Optimal Piperacillin-Tazobactam Dosing Strategies against Extended-Spectrum-β-Lactamase-Producing .

Piperacillin-tazobactam has been proposed as an alternative to carbapenems for the treatment of infections caused by extended-spectrum-β-lactamase (ESBL)-producing However, limited understanding of optimal dosing strategies for this combination may curtail its utility. In this study, we correlated various exposures of piperacillin-tazobactam to efficacy, using a modified pharmacokinetic/pharmacodynamic index. Using a clinical isolate expressing CTX-M-15, piperacillin MIC values were determined with increasing tazobactam concentrations and fitted to a sigmoid inhibitory maximum effect () model.

Prevalence of extended-spectrum beta-lactamase and carbapenemase-producing bloodstream isolates of Klebsiella pneumoniae in a tertiary care hospital.

To improve prescribing of empiric therapy, the local molecular epidemiology of extended-spectrum beta-lactamases (ESBLs) and Klebsiella pneumoniae carbapenemases (KPCs) in bloodstream isolates of K. pneumoniae were evaluated. Isolates resistant to third generation cephalosporins were screened phenotypically for ESBLs and carbapenemases, and subsequently confirmed by PCR for the presence of ESBL (bla, bla and bla) and carbapenemase (bla, bla, bla and bla) genes.

Pharmacokinetics and Pharmacodynamics of Minocycline against Acinetobacter baumannii in a Neutropenic Murine Pneumonia Model.

Multidrug-resistant (MDR) is increasingly more prevalent in nosocomial infections. Although susceptibility of to minocycline is promising, the efficacy of minocycline has not been well established. In this study, the activity of minocycline was evaluated in a neutropenic murine pneumonia model.

Determining β-lactam exposure threshold to suppress resistance development in Gram-negative bacteria.

Objectives: β-Lactams are commonly used for nosocomial infections and resistance to these agents among Gram-negative bacteria is increasing rapidly. Optimized dosing is expected to reduce the likelihood of resistance development during antimicrobial therapy, but the target for clinical dose adjustment is not well established. We examined the likelihood that various dosing exposures would suppress resistance development in an in vitro hollow-fibre infection model.

Analytical and functional determination of polymyxin B protein binding in serum.

To enhance our understanding of the pharmacological properties of polymyxin B, serum protein binding for polymyxin B1, B2, and B3 and for isoleucine-polymyxin B1 was evaluated. Using equilibrium dialysis and ultrafiltration, comparable protein binding was found in all 4 components of polymyxin B (92% to 99%). Protein binding in human serum was further assessed using a functional assay, the results of which were in general agreement with previous findings (approximately 90%).

Uptake of polymyxin B into renal cells.

Polymyxin B is increasingly used as a treatment of last resort against multidrug-resistant Gram-negative infections. Using a mammalian kidney cell line, we demonstrated that polymyxin B uptake into proximal tubular epithelial cells was saturable and occurred primarily through the apical membrane, suggesting the involvement of transporters in the renal uptake of polymyxin B. Megalin might play a role in the uptake and accumulation of polymyxin B into renal cells.

An evaluation of multiple phenotypic screening methods for Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae.

Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae may display MICs to carbapenems within susceptible or intermediate ranges, prompting confirmatory testing. Four phenotypic methods to detect KPC producers were evaluated against a collection of clinical Enterobacteriaceae isolates. Meropenem-phenylboronic acid double disk synergy testing demonstrated the best performance with 100% sensitivity and specificity.

Assessment of antimicrobial combinations for Klebsiella pneumoniae carbapenemase-producing K. pneumoniae.

Background: The prevalence of bla(KPC) among gram-negative bacteria continues to increase worldwide. Limited treatment options exist for this multidrug-resistant phenotype, often necessitating combination therapy. We investigated the in vitro and in vivo efficacy of multiple antimicrobial combinations.

In vitro pharmacodynamics of AZD5206 against Staphylococcus aureus.

AZD5206 is a novel antimicrobial agent with potent in vitro activity against Staphylococcus aureus. We evaluated the in vitro pharmacodynamics of AZD5206 against a standard wild-type methicillin-susceptible strain (ATCC 29213) and a clinical strain of methicillin-resistant S. aureus (SA62).

In vitro activity of MK-7655, a novel β-lactamase inhibitor, in combination with imipenem against carbapenem-resistant Gram-negative bacteria.

Carbapenem-resistant bacteria represent a significant treatment challenge due to the lack of active antimicrobials available. MK-7655 is a novel β-lactamase inhibitor under clinical development. We investigated the combined killing activity of imipenem and MK-7655 against four imipenem-resistant bacterial strains, using a mathematical model previously evaluated in our laboratory.

Novel modeling framework to guide design of optimal dosing strategies for β-lactamase inhibitors.

The scarcity of new antibiotics against drug-resistant bacteria has led to the development of inhibitors targeting specific resistance mechanisms, which aim to restore the effectiveness of existing agents. However, there are few guidelines for the optimal dosing of inhibitors. Extending the utility of mathematical modeling, which has been used as a decision support tool for antibiotic dosing regimen design, we developed a novel mathematical modeling framework to guide optimal dosing strategies for a beta-lactamase inhibitor.

A model to predict mortality following Pseudomonas aeruginosa bacteremia.

Infections caused by Pseudomonas aeruginosa are associated with significant mortality. Existing mathematical models identifying mortality risk factors lack validation. We developed and validated a model to predict mortality in patients with P.

Quantitative impact of neutrophils on bacterial clearance in a murine pneumonia model.

The rapid increase in the prevalence of antibiotic-resistant pathogens is a global problem that has challenged our ability to treat serious infections. Currently, clinical decisions on treatment are often based on in vitro susceptibility data. The role of the immune system in combating bacterial infections is unequivocal, but it is not well captured quantitatively.

Modelling biphasic killing of fluoroquinolones: guiding optimal dosing regimen design.

Objectives: Fluoroquinolones are commonly believed to exhibit concentration-dependent killing, but time-kill studies have revealed that fluoroquinolone activity could be a complex combination of concentration-dependent and -independent killing. We had previously developed a mathematical modelling framework to describe the dynamics of bacterial populations under the effect of antimicrobials, which could facilitate the design of optimal dosing regimens. Our objective was to extend the framework to describe the effect of fluoroquinolones on heterogeneous populations of Escherichia coli and Staphylococcus aureus.

Mathematical modeling to characterize the inoculum effect.

Killing by beta-lactams is well known to be reduced against a dense bacterial population, commonly known as the inoculum effect. However, the underlying mechanism of this phenomenon is not well understood. We proposed a semi-mechanistic mathematical model to account for the reduced in vitro killing observed.

Impact of recA on levofloxacin exposure-related resistance development.

Genetic mutations are one of the major mechanisms by which bacteria acquire drug resistance. One of the known mechanisms for inducing mutations is the SOS response system. We investigated the effect of disrupting recA, an inducer of the SOS response, on resistance development using an in vitro hollow-fiber infection model.

Impact of multidrug-resistant Pseudomonas aeruginosa bacteremia on patient outcomes.

Trends of rising rates of resistance in Pseudomonas aeruginosa make selection of appropriate empirical therapy increasingly difficult, but whether multidrug-resistant (MDR) P. aeruginosa is associated with worse clinical outcomes is not well established. The objective of this study was to determine the impact of MDR (resistance to three or more classes of antipseudomonal agents) P.

Prevalence, resistance mechanisms, and susceptibility of multidrug-resistant bloodstream isolates of Pseudomonas aeruginosa.

Pseudomonas aeruginosa is an important pathogen commonly implicated in nosocomial infections. The occurrence of multidrug-resistant (MDR) P. aeruginosa strains is increasing worldwide and limiting our therapeutic options.

Pharmacodynamics of moxifloxacin against a high inoculum of Escherichia coli in an in vitro infection model.

Objectives: Escherichia coli is the leading bacterial species implicated in intra-abdominal infections. In these infections a high bacterial burden with pre-existing resistant mutants are likely to be encountered and resistance could be amplified with suboptimal dosing. Our objective was to investigate the pharmacodynamics of moxifloxacin against a high inoculum of E.

Killing of Escherichia coli by beta-lactams at different inocula.

Escherichia coli is a common pathogen implicated in intra-abdominal infections; a heavy bacterial burden is often encountered, and the clinical utility of beta-lactams may be limited by the inoculum effect. We examined the impact of a high inoculum on the bactericidal activity of various beta-lactams against E. coli.

Impact of AmpC overexpression on outcomes of patients with Pseudomonas aeruginosa bacteremia.

AmpC overexpression (AmpC++) is a significant mechanism of beta-lactam resistance in Pseudomonas aeruginosa, but its impact on clinical outcomes is not well established. To examine the influence of AmpC++ on clinical outcomes of patients with P. aeruginosa bacteremia, we screened all bloodstream P.

Quantitative assessment of combination antimicrobial therapy against multidrug-resistant Acinetobacter baumannii.

Treatment of multidrug-resistant bacterial infections poses a therapeutic challenge to clinicians; combination therapy is often the only viable option for multidrug-resistant infections. A quantitative method was developed to assess the combined killing abilities of antimicrobial agents. Time-kill studies (TKS) were performed using a multidrug-resistant clinical isolate of Acinetobacter baumannii with escalating concentrations of cefepime (0 to 512 mg/liter), amikacin (0 to 256 mg/liter), and levofloxacin (0 to 64 mg/liter).

Racing pigeon identification using STR and chromo-helicase DNA binding gene markers.

Pigeon racing appeals to many in Taiwan, due in part to the potential large financial gains based on illegal betting. The races are unregulated with frequent examples of fraud, such as substitution of one bird for a substandard one. There is no test available to reliably verify the bloodline of pigeons and thus help to resolve such disputes.

Prevalence, mechanisms, and risk factors of carbapenem resistance in bloodstream isolates of Pseudomonas aeruginosa.

We examined the prevalence of various carbapenem resistance mechanisms in Pseudomonas aeruginosa bloodstream isolates from a university-affiliated hospital. Isolates obtained in 2003 and 2004 were screened for meropenem/imipenem resistance, and clonality was assessed by repetitive-element-based polymerase chain reaction. The presence of carbapenemase and AmpC overexpression was ascertained by spectrophotometric assays.