David S. Burgess

Antimicrobial breakpoints for Gram-negative aerobic bacteria based on pharmacokinetic–pharmacodynamic models with Monte Carlo simulation

OBJECTIVESnThis study describes a comprehensive programme designed to develop pharmacokinetic-pharmacodynamic (PK-PD) breakpoints for numerous antimicrobial classes against key gram-negative aerobic bacteria.nnnMETHODSnA 10,000 subject Monte Carlo simulation was constructed for 13 antimicrobials (21 dosing regimens). Published pharmacokinetic data and protein binding were varied according to log-normal and uniform distributions. MICs were fixed at single values from 0.03 to 64 mg/L. The PK-PD susceptible breakpoint was defined as the MIC at which the probability of target attainment was > or = 90%. PK-PD, CLSI and European Committee on Antimicrobial Susceptibility Testing breakpoints were applied to MICs from the 2005 worldwide Meropenem Yearly Susceptibility Test Information Collection database to evaluate the impact of breakpoint discrepancies.nnnRESULTSnPK-PD breakpoints were within one dilution of the CLSI and European breakpoints for all antimicrobials tested--with a few exceptions. When discrepancies were noted, the PK-PD breakpoint was lower than the CLSI breakpoint [ceftriaxone (0.5 versus 8 mg/L), ertapenem (0.25 versus 2 mg/L), ciprofloxacin (0.125 versus 1 mg/L) and levofloxacin (0.25-0.5 versus 2 mg/L)] and higher than the European breakpoint [ceftazidime (4-8 versus 1 mg/L), aztreonam (4-8 versus 1 mg/L), although ciprofloxacin was an exception to this pattern (0.125 versus 0.5-1 mg/L)]. For Enterobacteriaceae, breakpoint discrepancies resulted in modest (< or = 10%) differences in the percentages susceptible. In contrast, large (> 15%) discrepancies were noted for Pseudomonas aeruginosa and Acinetobacter baumannii.nnnCONCLUSIONSnBreakpoint agreement exists for imipenem, meropenem and the aminoglycosides. In contrast, discrepancies exist for piperacillin/tazobactam, cephalosporins, ertapenem, aztreonam and the fluoroquinolones. These discrepancies are most pronounced for P. aeruginosa and A. baumannii.

Pharmacokinetics and pharmacodynamics of cefepime administered by intermittent and continuous infusion

OBJECTIVEnThis study assessed the pharmacokinetics and pharmacodynamics of cefepime administered by intermittent and continuous infusion against clinical isolates of Pseudomonas aeruginosa, Enterobacter cloacae, and Staphylococcus aureus.nnnBACKGROUNDnBecause beta-lactam antibiotics exhibit time-dependent bactericidal activity and lack prolonged postantibiotic effects against many bacteria, the goal of therapy is to maintain serum drug concentrations above the minimum inhibitory concentration (MIC) for the relevant pathogen over most of the dosing interval. Continuous infusion is a mode of drug administration that can provide serum drug concentrations continuously above the MIC for most bacterial pathogens.nnnMETHODSnTwelve healthy volunteers were enrolled. Each received cefepime 2 g by intermittent bolus q12h and, on another day, was randomly assigned to receive 4 or 3 g administered by continuous infusion over 24 hours.nnnRESULTSnFor the intermittent regimen, the mean (+/- SD) pharmacokinetic findings were: maximum serum concentration, 112.9 +/- 21.1 microg/mL; minimum serum concentration, 1.3 +/- 0.5 microg/mL; and half-life, 2.6 +/- 0.4 hours. For the 3- and 4-g continuous infusion regimens, steady-state serum concentrations (C(SS)) were 13.9 +/- 3.8 and 20.3 +/- 3.3 microg/mL, respectively. MICs ranged from 2 to 4, 0.125 to 8, and 2 to 8 microg/mL against P. aeruginosa, E. cloacae, and S. aureus, respectively. For the intermittent regimen, serum inhibitory titers (SITs) at 24 hours were > or = 1:2 in 46% of subjects against P. aeruginosa, 48% against E. cloacae, and 2% against S. aureus. For both continuous infusion regimens, SITs for each organism were > or = 1:2 in all subjects.nnnCONCLUSIONSnThe intermittent regimen maintained serum concentrations above the MIC for P. aeruginosa and E. cloacae in > or = 92% (11/12) of subjects for > or = 70% of the dosing interval, provided the MIC was < or = 4 microg/mL. Both continuous infusion regimens provided a C(SS) above the MIC for all organisms. However, the C(SS) was > or = 4 times the MIC only if the MIC was < or = 2 microg/mL. Only the 4-g regimen provided such concentrations against isolates with an MIC of 4 microg/mL, and neither regimen provided such concentrations when the MIC was 8 microg/mL. These findings should be applied in comparative clinical studies.

Effectiveness of statins in reducing the rate of severe sepsis : A retrospective evaluation

Study Objectives. To determine whether use of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) is associated with a reduced rate of severe sepsis, and to further characterize the effect of statins on the frequency of organ dysfunction in patients with severe sepsis.

Guideline-Concordant Antibiotic Use and Survival Among Patients With Community-Acquired Pneumonia Admitted to the Intensive Care Unit

OBJECTIVEnThis study evaluated the survival benefit of US community-acquired pneumonia (CAP) practice guidelines in the intensive care unit (ICU) setting.nnnMETHODSnWe conducted a retrospective cohort study of adult patients with CAP who were admitted to 5 community hospital ICUs between November 1, 1999, and April 30, 2000. The guidelines for antibiotic prescriptions were the 2007 Infectious Diseases Society of America/American Thoracic Society guidelines. Guideline-concordant antimicrobial therapy was defined as a beta-lactam plus fluoroquinolone or macrolide, antipseudomonal beta-lactam plus fluoroquinolone, or antipseudomonal beta-lactam plus aminoglycoside plus fluoroquinolone or macrolide. Patients with a documented beta-lactam allergy were considered to have received guideline-concordant therapy if they received a fluoroquinolone with or without clindamycin, or aztreonam plus fluoroquinolone with or without aminoglycoside. All other antibiotic regimens were considered to be guideline discordant. Time to clinical stability, time to oral antibiotics, length of hospital stay, and in-hospital mortality were evaluated with regression models that included the outcome as the dependent variable, guideline-concordant antibiotic therapy as the independent variable, and the Pneumonia Severity Index (PSI) score and facility as covariates.nnnRESULTSnThe median age of the 129 patients included in the study was 71 years (interquartile range, 60-79 years). Sixty-two of 129 patients (48%) were male. Comorbidities included liver dysfunction (7 patients [5%]), heart failure (62 [48%]), renal dysfunction (39 [30%]), cerebrovascular disease (21 [16%]), and cancer (14 [11%]). The median (25th-75th percentile) PSI score was 119 (98-142), and overall mortality was 19% (25 patients). Patient demographics were similar between groups. Fifty-three patients (41%) received guideline-endorsed therapies. Guideline-discordant therapy was associated with an increase in inpatient mortality (25% vs 11%; odds ratio = 2.99 [95% CI, 1.08-9.54]). Receipt of guideline-concordant antibiotics was not associated with reductions in time to clinical stability, time to oral antibiotics, or length of hospital stay when patients who died were excluded from the analysis.nnnCONCLUSIONnGuideline-concordant empiric antibiotic therapy was associated with improved survival among these patients with CAP who were admitted to 5 ICUs.

Clinical and microbiologic analysis of a hospital's extended-spectrum β-lactamase-producing isolates over a 2-year period

Study Objective. To evaluate the microbiologic and clinical outcomes of patients with extended‐spectrum β‐lactamase (ESBL)‐producing isolates over a 2‐year period.

Effect of macrolides as part of initial empiric therapy on medical outcomes for hospitalized patients with community-acquired pneumonia

OBJECTIVEnThe goal of this study was to compare the outcomes of hospitalized patients receiving a nonpseudomonal third-generation cephalosporin with or without a macrolide for the treatment of community-acquired pneumonia (CAP).nnnBACKGROUNDnThe initial treatment of CAP is usually based on empirically selected antibiotic therapy. The need for coverage of atypical pathogens in hospitalized patients is widely debated, and regional variations may exist.nnnMETHODSnAll patients admitted to a community hospital or to a university hospital for 1 year who were aged > or =18 years and had a principal discharge diagnosis of pneumonia with no organism specified according to the International Classification of Diseases, Ninth Revision, Clinical Modification were evaluated. Each patients medical chart was reviewed by a clinical pharmacist at each facility. The following information was collected for each patient using a standardized form: demographic characteristics, coexisting illnesses, length of hospital and intensive care unit stays, antibiotic regimens, length of parenteral and oral therapy, laboratory and radiographic findings (ie, blood urea nitrogen, glucose, hematocrit, sodium, PO2, pH, and pleural effusion), physical examination results, and mortality. Patients treated with a nonpseudomonal third-generation cephalosporin with or without a macrolide were included in this analysis. Categoric variables were compared using the chi-square test or the Fisher exact test, and continuous variables were compared using the Mann-Whitney U test. A P value < 0.05 was considered statistically significant.nnnRESULTSnA total of 213 patients met the entry criteria and were treated with a nonpseudomonal third-generation cephalosporin with (116 patients) or without (97 patients) a macrolide. The mean (+/- SD) age of the patients was 62.2+/-19.6 years; 47% were male. The most common comorbid conditions were chronic obstructive pulmonary disease, diabetes mellitus, congestive heart failure, and cerebrovascular accident (CVA). Of the 116 patients who received a macrolide, the majority (66%) received erythromycin. Other macrolides used were clarithromycin (19%) and oral azithromycin (15%). There were no statistical differences between patients who did and did not receive a macrolide in terms of comorbid illnesses, length of hospital stay (5.2+/-2.8 vs 5.2+/-3.4 days, respectively), length of intravenous antibiotic therapy (4.4+/-2.5 vs 4.1+/-2.3 days, respectively), or mortality (0.9% vs 3.1%, respectively; P = 0.333). The only difference between the groups was in age. Those patients who received a macrolide were significantly younger than those who received only a nonpseudomonal third-generation cephalosporin (57.4+/-19.2 years vs 67.9+/-18.5 years; P < 0.001). However, when age and severity of illness were taken into account, no difference existed between the patients who received a nonpseudomonal third-generation cephalosporin alone or in combination with a macrolide.nnnCONCLUSIONSnWe concluded that the addition of a macrolide to a nonpseudomonal third-generation cephalosporin as initial therapy for the treatment of CAP may not be necessary. A randomized, prospective clinical trial comparing a nonpseudomonal third-generation cephalosporin alone and in combination with a macrolide is warranted.

Targeted high lung concentrations of itraconazole using nebulized dispersions in a murine model

PurposeThe purpose of this study was to investigate the delivery of itraconazole (ITZ) particles to a murine lung model by nebulization.MethodsThree ITZ formulations were prepared and characterized in the dry state using contact angle, dissolution, X-ray powder diffraction, scanning electron microscopy, and Brunauer–Emmett–Teller surface area analysis. Aerodynamic particle size distributions and lung deposition studies in 14 outbred male ICR mice were performed using aqueous dispersions of all the formulations. A separate dosing uniformity study was also performed to qualify use of the chamber.ResultsAll formulations had an aggregated particle size of approximately 30xa0μm in diameter. Two formulations showed that 80% of the drug dissolved in less than 5xa0min. The remaining ITZ formulation had a slower dissolution and the lowest total emitted dose from the nebulizer used. High concentrations of ITZ were shown to be present in the mouse lung during the lung deposition study, up to 16.8 ± 0.13xa0μg/g (± SE) were achieved. Concentrations of up to 0.76 ± 0.03xa0μg/g (± SE) could be maintained from the single nebulized dose for at least 24xa0h.ConclusionAn effective method of targeted delivery of ITZ to the deep lung is presented that may be useful for the treatment and prevention of acute fungal infections.

Cefepime, piperacillin/tazobactam, gentamicin, ciprofloxacin, and levofloxacin alone and in combination against Pseudomonas aeruginosa

A beta-lactam plus an aminoglycoside is the standard for treating severe Pseudomonas aeruginosa infections. However, the fluoroquinolones are safer and have been widely used as an alternative to the aminoglycosides in this setting. In this study we compared the synergistic activities of piperacillin/tazobactam and cefepime when either drug was combined with gentamicin, ciprofloxacin, or levofloxacin against P. aeruginosa. Susceptibility testing and time-kill curves were performed against 12 clinical isolates of P. aeruginosa. All combinations were bactericidal and retained this activity over the 24 hr period except for piperacillin/tazobactam in combination with levofloxacin or ciprofloxacin against 2 isolates and cefepime in combination with levofloxacin against 1 isolate. None of the combinations were antagonistic. No statistical difference in the frequency of synergy exists between the beta-lactam plus gentamicin (79%) and the beta-lactams plus either ciprofloxacin or levofloxacin combinations (58%, 67%). Furthermore, no differences in synergistic activity were noted between ciprofloxacin combinations (58%) and levofloxacin combinations (67%). In conclusion, the degree of synergy between a beta-lactam plus aminoglycoside and a beta-lactam plus fluoroquinolone seem to be comparable. Furthermore, there is a similar rate of synergy among different fluoroquinolone-based combinations. However, faster killing, less regrowth, and decrease in the development of resistance were seen with the beta-lactam plus aminoglycoside combination.

Pharmacodynamics of fluconazole, itraconazole, and amphotericin B against Candida albicans<

The objective of this study was to evaluate the pharmacodynamic activity of fluconazole, itraconazole, and amphotericin B against Candida albicans. Susceptibilities were determined according to the NCCLS guidelines (M27). Time-kill studies were performed using antifungal concentrations of 0.25-32 x MIC. Samples were withdrawn at predetermined timepoints, then plated using a spiral plater. Colony counts were determined after incubation at 35 degrees C for 24 h. The AUKC(0-48) was plotted against the concentration/MIC ratio. Candida isolates (95-2672, 96-15, and 95-2542) were classified as susceptible, susceptible-dose dependent, and resistant to fluconazole and itraconazole (MIC = 0.25 and 0.03 microg/mL, 32 and 0.5 microg/mL, 64 and 1 microg/mL; respectively). All three isolates were susceptible to amphotericin B (MIC = 0.13 microg/mL). Fluconazole inhibited the growth of the susceptible and S-DD isolates and was ineffective at all concentrations against the resistant isolate. Itraconazole, on the other hand, inhibited growth of the susceptible isolate, but was ineffective for the S-DD and resistant isolates. Maximal effectiveness was noted at the concentration 8 x MIC and 2 x MIC for fluconazole and itraconazole, respectively. Amphotericin B demonstrated concentration-dependent antifungal activity. The times necessary for the colony counts to fall below the limit of quantification were inversely related to increasing concentrations of amphotericin B. The maximal effect for amphotericin B was recorded at 2 x MIC. In summary, the triazoles inhibit growth of susceptible C. albicans; however, careful consideration should be given to the MIC for S-DD isolates because itraconazole may not be active if the MIC is reported in the higher susceptible-dose dependency range. In reference to amphotericin B, optimal activity may be achieved by maximizing the peak drug concentration/MIC ratio.

Increases in SLT2 Expression and Chitin Content Are Associated with Incomplete Killing of Candida glabrata by Caspofungin

ABSTRACT Incomplete killing was observed for caspofungin against Candida glabrata, which was associated with increased SLT2 expression and elevated chitin content. In contrast, fungicidal activity and no chitin increase were observed in an isogenic Δslt2 strain, suggesting a role for SLT2 and chitin production in the response of C. glabrata to caspofungin.