Judith N. Steenbergen

Ceftolozane/Tazobactam Plus Metronidazole for Complicated Intra-abdominal Infections in an Era of Multidrug Resistance: Results From a Randomized, Double-Blind, Phase 3 Trial (ASPECT-cIAI)

This phase 3 trial compared ceftolozane/tazobactam plus metronidazole vs meropenem for the treatment of complicated intra-abdominal infections. Ceftolozane/tazobactam plus metronidazole was noninferior to meropenem. High rates of presumed microbiological eradication of Enterobacteriaceae and Pseudomonas aeruginosa were found with both regimens.

Daptomycin Rapidly Penetrates a Staphylococcus epidermidis Biofilm

ABSTRACT Fluorescently tagged daptomycin accessed the interior of Staphylococcus epidermidis biofilm cell clusters within minutes. The diffusion coefficient of daptomycin in the biofilm was 28% of its value in pure water. Daptomycin activity against staphylococci embedded in biofilms is unlikely to be limited by penetration of the antibiotic into the biofilm.

Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI)

BACKGROUND Treatment of complicated urinary-tract infections is challenging due to rising antimicrobial resistance. We assessed the efficacy and safety of ceftolozane-tazobactam, a novel antibacterial with Gram-negative activity, in the treatment of patients with complicated lower-urinary-tract infections or pyelonephritis. METHODS ASPECT-cUTI was a randomised, double-blind, double-dummy, non-inferiority trial done in 209 centres in 25 countries. Between July, 2011, and September, 2013, hospital inpatients aged 18 years or older who had pyuria and a diagnosis of a complicated lower-urinary-tract infection or pyelonephritis were randomly assigned in a 1:1 ratio to receive intravenous 1·5 g ceftolozane-tazobactam every 8 h or intravenous high-dose (750 mg) levofloxacin once daily for 7 days. The randomisation schedule was computer generated in blocks of four and stratified by study site. The next allocation was obtained by the study site pharmacist via an interactive voice-response system. The primary endpoint was a composite of microbiological eradication and clinical cure 5-9 days after treatment in the microbiological modified intention-to-treat (MITT) population, with a non-inferiority margin of 10%. This study is registered with ClinicalTrials.gov, numbers NCT01345929 and NCT01345955. FINDINGS Of 1083 patients enrolled, 800 (73·9%), of whom 656 (82·0%) had pyelonephritis, were included in the microbiological MITT population. Ceftolozane-tazobactam was non-inferior to levofloxacin for composite cure (306 [76·9%] of 398 vs 275 [68·4%] of 402, 95% CI 2·3-14·6) and, as the lower bound of the two-sided 95% CI around the treatment difference was positive and greater than zero, superiority was indicated. Adverse event profiles were similar in the two treatment groups and were mainly non-serious. INTERPRETATION Treatment with ceftolozane-tazobactam led to better responses than high-dose levofloxacin in patients with complicated lower-urinary-tract infections or pyelonephritis. FUNDING Cubist Pharmaceuticals.

Susceptibility relationship between vancomycin and daptomycin in Staphylococcus aureus: facts and assumptions

The decrease in vancomycin treatment efficacy that is accompanying increases in vancomycin minimum inhibitory concentration (MIC) within the susceptible range (so-called MIC creep) has led to the suggestion that vancomycin is losing its potency in treating serious Staphylococcus aureus infections. Understanding the clinical importance of the microbiological effects of glycopeptides on bacterial lipopeptides and lipoglycopeptides will be crucial in treating serious meticillin-resistant S aureus infections. We review the observed effects of reduced glycopeptide susceptibility on the activities of daptomycin in S aureus in vitro and in vivo. Factors associated with loss of susceptibility and ways to reduce the risk of resistance to daptomycin are reviewed, including the importance of prompt mechanical reduction of bacterial inoculum through surgery or through potent or combination antibiotic therapy, as well as optimisation of daptomycin pharmacodynamic exposure.

Associations between the Genotypes of Staphylococcus aureus Bloodstream Isolates and Clinical Characteristics and Outcomes of Bacteremic Patients

ABSTRACT We investigated associations between the genotypic and phenotypic features of Staphylococcus aureus bloodstream isolates and the clinical characteristics of bacteremic patients enrolled in a phase III trial of S. aureus bacteremia and endocarditis. Isolates underwent pulsed-field gel electrophoresis, PCR for 33 putative virulence genes, and screening for heteroresistant glycopeptide intermediate S. aureus (hGISA). A total of 230 isolates (141 methicillin-susceptible S. aureus and 89 methicillin-resistant S. aureus [MRSA]) were analyzed. North American and European S. aureus isolates differed in their genotypic characteristics. Overall, 26% of the MRSA bloodstream isolates were USA 300 strains. Patients with USA 300 MRSA bacteremia were more likely to be injection drug users (61% versus 15%; P < 0.001), to have right-sided endocarditis (39% versus 9%; P = 0.002), and to be cured of right-sided endocarditis (100% versus 33%; P = 0.01) than patients with non-USA 300 MRSA bacteremia. Patients with persistent bacteremia were less likely to be infected with Panton-Valentine leukocidin gene (pvl)-constitutive MRSA (19% versus 56%; P = 0.005). Although 7 of 89 MRSA isolates (8%) exhibited the hGISA phenotype, no association with persistent bacteremia, daptomycin resistance, or bacterial genotype was observed. This study suggests that the virulence gene profiles of S. aureus bloodstream isolates from North America and Europe differ significantly. In this study of bloodstream isolates collected as part of a multinational randomized clinical trial, USA 300 and pvl-constitutive MRSA strains were associated with better clinical outcomes.

Effects of daptomycin in combination with other antimicrobial agents: a review of in vitro and animal model studies

This review summarizes the in vitro and animal model data available on antibiotic combinations with daptomycin. The majority of studies focus on the clinically relevant combinations of daptomycin with rifampicin or with gentamicin. These studies demonstrate that daptomycin does not adversely affect the activity of other antimicrobial agents that may be administered concomitantly. Overall, additive or indifferent effects with daptomycin combinations were observed; however, synergy was observed for certain isolates of vancomycin-resistant enterococci when exposed to daptomycin and rifampicin. Unexpected synergy was demonstrated against methicillin-resistant Staphylococcus aureus by daptomycin and beta-lactams. Most importantly, no in vitro antagonism of daptomycin with any other agent tested was confirmed in these studies. The most striking in vivo effects were noted in two different complicated infection models; i.e. osteomyelitis and implant infections, where rifampicin combinations with daptomycin increased efficacy and reduced the incidence of rifampicin resistance.

Pharmacokinetics-Pharmacodynamics of Tazobactam in Combination with Piperacillin in an In Vitro Infection Model

ABSTRACT Despite β-lactamase inhibitors being available for clinical use for nearly 30 years, a paucity of data exists describing the pharmacokinetic-pharmacodynamic (PK-PD) determinants of efficacy for these agents. Herein, we describe dose fractionation studies designed to determine the exposure measure most predictive of tazobactam efficacy in combination with ceftolozane and the magnitude of this measure necessary for efficacy in a PK-PD in vitro infection model. The challenge organism panel was comprised of an isogenic CTX-M-15-producing Escherichia coli triplet set, genetically engineered to transcribe different levels of blaCTX-M-15. These recombinant strains exhibited ceftolozane MIC values of 4, 16, and 64 μg/ml representing low, moderate, and high levels of CTX-M-15, respectively. Different blaCTX-M-15 transcription levels were confirmed by relative quantitative real-time PCR (qRT-PCR) and β-lactamase hydrolytic assays. The exposure measure associated with efficacy was the percentage of the dosing interval that tazobactam concentrations remained above a threshold (%Time>threshold), regardless of enzyme expression (r2 = 0.938). The threshold concentrations identified were 0.05 μg/ml for low and moderate and 0.25 μg/ml for the high-β-lactamase expression strain constructs. The magnitudes of %Time>threshold for tazobactam associated with net bacterial stasis and a 1- and 2-log10 CFU reduction in bacteria at 24 h were approximately 35, 50, and 70%, respectively. These data provide an initial target tazobactam concentration-time profile and a paradigm to optimize tazobactam dosing when combined with ceftolozane.

Pharmacological Basis of β-Lactamase Inhibitor Therapeutics: Tazobactam in Combination with Ceftolozane

ABSTRACT We recently investigated the pharmacokinetics-pharmacodynamics (PK-PD) of tazobactam in combination with ceftolozane against an isogenic CTX-M-15-producing Escherichia coli triplet set, genetically engineered to transcribe different levels of blaCTX-M-15. The percentage of the dosing interval that tazobactam concentrations remained above a threshold (%Time>threshold) was identified as the PK-PD exposure measure that was most closely associated with efficacy. Moreover, the tazobactam concentration was dependent upon the enzyme transcription level. Given that the aforementioned strains were genetically engineered to transcribe a single β-lactamase enzyme and that clinical isolates typically produce multiple β-lactamase enzymes with various transcription levels, it is likely that the tazobactam threshold concentration is isolate/enzyme dependent. Our first objective was to characterize the relationship between the tazobactam %Time>threshold in combination with ceftolozane and efficacy using clinical isolates in an in vitro PK-PD infection model. Our second objective was to identify a translational relationship that would allow for the comodeling across clinical isolates. The initial challenge panel included four well-characterized β-lactamase-producing E. coli strains with variable enzyme expression and other resistance determinants. As evidenced by r2 values of ranging from 0.90 to 0.99 for each clinical isolate, the observed data were well described by fitted functions describing the relationship between the tazobactam %Time>threshold and change in log10 CFU from baseline; however, the data from the four isolates did not comodel well. The threshold concentration identified for each isolate ranged from 0.5 to 4 mg/liter. We identified an enabling translational relationship for the tazobactam threshold that allowed comodeling of all four clinical isolates, which was the product of the individual isolates ceftolozane-tazobactam MIC value and 0.5. As evidenced by an r2 value of 0.90, the transformed data were well described by a fitted function describing the relationship between tazobactam %Time>threshold and change in log10 CFU from baseline. Due to these findings, the challenge panel was expanded to include three well-characterized β-lactamase-producing Klebsiella pneumoniae strains with variable enzyme expression and other resistance determinants. The translational relationship for the tazobactam threshold that allowed for the comodeling of the four E. coli isolates performed well for the expanded data set (seven isolates in total; four E. coli and three K. pneumoniae), as evidenced by an r2 value of 0.84. This simple translational relationship is especially useful as it is directly linked to in vitro susceptibility test results, which are used to guide the clinicians choice of drug and dosing regimen.

Inhibitory and Bactericidal Activities of Daptomycin, Vancomycin, and Teicoplanin against Methicillin-Resistant Staphylococcus aureus Isolates Collected from 1985 to 2007

ABSTRACT The inhibitory and bactericidal activities of daptomycin, vancomycin, and teicoplanin against a collection of 479 methicillin-resistant Staphylococcus aureus isolates were assessed. The isolates were collected from U.S. and European hospitals from 1985 to 2007 and were primarily from blood and abscess cultures. The MICs and minimum bactericidal concentrations (MBCs) of the three agents were determined, and the MBC/MIC ratios were calculated to determine the presence or absence of tolerance. Tolerance was defined as an MBC/MIC ratio of ≥32 or an MBC/MIC ratio of ≥16 when the MBC was greater than or equal to the breakpoint for resistance. Tolerance to vancomycin and teicoplanin was observed in 6.1% and 18.8% of the strains, respectively. Tolerance to daptomycin was not observed.

Outcomes with daptomycin in the treatment of Staphylococcus aureus infections with a range of vancomycin MICs

Objectives Recent recommendations by the Infectious Diseases Society of America for the treatment of Staphylococcus aureus suggest the use of alternative agents when vancomycin MIC values are ≥2 mg/L. This study examines the outcome of patients treated with daptomycin for S. aureus infections with documented vancomycin MICs. Patients and methods All patients with skin, bacteraemia and endocarditis infections due to S. aureus with vancomycin MIC values in CORE 2005–08, a retrospective, multicentre, observational registry, were studied. The outcome (cure, improved, failure or non-evaluable) was the investigator assessment at the end of daptomycin therapy. Success was defined as cure or improved. Results Five hundred and forty-seven clinically evaluable patients were identified with discrete vancomycin MIC values [MIC <2 mg/L: 451 (82%); MIC ≥2 mg/L: 96 (18%)]. The vancomycin MIC groups were well matched for patient characteristics, types of infections, first-line daptomycin use (19%) and prior vancomycin use (58%). Clinical success was reported in 94% of patients. No differences were detected in the daptomycin success rate by the vancomycin MIC group overall or by the infection type. A multivariate logistic regression also failed to identify vancomycin MIC as a predictor of daptomycin failure. Adverse event (AE) rates were not different when analysed by MIC group; both groups had ∼17% of patients with one AE. Conclusions In this diverse population, daptomycin was associated with similar outcomes for patients, regardless of whether the vancomycin MIC was categorized as <2 or ≥2 mg/L. Further studies are warranted.