Ellie Hershberger

In Vitro Activities of Daptomycin, Vancomycin, Linezolid, and Quinupristin-Dalfopristin against Staphylococci and Enterococci, Including Vancomycin- Intermediate and -Resistant Strains

ABSTRACT The in vitro activity of daptomycin was compared with those of vancomycin, linezolid, and quinupristin-dalfopristin against a variety (n = 203) of gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and S. epidermidis (MRSA and MRSE, respectively), vancomycin-resistant enterococci (VRE), and vancomycin-intermediate S. aureus(VISA). Overall, daptomycin was more active against all organisms tested, except Enterococcus faecium and VISA, against which its activity was similar to that of quinupristin-dalfopristin. In time-kill studies with MRSA, MRSE, VRE, and VISA, daptomycin demonstrated greater bactericidal activity than all other drugs tested, killing ≥3 log CFU/ml by 8 h. Daptomycin may be a potential alternative drug therapy for multidrug-resistant gram-positive organisms and warrants further investigation.

Relationship between Fluoroquinolone Use and Changes in Susceptibility to Fluoroquinolones of Selected Pathogens in 10 United States Teaching Hospitals, 1991-2000

We retrospectively examined the relationship between fluoroquinolone use and the susceptibilities of 11 bacterial pathogens to fluoroquinolones in 10 US teaching hospitals from 1991 through 2000. Statistical significance was determined by 2-way analysis of variance, with the number of isolates tested each year as a weighting factor. The analysis of baseline-to-end point change in the percentage of susceptibility and the slope of the regression line (trend line) for logit percentage of susceptibility showed that the overall percentage of susceptibility to fluoroquinolones decreased significantly during the study period (P<.05) and that change in percentage of susceptibility was significantly related to change in fluoroquinolone use (P<.05). Particularly notable were the decreases in the susceptibilities of Pseudomonas aeruginosa, Proteus mirabilis, and Escherichia coli (decreases of 25.1%, 11.9%, and 6.8%, respectively).

Pharmacokinetics and Safety of Intravenous Ceftolozane-Tazobactam in Healthy Adult Subjects following Single and Multiple Ascending Doses

ABSTRACT The pharmacokinetics and safety of ceftolozane, a novel cephalosporin, and tazobactam, a β-lactamase inhibitor, alone and in combination as a 2:1 ratio in single doses of up to 2,000 and 1,000 mg of ceftolozane and tazobactam, respectively, and multiple doses of up to 3,000 and 1,500 mg of ceftolozane and tazobactam, respectively, per day were evaluated in healthy adult subjects. In part 1, groups of six subjects each received single ascending doses of ceftolozane, tazobactam, and ceftolozane-tazobactam in a within-cohort crossover design. In part 2, groups of 5 or 10 subjects each received multiple doses of ceftolozane, tazobactam, or ceftolozane-tazobactam for 10 days. After a single dose of ceftolozane alone, the ranges of mean values for half-life (2.48 to 2.64 h), the total clearance (4.35 to 6.01 liters/h), and the volume of distribution at steady state (11.0 to 14.1 liters) were consistent across dose levels and similar to those observed when ceftolozane was coadministered with tazobactam. Mean values after multiple doses for ceftolozane alone and ceftolozane-tazobactam were similar to those seen following a single dose. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Ceftolozane-tazobactam was well tolerated and systemic adverse events were uncommon. Mild infusion-related adverse events were the most commonly observed following multiple-dose administration. Adverse events were not dose related, and no dose-limiting toxicity was identified.

Activities of Trovafloxacin, Gatifloxacin, Clinafloxacin, Sparfloxacin, Levofloxacin, and Ciprofloxacin against Penicillin-Resistant Streptococcus pneumoniae in an In Vitro Infection Model

ABSTRACT We adapted an in vitro pharmacodynamic model of infection to incorporate infected fibrin clots. The bactericidal activities of various fluoroquinolones against two strains of penicillin-resistantStreptococcus pneumoniae were studied over a 48-h period. Bacteria were prepared in Muller-Hinton broth by using colonies from a 24-h tryptic soy agar plus 5% sheep blood plate and were added to a mixture of cryoprecipitate (80%) and thrombin (10%) to achieve approximately 106 CFU of organism per fibrin clot. The fibrin clots were suspended into the models and removed, in triplicate, at various time points over 48 h. Control models were also conducted to characterize the growth of S. pneumoniae in the growth medium without antibiotic. Trovafloxacin, gatifloxacin, clinafloxacin, sparfloxacin, levofloxacin, and ciprofloxacin were administered to simulate their pharmacokinetic profiles in humans. Fibrin clot samples were also plated onto antibiotic-containing tryptic soy agar plus 5% lysed horse blood to detect resistance. The newer fluoroquinolones demonstrated better activity than ciprofloxacin against both isolates. In conclusion, the newer quinolones demonstrated significant activity against penicillin-resistant S. pneumoniae, with standard dosing resulting in area under the concentration-time curve/MIC ratios and peak concentration/MIC ratios that resulted in 99.9% killing against these isolates.

Comparison of a Rabbit Model of Bacterial Endocarditis and an In Vitro Infection Model with Simulated Endocardial Vegetations

ABSTRACT Animal models are commonly used to determine the efficacy of various antimicrobial agents for treatment of bacterial endocarditis. Previously we have utilized an in vitro infection model, which incorporates simulated endocardial vegetations (SEVs) to evaluate the pharmacodynamics of various antibiotics. In the present study, we compared four experimental rabbit endocarditis protocols to an in vitro infection model in an effort to determine if these models are comparable. We have evaluated the activity of clinafloxacin, trovafloxacin, sparfloxacin, and ciprofloxacin in rabbit models againstStaphylococcus aureus and Enterococcus spp. In vitro models were performed simulating the antibiotic pharmacokinetics obtained in the in vivo studies. Models were dosed the same as rabbit models, and SEVs were evaluated at the same time the rabbit vegetations were examined. Clinafloxacin and trovafloxacin were evaluated against methicillin-susceptible (MSSA1199) and -resistant (MRSA494) strains ofS. aureus. Ciprofloxacin was studied against MSSA1199 and MSSA487. Sparfloxacin and clinafloxacin were evaluated againstEnterococcus faecium SF2149 and Enterococcus faecalis WH245, respectively. We found that reductions in SEV bacterial density obtained in the in vitro model were similar to those obtained in rabbit vegetations, indicating that the SEV model may be a valuable tool for assessing antibiotic potential in the treatment of bacterial endocarditis.

Activities of Trovafloxacin and Ampicillin-Sulbactam Alone or in Combination versus Three Strains of Vancomycin- Intermediate Staphylococcus aureus in an In Vitro Pharmacodynamic Infection Model

ABSTRACT The recent isolation of clinical strains of methicillin-resistantStaphylococcus aureus (MRSA) with intermediate susceptibility (MICs, 8 μg/ml) to vancomycin (vancomycin-intermediateS. aureus [VISA]) emphasizes the importance of developing novel antimicrobial regimens and/or agents for future treatment. We studied the activities of ampicillin-sulbactam and trovafloxacin alone or in combination against three unique strains of VISA in an in vitro infection model. Two VISA strains were trovafloxacin susceptible (MICs, ≤2 μg/ml); one VISA strain was trovafloxacin resistant (MIC, 4 μg/ml). Trovafloxacin was administered to simulate a dose of 200 or 400 mg every 24 h. Ampicillin-sulbactam was administered to simulate a dose of 3 g every 6 h. Samples were removed from the infection models over 48 h, and reductions in colony counts were compared between regimens. Trovafloxacin (200 mg) produced rapid killing of a control MRSA strain over the 48-h experiment but produced only slight killing of all three VISA strains. The higher dose of trovafloxacin improved killing but did not produce bactericidal activity at 48 h. Ampicillin-sulbactam produced rapid bactericidal activity against all four strains tested, and colony counts at 8 h were at the limits of detection. However, regrowth occurred by 48 h for each strain. The combination of ampicillin-sulbactam and trovafloxacin provided additive activity against two of the three VISA strains. In conclusion, trovafloxacin or ampicillin-sulbactam alone did not provide adequate activity against the VISA strains for the 48-h evaluation period, but the combination could help improve activity against some strains of VISA.

Pharmacokinetics and Safety of Ceftolozane/Tazobactam in Adolescents and Young Children with Proven or Suspected Gram-negative Infection

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251Characteristics and Outcomes of Complicated Intra-abdominal Infections Involving Pseudomonas aeruginosa from a Phase 3 Ceftolozane/Tazobactam Study

BACKGROunD: Ceftolozane/tazobactam (C/T) is a novel antimicrobial with activity against pathogens causing complicated intra-abdominal infections (cIAIs), including extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae and drug-resistant Pseudomonas aeruginosa. The efficacy and safety of C/T + metronidazole (MTZ) compared with meropenem (MEM) were evaluated in a randomized, double-blind Phase 3 trial in hospitalized patients with cIAI. This analysis provides information on cIAI involving P. aeruginosa, a pathogen poorly described in cIAI. METHODS: Hospitalized patients with cIAI were randomized to 4-14 days of intravenous (IV) C/T (1.5 g) + MTZ (500 mg) every 8 hours or IV MEM (1 g every 8 hours). Baseline intra-abdominal cultures were obtained. The primary efficacy endpoint was the clinical response at the test-of-cure (TOC) visit 26-30 days after the start of study therapy. RESul TS: In the microbiological intent-to-treat (MITT) population (N = 806), P. aeruginosa was isolated in 72 (8.9%) patients (38 C/T + MTZ, 34 MEM); the incidence of P. aeruginosa in North America was 18%. P. aeruginosa was more frequently associated with polymicrobial infection (94% vs 65%). The highest incidence of P. aeruginosa occurred in patients with infections arising from the colon (14%) or appendix (11%). P. aeruginosa infections were less likely to be hospital-acquired (2.8% vs 7.1%) but occurred more commonly in those receiving prior antibiotic therapy (65% vs 57%). C/T and MEM were highly active in vitro against P. aeruginosa , with a minimum inhibitory concentration against 90% of pathogens (MIC 90) of 2 µg/mL and 4 µg/mL, respectively. Clinical cure rates in the microbiologically evaluable patients with P. aeruginosa were 100% (25/25) and 96% (27/28) for C/T + MTZ and MEM, respectively. COnCluSIOnS: In this Phase 3 study in hospitalized patients with cIAI, P. aeruginosa was isolated in 8.9% of MITT patients. Interestingly, P. aeruginosa was most commonly isolated in community-acquired infections of the colon and appendix. Prior use of MTZ and third-generation cephalosporins may have predisposed patients to infection with P. aeruginosa. Overall, patients with P. aeruginosa responded well to therapies in this study, as demonstrated by the high clinical cure rates. ABSTRACT ■ Characteristics of patients with P. aeruginosa were summarized for the microbiological intent-to-treat (MITT) population. - The MITT population included all randomized patients who had a baseline intra- abdominal pathogen, regardless of its susceptibility to study drug. � ■ Efficacy outcomes were assessed at the test-of-cure (TOC) visit 26 to 30 days after the initiation of study drug in the microbiologically evaluable (ME) population. - The ME population included patients who received study drug, had a susceptible baseline intra-abdominal pathogen, and adhered to the protocol. � ■ Clinical cure was defined as complete resolution/significant improvement of the signs and symptoms of the index infection, with no additional antibiotics or surgical procedure required. � ■ Microbiological eradication was defined as absence of the baseline pathogen in a specimen appropriately obtained from the original site of infection or presumed eradication, which was defined as a lack of clinical indication for subsequent culture in a patient who was assessed as a clinical cure. � ■ Pathogen speciation and susceptibility testing were performed at a central laboratory (ICON Laboratories, Farmingdale, NY, USA) using Clinical and Laboratory Standards Institute (CLSI) 7 breakpoints for meropenem and provisional breakpoints for ceftolozane/ ■ The most frequently used prior agents in patients with P. aeruginosa were metronidazole (41.7%), ceftriaxone (12.5%), and cefotaxime (8.3%). � ■ The distribution of minimum inhibitory concentrations (MICs) for P. aeruginosa for ceftolozane/tazobactam and meropenem are presented in Figure 2. Both treatments were highly active in vitro against P. aeruginosa , with an MIC against 90% of pathogens (MIC90) of 1 µg/mL for ceftolozane/tazobactam and 2 µg/mL for meropenem. � ■ Baseline demographics were comparable between patients with and without P. aeruginosa infections ( Table 1). In North America, the frequency of P. aeruginosa infection was 17.6% (Figure 3). � ■ Overall, the majority of cIAIs were categorized as community-acquired. Patients with a P. aeruginosa infection were more likely to have a community-acquired infection (70/72 (97.2%)) than those who were not infected with P. aeruginosa (682/734 (92.9%)). � ■ P. aeruginosa was more likely to be isolated as part of a polymicrobial infection (68/72 (94.4%)) than being the sole pathogen (4/72 (5.6%)) in cIAI.