A novel framework to compare the effectiveness of ß-lactamase inhibitors against extended-spectrum ß-lactamase-producing Enterobacteriaceae.

OBJECTIVES: Extended-spectrum ß-lactamases (ESBLs) present a serious challenge in the treatment of Gram-negative bacterial infections. ESBLs mediate resistance to most ß-lactams, which may be reversed with the addition of an active ß-lactamase inhibitor (such as tazobactam, relebactam and avibactam). However, various ESBLs may exhibit different susceptibilities to these inhibitors, which could impact efficacy. We proposed a framework for comparing the efficacy of these inhibitors when combined with the same ß-lactam. METHODS: Three clinical isolates of Klebsiella pneumoniae harbouring CTX-M-15 and one Escherichia coli isolate with SHV-12 were examined. Piperacillin MICs were determined by broth dilution using escalating concentrations of tazobactam, relebactam and avibactam. The resulting MICs were characterized as response to inhibitor concentrations using an inhibitory sigmoid Emax model. Using the best-fit parameter values, the model was conditioned with fluctuating inhibitor concentrations to simulate instantaneous MICi profiles for each isolate-inhibitor pair. Using a simulated exposure of 4 g piperacillin every 8 h, %fT > MICi was estimated for each piperacillin/inhibitor combination. A hollowfibre infection model was subsequently used to validate the predicted effectiveness of selected combinations. RESULTS: In all scenarios, piperacillin MIC reductions were well characterized with increasing inhibitor concentrations. As predicted by %fT > MICi, combining piperacillin with avibactam (61.4%-73.6%) was found to be superior to tazobactam (13.5%-44.5%) for suppressing bacterial growth over time. CONCLUSION: We illustrated a practical approach to compare the performance of different inhibitors. This platform may be used clinically to identify the optimal pairing of various ß-lactams and ß-lactamase inhibitors for individual isolates producing ESBLs.

The role of infection models and PK/PD modelling for optimising care of critically ill patients with severe infections.

Critically ill patients with severe infections are at high risk of suboptimal antimicrobial dosing. The pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in these patients differ significantly from the patient groups from whose data the conventional dosing regimens were developed. Use of such regimens often results in inadequate antimicrobial concentrations at the site of infection and is associated with poor patient outcomes. In this article, we describe the potential of in vitro and in vivo infection models, clinical pharmacokinetic data and pharmacokinetic/pharmacodynamic models to guide the design of more effective antimicrobial dosing regimens. Individualised dosing, based on population PK models and patient factors (e.g. renal function and weight) known to influence antimicrobial PK, increases the probability of achieving therapeutic drug exposures while at the same time avoiding toxic concentrations. When therapeutic drug monitoring (TDM) is applied, early dose adaptation to the needs of the individual patient is possible. TDM is likely to be of particular importance for infected critically ill patients, where profound PK changes are present and prompt appropriate antibiotic therapy is crucial. In the light of the continued high mortality rates in critically ill patients with severe infections, a paradigm shift to refined dosing strategies for antimicrobials is warranted to enhance the probability of achieving drug concentrations that increase the likelihood of clinical success.

Prevalence of type III secretion protein exoenzymes and antimicrobial susceptibility patterns from bloodstream isolates of patients with Pseudomonas aeruginosa bacteremia.

The purpose of this study was to determine the prevalence of two type III secretion effector proteins, exoU and exoS from bloodstream isolates of hospitalized patients with Pseudomonas aeruginosa (PSA) bacteremia, to characterize antimicrobial susceptibility patterns, and to compare mortality rates. PSA bloodstream isolates and antibiotic susceptibility profiles were collected from a university-affiliated hospital. ExoS and exoU genes were detected by polymerase chain reaction. Hospital mortality was assessed by medical chart review. 119 of 122 (97.5%) PSA bloodstream isolates contained either the exoS or exoU genes. ExoS was the most prevalent (n=86; 70.5%) followed by exoU (n=31; 25.4%), both genes (n=2; 1.6%) or neither gene (n=3; 2.5%). Isolates containing the exoU gene were significantly more likely to be resistant to cefepime, ceftazidime, piperacillintazobactam, carbapenems, fluoroquinolones, and gentamicin (p<0.05 for all). Mortality was high in patients with PSA bacteremia and did not differ among patients infected with the exoS isolates (n=37; 43%) or exoU isolates (n=11; 35%). One of two type III secretion effector proteins were almost universally present in PSA bloodstream isolates. Isolates containing the exoU gene were more likely to be resistant to multiple antibiotics.

Impact of drug-exposure intensity and duration of therapy on the emergence of Staphylococcus aureus resistance to a quinolone antimicrobial.

We have shown previously in animal model and in vitro systems that antimicrobial therapy intensity has a profound influence on subpopulations of resistant organisms. Little attention has been paid to the effect of therapy duration on resistant subpopulations. We examined the influence of therapy intensity (area under the concentration/time curve for 24 h:minimum inhibitory concentration [AUC24:MIC] ratio) and therapy duration on resistance emergence using an in vitro model of Staphylococcus aureus infection. AUC24:MIC ratios of>or=100 were necessary to kill a substantial portion of the total population. Importantly, we demonstrated that therapy duration is a critical parameter. As the duration increased beyond 5 days, the intensity needed to suppress the antibiotic-resistant subpopulations increased, even when the initial bacterial kill was>4 log10 (cfu/mL). These findings were prospectively validated in an independent experiment in which exposures were calculated from the results of fitting a large mathematical model to all data simultaneously. All of the prospectively determined predictions were fulfilled in this validation experiment.

Prevalence of AmpC over-expression in bloodstream isolates of Pseudomonas aeruginosa.

This study examined the contribution of AmpC over-expression to beta-lactam resistance in clinical isolates of Pseudomonas aeruginosa obtained from a hospital in Houston, TX, USA. Seventy-six non-repeat bloodstream isolates obtained during 2003 were screened for ceftazidime resistance in the presence and absence of clavulanic acid 4 mg/L. AmpC was identified by isoelectric focusing (with and without cloxacillin inhibition); stable derepression was ascertained phenotypically by a spectrophotometric assay (with and without preceding induction by imipenem) using nitrocefin as the substrate, and was confirmed subsequently by quantitative RT-PCR of the ampC gene. The clonal relatedness of the AmpC-over-expressing isolates was assessed by pulsed-field gel electrophoresis. In addition, the ampC and ampR gene sequences were determined by PCR and sequencing. For comparison, two standard wild-type strains (PAO1 and ATCC 27853) and three multidrug-susceptible isolates were used as controls. AmpC over-expression was confirmed in 14 ceftazidime-resistant isolates (overall prevalence rate, 18.4%), belonging to seven distinct clones. The most prevalent point mutations in ampC were G27D, V205L and G391A. Point mutations in ampR were also detected in eight ceftazidime-resistant isolates. AmpC over-expression appears to be a significant mechanism of beta-lactam resistance in P. aeruginosa. Understanding the prevalence and mechanisms of beta-lactam resistance in P. aeruginosa may guide the choice of empirical therapy for nosocomial infections in hospitals.

Risk factors for postoperative chest wound infections due to gram-negative bacteria in cardiac surgery patients.

Gram-negative bacteria account for up to 35% of postoperative sternal wound infections (SWI) in patients undergoing cardiac surgery. Despite this, risk factors for Gram-negative SWI have not been investigated. The objective of this study was to define risk factors associated with Gram-negative SWI in patients undergoing cardiac surgery. 2590 patients undergoing cardiac surgery between 2002-2005 were prospectively monitored for development of SWI. Patient, operative, and post-operative risk factors were compared among patients that developed Gram-negative SWI and Gram-positive SWI to uninfected controls using univariate and multivariate analysis. A p < 0.05 was considered significant. Surgical site infections developed in 152 (5.9%) patients. Isolates were recovered from the sternum for 128 (5.0%) patients, from the leg donor site for 19 (0.73%) patients, and from the sternum and donor site for 5 (0.19%) patients. Gram-positive pathogens were isolated from 83 (3.3%) patients, Gram-negative pathogens from 42 (1.6%) patients, and mixed pathogens from 27 (1.0%) patients. Hospital admission greater than 48 hours before surgery (OR: 2.25; 95% CI: 1.11 - 4.58), ventilator-dependency preoperatively (OR: 5.32 95% CI: 2.22 - 12.75), and thoracentesis procedure postoperatively (OR: 3.71; 95% CI: 1.45 - 9.49) and diabetes (OR: 2.04; 95% CI: 1.17 - 3.55) were identified as significant risk factors for SWI due to Gram-negative bacteria using multivariate logistic regression. Diabetes, increased age, and peripheral vascular disease were identified as significant risk factors for SWI due to Gram-positive bacteria (p < 0.05, each). The risk factors associated with Gram-negative SWI differed significantly from those associated with Gram-positive SWI. Risk factors associated with Gram-negative SWI were identified. Unique interventions may be necessary to prevent Gram-negative SWI in cardiac surgery patients.

Rhodococcus equi pneumonia in a patient with human immunodeficiency virus: case report and review.

Rhodococcus equi is a facultative, intracellular, gram-positive coccobacillus increasingly reported as an opportunistic pathogen in patients positive for human immunodeficiency virus (HIV). An HIV-positive man developed R. equi pneumonia and sepsis. He failed to improve despite surgical drainage of localized infection and many empiric antibiotics. Time-kill studies of R. equi isolated from the patient were performed against various antimicrobial agents to optimize therapy. Levofloxacin seemed to offer excellent in vitro bactericidal activity. Antagonism was observed with certain antibiotic combinations. Our anecdotal case report suggests that fluoroquinolones such as levofloxacin may offer superior efficacy to standard therapy in rhodococcal infections; their clinical utility deserves further investigation. In view of potential antagonism, prospective susceptibility testing for various drugs and drug combinations should be considered when clinically indicated.

New antibiotics for infections caused by resistant organisms.

A continued increase in the expression of resistance among bacterial pathogens has prompted the development of a variety of new compounds directed against resistant strains of bacteria. Recently, the most dramatic increase in resistance has been among gram-positive organisms, and the predominant areas of development have been within a few classes of agents. Expanded spectrum fluoroquinolones offer advantages against many resistant gram-positive organisms, including S. pneumoniae and S. aureus. Newly developed classes of antimicrobials offer some unique activity against resistant staphylococci and enterococci. The first classes approved for use in the US are the streptogramins, specifically quinupristin/dalfopristin (Synercid), and the oxazolidinone linezolid (Zyvox). Other new classes of agents, including the ketolides, everninomycins, and newer glycopeptides, such as LY-333328, are in the early stages of development.

Once-daily aminoglycoside in the treatment of Enterococcus faecalis endocarditis: case report and review.

Once-daily administration of aminoglycosides (ODA) is effective and safe for many indications. By optimizing pharmacodynamic principles, it enhances bactericidal activity and minimizes toxicity. Its use for the treatment of enterococcal infection is controversial, however, and results of in vitro studies and animal models of endocarditis are conflicting. To date, no case reports or clinical trials have examined its utility in human enterococcal endocarditis. A patient with right-sided endocarditis caused by Enterococcus faecalis was managed by once-daily gentamicin. Clinical and bacteriologic cures of this patient raise questions as to whether enterococcal endocarditis should be regarded as contraindication to ODA. The clinical utility of ODA in this disease deserves further investigation.

Once-daily aminoglycosides in the treatment of gram-positive endocarditis.

OBJECTIVE: To examine the role of once-daily aminoglycosides (ODA) in the treatment of gram-positive endocarditis. DATA SOURCES: A MEDLINE search was conducted from January 1984 to August 1998, and a Current Contents search was performed from September 1998 to December 1998, using endocarditis or aminoglycoside as key words. In addition, relevant articles were cross-referenced to screen for additional information. DATA EXTRACTION: Data published in English regarding the use of aminoglycosides in endocarditis are cited. Emphasis was placed on animal and human studies, but in vitro studies and review articles are also included. DATA SYNTHESIS: Endocarditis and the pharmacology of aminoglycosides are briefly reviewed. ODA is an alternative to conventional dosing in the treatment of endocarditis. Extensive work in endocarditis has been done recently in animals and humans to add to our understanding. Limited clinical data exist to support the theoretical advantages of increased efficacy, reduced toxicity, and potential cost savings versus traditional synergistic aminoglycoside dosing. Optimal monitoring of ODA remains undefined. CONCLUSIONS: Routine use of ODA for the treatment of endocarditis is not yet advocated. Promising supporting evidence and speculation of success of ODA in gram-positive endocarditis justify well-designed trials to further define its role in therapy.

Vancomycin peak serum concentration monitoring.

Vancomycin is a glycopeptide antibiotic commonly used in the treatment of gram-positive bacterial infections. With the rising prevalence of resistant gram-positive bacterial infections in healthcare institutions and the advent of attempts to curb escalating medical cost, vancomycin is being used with increasing frequency in the homecare setting for infection management. In view of its variability in pharmacokinetics and the potential for toxicities, serum concentrations often are measured. This article reviews the pharmacology of vancomycin and suggests a practical approach to serum concentration monitoring in homecare.