Elizabeth A. Coyle

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).

Optimization of Meropenem Minimum Concentration/MIC Ratio To Suppress In Vitro Resistance of Pseudomonas aeruginosa

ABSTRACT Suppression of resistance in a dense Pseudomonas aeruginosa population has previously been shown with optimized quinolone exposures. However, the relevance to β-lactams is unknown. We investigated the bactericidal activity of meropenem and its propensity to suppress P. aeruginosa resistance in an in vitro hollow-fiber infection model (HFIM). Two isogenic strains of P. aeruginosa (wild type and an AmpC stably derepressed mutant [MIC = 1 mg/liter]) were used. An HFIM inoculated with approximately 1 × 108 CFU/ml of bacteria was subjected to various meropenem exposures. Maintenance doses were given every 8 h to simulate the maximum concentration achieved after a 1-g dose in all regimens, but escalating unbound minimum concentrations (Cmins) were simulated with different clearances. Serial samples were obtained over 5 days to quantify the meropenem concentrations, the total bacterial population, and subpopulations with reduced susceptibilities to meropenem (>3× the MIC). For both strains, a significant bacterial burden reduction was seen with all regimens at 24 h. Regrowth was apparent after 3 days, with the Cmin/MIC ratio being ≤1.7 (time above the MIC, 100%). Selective amplification of subpopulations with reduced susceptibilities to meropenem was suppressed with a Cmin/MIC of ≥6.2 or by adding tobramycin to meropenem (Cmin/MIC = 1.7). Investigations that were longer than 24 h and that used high inocula may be necessary to fully evaluate the relationship between drug exposures and the likelihood of resistance suppression. These results suggest that the Cmin/MIC of meropenem can be optimized to suppress the emergence of non-plasmid-mediated P. aeruginosa resistance. Our in vitro data support the use of an extended duration of meropenem infusion for the treatment of severe nosocomial infections in combination with an aminoglycoside.

Influences of Linezolid, Penicillin, and Clindamycin, Alone and in Combination, on Streptococcal Pyrogenic Exotoxin A Release

ABSTRACT An in vitro model was used to compare the effects of linezolid, clindamycin, and penicillin, alone and in combination, on streptococcal pyrogenic exotoxin A (SPE A) release against virulent group A streptococci (GAS). All regimens exhibited lower (P < 0.05) SPE A release at 1 h than those with penicillin alone. Linezolid and clindamycin, alone or in combination with penicillin, may optimize the treatment of GAS infections by reducing bacterial burden and exotoxin release.

Comparative Pharmacodynamics of Gentamicin against Staphylococcus aureus and Pseudomonas aeruginosa

ABSTRACT Aminoglycosides are often used to treat severe infections with gram-positive organisms. Previous studies have shown concentration-dependent killing by aminoglycosides of gram-negative bacteria, but limited data are available for gram-positive bacteria. We compared the in vitro pharmacodynamics of gentamicin against Staphylococcus aureus and Pseudomonas aeruginosa. Five S. aureus strains were examined (ATCC 29213 and four clinical isolates). Time-kill studies (TKS) in duplicate (baseline inocula of 107 CFU/ml) were conducted to evaluate bacterial killing in relation to increasing gentamicin concentrations (0 to 16 times the MIC). Serial samples were obtained over 24 h to quantify bacterial burden. Similar TKS with P. aeruginosa ATCC 27853 were conducted, and the time courses of the all bacterial strains were mathematically modeled for quantitative comparison. A dose fractionation study (using identical daily doses of gentamicin) in an in vitro hollow-fiber infection model (HFIM) over 5 days was subsequently used for data validation for the two ATCC strains. Model fits to the data were satisfactory; r2 values for the S. aureus and P. aeruginosa ATCC strains were 0.915 and 0.956, respectively. Gentamicin was found to have a partially concentration-dependent killing effect against S. aureus; concentrations beyond four to 8 times the MIC did not result in significantly faster bacterial killing. In contrast, a concentration-dependent profile was demonstrated in suppressing P. aeruginosa regrowth after initial decline in bacterial burden. In HFIM, thrice-daily gentamicin dosing appeared to be superior to once-daily dosing for S. aureus, but they were similar for P. aeruginosa. Different killing profiles of gentamicin were demonstrated against S. aureus and P. aeruginosa. These results may guide optimal dosing strategies of gentamicin in S. aureus infections and warrant further investigations.

Activities of Newer Fluoroquinolones against Ciprofloxacin-Resistant Streptococcus pneumoniae

ABSTRACT The incidence of ciprofloxacin resistance in Streptococcus pneumoniae is low but steadily increasing, which raises concerns regarding the clinical impact of potential cross-resistance with newer fluoroquinolones. To investigate this problem, we utilized an in vitro pharmacodynamic model and compared the activities of gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin to that of ciprofloxacin against two laboratory-derived, ciprofloxacin-resistant derivatives of S. pneumoniae (strains R919 and R921). Ciprofloxacin resistance in these strains involved the activity of a multidrug efflux pump and possibly, for R919, a mutation resulting in an amino acid substitution in GyrA. Gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin achieved 99.9% killing of both R919 and R921 in ≤28 h. With respect to levofloxacin, significant regrowth of both mutants was observed at 48 h (P < 0.05). For gatifloxacin, grepafloxacin, moxifloxacin, and trovafloxacin, regrowth was minimal at 48 h, with each maintaining 99.9% killing against both mutants. No killing of either R919 or R921 was observed with exposure to ciprofloxacin. During model experiments, resistance to gatifloxacin, grepafloxacin, moxifloxacin, and trovafloxacin did not develop but the MICs of ciprofloxacin and levofloxacin increased 1 to 2 dilutions for both R919 and R921. Although specific area under the concentration-time curve from 0 to 24 h (AUC0–24)/MIC and maximum concentration of drug in serum (Cmax)/MIC ratios have not been defined for the fluoroquinolones with respect to gram-positive organisms, our study revealed that significant regrowth and/or resistance was associated with AUC0–24/MIC ratios of ≤31.7 and Cmax/MIC ratios of ≤3.1. It is evident that the newer fluoroquinolones tested possess improved activity against S. pneumoniae, including strains for which ciprofloxacin MICs were elevated.

Targeting Bacterial Virulence: The Role of Protein Synthesis Inhibitors in Severe Infections

Morbidity and mortality due to certain bacterial pathogens have not declined despite the availability of effective antimicrobial treatments. Staphylococcus aureus and Streptococcus pyogenes cause a number of serious infections, such as necrotizing fasciitis and toxic shock syndrome, which are associated with the release of bacterial toxins. Animal studies have demonstrated clindamycin, a protein synthesis inhibitor, to be more effective in treating these severe infections than other more susceptible antimicrobial treatments. Linezolid, another protein synthesis inhibitor, also has shown efficacy in in vitro studies. Human trials to validate the effects of antibiotic therapies on bacterial virulence have not been performed. Future animal and human studies are needed to help elucidate the immunomodulatory mechanisms of protein synthesis inhibitors in order to optimize antimicrobial treatment and decrease the morbidity and mortality associated with severe bacterial infections.

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.

Escherichia coli resistance to quinolones at a comprehensive cancer center

As part of Meropenem Yearly Susceptibility Test Information Collection/USA Surveillance Programme, we monitored the occurrence of quinolone resistance in Escherichia coli over a 10-year period. A total of 271 E. coli isolates from our institution were tested over a 10-year period. Screening for quinolone resistance (qnr) gene was performed. A decline in susceptibility of E. coli isolates to quinolones and aminoglycosides was noted over the 10-year span (P < 0.0001), which was significantly reduced compared with the average susceptibility of all sites. Introduction of quinolone prophylaxis has led to a significant decline in susceptibility of E. coli to all quinolones. The organisms remain susceptible to carbapenems, cefepime, and piperacillin/tazobactam. Periodic surveillance allows for detection of resistance patterns and adjustment of empiric antibiotic choice in patients at high risk for infection.

Factors That Influence Student Completion of Course and Faculty Evaluations

Objective. To determine if there is a relationship between students’ grades, gender, age, or ethnicity and their completion of course and/or faculty evaluations. Methods. Data were collected and analyzed for relationships among students’ gender, age, ethnicity, and course grade on their completion rates of course and faculty evaluations. Results. The grade a student received in a course was not related to completion rates for course or faculty evaluations. Students born in 1987 or earlier were significantly more likely to complete course or faculty evaluations. Significant differences in completion rates were also found based on the course taken and the gender and ethnicity of the students. Conclusions. Several demographic characteristics were identified that correlated with the completion of course and/or faculty evaluations. However, no correlation was found with the grade a student receives in a course and completion of either course or faculty evaluations. In order to improve course and faculty evaluation rates, further analysis of the influence of demographics on completion rates is warranted.

Spectrum of Gram-positive bacteraemia and in vitro activities of daptomycin, linezolid and vancomycin against organisms isolated from cancer patients

Gram-positive organisms are the predominant bacterial pathogens in cancer patients. A survey indicated that coagulase-negative staphylococci (CoNS) (29.5%), Staphylococcus aureus (18.0%), Enterococcus spp. (12.1%) and viridans group streptococci (VGS) (9.1%) are isolated most often. The rate of reduced susceptibility to vancomycin (minimum inhibitory concentration ≥1.0 μg/mL) was 100% for meticillin-susceptible S. aureus and 99% for meticillin-resistant S. aureus, and 100% for meticillin-susceptible CoNS and 98% for meticillin-resistant CoNS. More than 98% of these isolates were susceptible to daptomycin and linezolid. Daptomycin and linezolid had comparable in vitro activity to vancomycin against Bacillus spp., Corynebacterium spp., Rhodococcus spp., Micrococcus spp., Stomatococcus mucilaginosus and VGS. Both agents were active against the majority (95%) of vancomycin-resistant organisms, including vancomycin-resistant enterococci, Pediococcus spp. and Leuconostoc spp. These data suggest that daptomycin and linezolid have an adequate antimicrobial spectrum and potent in vitro activity against Gram-positive isolates from cancer patients and may be considered as alternatives to vancomycin for empirical or targeted therapy in this setting.