortality (OR; 1.09; 95 % CI 0.75-1.60) or clinical success (OR 1.07; 95 % CI 0.68-1.68). CONCLUSION: In this study, high vancomycin trough levels were identified as an independent factor associated with risk of nephrotoxicity in MRSA-infected patients. Association between vancomycin trough levels and both adverse effects and clinical outcomes requires further study.

Effectiveness and Safety of Generic Formulation of Cefoperazone/Sulbactam (Bacticep®) in Treatment of Infections at Siriraj Hospital.

OBJECTIVE: To compare the effectiveness and safety of generic cefoperazone/sulbactam (Bacticep®) and original cefoperazone/ sulbactam (Sulperazon®) in treatment of infections in hospitalized patients at Siriraj Hospital. MATERIAL AND METHOD: Hospitalized patients aged 18 years and older who received cefoperazone/sulbactam for at least 48 hours were identifed from the Siriraj Hospital pharmacy database. Medical records of identified patients were reviewed and relevant information was extracted and transferred onto pre-printed case record forms. Patient data relating to demographics, clinical features of infections, antibiotic therapy, and treatment outcomes were evaluated and compared between patients who received generic and original cefoperazone/sulbactam. RESULTS: Two hundred twenty nine hospitalized patients who had infections and received original or generic cefoperazonel sulbactam were included. Baseline characteristics and clinical features of infections in both groups were comparable. Favorable outcomes (72.9% vs. 72.2%, p = 1.00) and infection-related deaths (4.7% vs. 11.1%, p = 0.16) between generic cefoperazone/sulbactam group and original cefoperazone/sulbactam group, respectively, were not significantly different. Generic cefoperazone/sulbactam favorable outcomes were found to be non-inferior to original cefoperazone/sulbactam (p = 0.04), with lower bound of one-sided 95% CI for difference in favorable outcome within the pre-specified non-inferiority margin of -10% (95% CI: 0.7% with lower bound of -9.3). No significant differences in adverse events were observed between groups. CONCLUSION: Generic cefoperazone/sulbactam (Bacticep®) was found to be non-inferior to original cefoperazone/sulbactam for therapy of infections in hospitalized patients at Siriraj Hospital.

Application of Pharmacodynamic Profiling for the Selection of Optimal ß-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 ß-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.

NOCARDIA BEIJINGENSIS BRAIN ABSCESS IN AN HIV INFECTED PATIENT: A FIRST CASE REPORT AND LITERATURE REVIEW.

We report here brain abscesses caused by Nocardia beijingensis in a 59-year-old-Thai male with human immunodeficiency virus (HIV) infection presenting with progressive right sided hemiparesis. A computed tomography scan of the brain showed multiple brain abscesses. A stereotactic brain biopsy and 16S rRNA sequencing showed Nocardia beijingensis. The patient was treated with trimethoprim-sulfamethoxazole and recovered completely. As far as we are aware, this is the first reported case of a brain abscess in an HIV infected patient due to Nocardia beijingensis.

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.

Pharmacokinetics of colistin methanesulfonate and formed colistin in end-stage renal disease patients receiving continuous ambulatory peritoneal dialysis.

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.

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

INTRODUCTION: Chylothorax 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 PRESENTATION: A 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. CONCLUSIONS: Although 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.

Can we predict final outcome of internal medicine residents with in-training evaluation.

OBJECTIVE: To assess the predictive value of in-training evaluation for determining future success in the internal medicine board certifying examination. MATERIAL AND METHOD: Ninety-seven internal medicine residents from Faculty of Medicine Siriraj Hospital who undertake the Thai Board examination during the academic year 2006-2008 were enrolled. Correlation between the scores during internal medicine rotation and final scores in board examination were then examined. RESULTS: Significant positive linear correlation was found between scores from both written and clinical parts of board certifying examination and scores from the first-year summative written and clinical examinations and also the second-year formative written examination (r = 0.43-0.68, p < 0.001). Monthly evaluation by attending staffs was less well correlated (r = 0.29-0.36) and the evaluation by nurses or medical students demonstrated inverse relationship (r = -0.2, p = 0.27 and r = -0.13, p = 0.48). CONCLUSION: Some methods of in-training evaluation can predict successful outcome of board certifying examination. Multisource assessments cannot well extrapolate some aspects of professional competences and qualities.

Linezolid penetration into wound tissue of two diabetic patients before and after hyperbaric oxygen therapy.

OBJECTIVE: We describe linezolid tissue penetration in two diabetic patients with lower-extremity ulcers, measured by in vivo microdialysis, before and after hyperbaric oxygen (HBO2) therapy. METHODS: Each diabetic patient received a single orally administered dose of linezolid 600 mg within one week of initiating an eight-week HBO2 course for treatment of his or her Wagner Grade 3 lower-extremity wound. A microdialysis catheter was placed at the margin of the wound for collection of extracellular tissue fluid. Blood and tissue samples were collected hourly over the following 12 hours. After completion of HBO2, each patient received a second dose of linezolid 600 mg, the microdialysis catheter was reinserted in same location, and blood/tissue samples were recollected for comparison. RESULTS: Patient 1 completed all eight weeks of HBO2, while Patient 2 completed only five of eight weeks. Based on the 12-hour area under the curve ratio between extracellular tissue fluid and blood, linezolid penetration was 0.474 and 0.479 for Patients 1 and 2, respectively, at the beginning of HBO2. After completing HBO2, penetration improved in both patients to 0.950 and 0.757, respectively. CONCLUSION: Tissue concentrations of linezolid at the site of lower extremity ulcers improved following a course of HBO2 in two patients with diabetes.

In vitro pharmacodynamics of simulated pulmonary exposures of tigecycline alone and in combination against Klebsiella pneumoniae isolates producing a KPC carbapenemase.

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 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.

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.

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

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 (r(2) = 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-log(10)-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.