Adjunctive rifampin is crucial to optimizing daptomycin efficacy against rabbit prosthetic joint infection due to methicillin-resistant Staphylococcus aureus.

Daptomycin is an attractive option for treating prosthetic joint infection, but the 6-mg/kg of body weight/day dose was linked to clinical failure and emergence of resistance. Using a methicillin-resistant Staphylococcus aureus (MRSA) knee prosthesis infection in rabbits, we studied the efficacies of high-dose daptomycin (22 mg/kg given intravenously [i.v.] once daily [o.d.]; equivalent to 8 mg/kg/day in humans) or vancomycin (60 mg/kg given intramuscularly [i.m.] twice daily [b.i.d.]), both either alone or with adjunctive rifampin (10 mg/kg i.m. b.i.d.). After partial knee replacement with a silicone implant, 10(7) MRSA CFU was injected into the knees. Treatment started 7 days postinoculation and lasted 7 days. Positive cultures were screened for the emergence of mutant strains, defined as having 3-fold-increased MICs. Although in vivo mean log(10) CFU/g of daptomycin-treated (4.23 ± 1.44; n = 12) or vancomycin-treated (4.63 ± 1.08; n = 12) crushed bone was significantly lower than that of controls (5.93 ± 1.15; n = 9) (P < 0.01), neither treatment sterilized bone (2/12 and 0/12 rabbits with sterile bone, respectively). Daptomycin mutant strains were found in 6/12, 3/12, and 2/9 daptomycin-treated, vancomycin-treated, and control rabbits, respectively; no resistant strains emerged (MIC was always <1 mg/liter). Adjunctive rifampin with daptomycin (1.47 ± 0.04 CFU/g of bone [detection threshold]; 11/11 sterile bones) or vancomycin (1.5 ± 0.12 CFU/g of bone; 6/8 sterile bones) was significantly more effective than monotherapy (P < 0.01) and prevented the emergence of daptomycin mutant strains. In this MRSA joint prosthesis infection model, combining rifampin with daptomycin was highly effective. Daptomycin mutant strains were isolated in vivo even without treatment, but adjunctive rifampin prevented this phenomenon, previously found after monotherapy in humans.

Development of a phenotypic method for detection of fecal carriage of OXA-48-producing enterobacteriaceae after incidental detection from clinical specimen.

We report incidental isolation of an OXA-48-producing Escherichia coli strain in urine of a 62-year-old woman recently returning from a 2-month vacation in Morocco. Commercially available extended-spectrum beta-lactamase (ESBL)-targeting medium failed to detect it in the patient's stools, although a locally developed and easy-to-implement method using ertapenem-supplemented brain heart infusion (BHI) broths could.

Comparative in vitro activity of Meropenem, Imipenem and Piperacillin/tazobactam against 1071 clinical isolates using 2 different methods: a French multicentre study.

BACKGROUND: Meropenem is a carbapenem that has an excellent activity against many gram-positive and gram-negative aerobic, facultative, and anaerobic bacteria. The major objective of the present study was to assess the in vitro activity of meropenem compared to imipenem and piperacillin/tazobactam, against 1071 non-repetitive isolates collected from patients with bacteremia (55%), pneumonia (29%), peritonitis (12%) and wound infections (3%), in 15 French hospitals in 2006. The secondary aim of the study was to compare the results of routinely testings and those obtained by a referent laboratory. METHOD: Susceptibility testing and Minimum Inhibitory Concentrations (MICs) of meropenem, imipenem and piperacillin/tazobactam were determined locally by Etest method. Susceptibility to meropenem was confirmed at a central laboratory by disc diffusion method and MICs determined by agar dilution method for meropenem, imipenem and piperacillin/tazobactam. RESULTS: Cumulative susceptibility rates against Escherichia coli were, meropenem and imipenem: 100% and piperacillin/tazobactam: 90%. Against other Enterobacteriaceae, the rates were meropenem: 99%, imipenem: 98% and piperacillin/tazobactam: 90%. All Staphylococci, Streptococci and anaerobes were susceptible to the three antibiotics. Against non fermeters, meropenem was active on 84-94% of the strains, imipenem on 84-98% of the strains and piperacillin/tazobactam on 90-100% of the strains. CONCLUSIONS: Compared to imipenem, meropenem displays lower MICs against Enterobacteriaceae, Escherichia coli and Pseudomonas aeruginosa. Except for non fermenters, MICs90 of carbapenems were <4 mg/L. Piperacillin/tazobactam was less active against Enterobacteriaceae and Acinetobacter but not P. aeruginosa. Some discrepancies were noted between MICs determined by Etest accross centres and MICs determined by agar dilution method at the central laboratory. Discrepancies were more common for imipenem testing and more frequently related to a few centres. Overall MICs determined by Etest were in general higher (0.5 log to 1 log fold) than MICs by agar dilution.

Risk factors for multidrug resistant bacteria and optimization of empirical antibiotic therapy in postoperative peritonitis.

INTRODUCTION: The main objective was to determine risk factors for presence of multidrug resistant bacteria (MDR) in postoperative peritonitis (PP) and optimal empirical antibiotic therapy (EA) among options proposed by Infectious Disease Society of America and the Surgical Infection Society guidelines. METHODS: One hundred patients hospitalised in the intensive care unit (ICU) for PP were reviewed. Clinical and microbiologic data, EA and its adequacy were analysed. The in vitro activities of 9 antibiotics in relation to the cultured bacteria were assessed to propose the most adequate EA among 17 regimens in the largest number of cases. RESULTS: A total of 269 bacteria was cultured in 100 patients including 41 episodes with MDR. According to logistic regression analysis, the use of broad-spectrum antibiotic between initial intervention and reoperation was the only significant risk factor for emergence of MDR bacteria (odds ratio (OR) = 5.1; 95% confidence interval (CI) = 1.7 - 15; P = 0.0031). Antibiotics providing the best activity rate were imipenem/cilastatin (68%) and piperacillin/tazobactam (53%). The best adequacy for EA was obtained by combinations of imipenem/cilastatin or piperacillin/tazobactam, amikacin and a glycopeptide, with values reaching 99% and 94%, respectively. Imipenem/cilastin was the only single-drug regimen providing an adequacy superior to 80% in the absence of broad spectrum antibiotic between initial surgery and reoperation. CONCLUSIONS: Interval antibiotic therapy is associated with the presence of MDR bacteria. Not all regimens proposed by Infectious Disease Society of America and the Surgical Infection Society guidelines for PP can provide an acceptable rate of adequacy. Monotherapy with imipenem/cilastin is suitable for EA only in absence of this risk factor for MDR. For other patients, only antibiotic combinations may achieve high adequacy rates.

Bactericidal activity of the combination of levofloxacin with rifampin in experimental prosthetic knee infection in rabbits due to methicillin-susceptible Staphylococcus aureus.

The combination of levofloxacin and rifampin has been recommended for the treatment of staphylococcal prosthetic infection. In a rabbit model of prosthetic knee infection due to a susceptible clinical strain of Staphylococcus aureus, the combination of levofloxacin and rifampin was bactericidal, significantly reduced bacterial titers in bone compared with levels for rifampin and controls (P < 0.05), sterilized 6 of 12 animals, and prevented the selection of resistant mutants that was observed with rifampin alone, validating clinical recommendations.

Prospective evaluation of virulence factors of enterococci isolated from patients with peritonitis: impact on outcome.

The objective of this study was to evaluate the prevalence of 4 virulence factors (VFs) of enterococci (cytolysin [cyl], gelatinase [gel], aggregation substance [agg], and enterococcal surface protein [esp]) and their relationship to outcome in patients with generalized peritonitis in a prospective cohort study. VF expression in each strain was assessed by polymerase chain reaction assay with specific primers. Outcome of the patients was recorded. Ninety-nine strains of Enterococcus were obtained from the peritoneal fluid of 81 patients. Fifty-eight patients had at least 1 strain bearing [cyl] (13.1% of the strains), [gel] (50.5% of the strains), [agg] (40.4% of the strains), and [esp] (34.3% of the strains). The presence of VF of Enterococcus was independently associated with mortality: odds ratio, 5.5; 95% confidence interval, 1.3-28.1. In conclusion, VF accounted for 72% of the patients with enterococci isolated from the peritoneal fluid and was independently associated with mortality in severe peritonitis.

Predictive factors of mortality due to polymicrobial peritonitis with Candida isolation in peritoneal fluid in critically ill patients.

BACKGROUND: Candida peritonitis (CP) is generally considered to be a severe disease, but its impact on outcome in critically ill patients remains unknown. HYPOTHESIS: The predictive factors of mortality due to CP can be determined by study of a population of patients with CP. DESIGN: A retrospective review of a prospective surgical intensive care unit (ICU) database of patients (January 1, 1994, through December 31, 2000). SETTING: University hospital in Paris, France. PATIENTS: Eighty-three patients with generalized CP. MAIN OUTCOME MEASURES: Demographic and microbiologic data and outcome were collected, and nonsurvivors were compared with survivors. RESULTS: Overall ICU mortality due to CP was 43 (52%) of 83 patients. In a stepwise multivariate logistic regression, the following 4 variables were independently associated with mortality: APACHE II (Acute Physiology and Chronic Health Evaluation II) score on admission of at least 17 (odds ratio [OR], 28.4; 95% confidence interval [CI], 5.7-142.5; P<.001), respiratory failure on admission (OR, 10.6; 95% CI, 2.2-51.2; P =.003), upper gastrointestinal tract site of peritonitis (OR, 7.7; 95% CI, 1.7-34.7; P =.007), and results of direct examination of peritoneal fluid that were positive for Candida (OR, 4.7; 95% CI, 1.2-19.7; P =.002). CONCLUSIONS: These results confirm the severity of CP in ICU patients and emphasize the prognostic value of direct examination of peritoneal fluid for Candida in this context.

Pseudomonas aeruginosa post-operative peritonitis: clinical features, risk factors, and prognosis.

BACKGROUND: Postoperative peritonitis (PP) is associated with a high rate of multi-drug-resistant micro-organisms. The role of Pseudomonas aeruginosa in this condition has never been assessed. We evaluated the risk factors and prognosis for PP caused by P. aeruginosa. METHODS: Patients hospitalized in the intensive care unit (ICU) after re-operation for PP were identified prospectively. Analyses were performed retrospectively. Specific risk factors were investigated by comparing P. aeruginosa PP with PP having other causes. The main outcome endpoint was death in the hospital. RESULTS: We found 55 P. aeruginosa PP among the 349 cases of PP (16%) in the ICU over 14 years. Factors associated with the presence of P. aeruginosa in peritoneal fluid culture were Acute Physiology and Chronic Health Evaluation (APACHE) II score (odds ratio [OR] 1.1; 95% confidence interval [CI] 1.02-1.09; p=0.004) and respiratory failure (OR 2.3; 95% CI 1.26-4.16; p=0.006). These criteria performed poorly in predicting P. aeruginosa PP. Such infections were associated with a higher hospital mortality rate, but not after adjustment for the severity score. Adequate antibiotic therapy comprising two antibiotics effective against P. aeruginosa was associated with a lower mortality rate for P. aeruginosa PP in the ICU. CONCLUSION: The prevalence of P. aeruginosa PP is not high. Risk factors do not allow accurate prediction of the infection. Our data suggest two drugs effective against P. aeruginosa should be considered for treating these infections.

Development of ertapenem resistance in a patient with mediastinitis caused by Klebsiella pneumoniae producing an extended-spectrum beta-lactamase.

The aim was to study the clinical and microbiological features associated with a carbapenem-resistant Klebsiella pneumoniae isolate that had been selected in vivo by an ertapenem-containing regimen in a patient with mediastinitis despite high blood and mediastinal levels of ertapenem. Carbapenem resistance was characterized by conjugation, PCR, DNA sequencing and analysis of outer-membrane proteins. The isolates susceptible and resistant to the carbapenems were compared by ribotyping and PFGE. Resistance to all available beta-lactams was most probably due to combined production of extended-spectrum beta-lactamase (ESBL) CTX-M-15 and loss of OmpK36 porin. The results of ribotyping and PFGE suggest that the carbapenem-resistant strain was a derivative of the original mediastinal isolate rather than a superinfecting isolate. This observation stresses the risk of selection of pan-penem resistant strains of enterobacteria when ertapenem is used for the treatment of severe infections due to ESBL-producing enterobacteria.

Rapid adaptation of antibiotic therapy for community-acquired peritonitis using direct cultures on antibiotic agar plates: pilot study.

BACKGROUND: Treatment of peritonitis requires prompt surgery and antibiotic therapy. It usually takes two or three days to obtain definitive results of peritoneal cultures and to adapt empirical antibiotic therapy. We assessed the potential time gain associated with direct culture of peritoneal samples on antibiotic agar (AA). METHODS: Peritoneal samples from 31 consecutive patients undergoing surgery for suspected community-acquired peritonitis were cultured according to the standard method and on AA containing one of the following five regimens: amoxicillin/clavulanic acid + gentamicin, ticarcillin/clavulanic acid + gentamicin, cefotaxime +metronidazole, piperacillin/tazobactam, or ertapenem. We compared the treatment modifications made by physicians aware only of the results of the standard method with the modifications the AA method would have indicated. RESULTS: Fewer isolates were identified by direct culture on AA than by the standard method (17 vs. 45; p = 0.0001), but definitive results were obtained much more rapidly (median 1 [range 1-3] days vs. 3 [range 2-7] days; p < 0.0001). Antibiotic regimens were changed for 14 patients on the basis of the results of the standard method (broader antibiotic spectrum and narrower spectrum in seven patients each). With the AA method, these changes could have been indicated after a median of 1 (range 1-2) days instead of 4 (range 1-11) days (p = 0.0006). The AA method missed only one resistant bacterial strain and isolated nine strains not detected by the standard method, including an extended-spectrum beta-lactamase-producing Escherichia coli. A complicated outcome was more frequent in patients having isolates found with the AA but not the standard method (86% vs. 21%; p = 0.003). CONCLUSION: Use of the AA method for culture of peritoneal samples from patients with community-acquired peritonitis speeds appropriate adaptation of antibiotic therapy and warrants further investigation.

Emergence of resistance in normal human aerobic commensal flora during telithromycin and amoxicillin-clavulanic acid treatments.

Mean fecal global yeast counts increased similarly during 7 days of treatment with telithromycin (800 mg once daily) or amoxicillin-clavulanic acid (amoxiclav) (1 g of amoxicillin and 125 mg of clavulanic acid 3 times daily) in human volunteers and decreased slowly thereafter. On skin, coagulase-negative staphylococci of decreased susceptibility (DS) to telithromycin increased in the telithromycin group, whereas those with DS to methicillin increased in the amoxiclav group. A similar antibiotic-related shift towards homologous DS was observed for oral nongroupable streptococci (NGS), but in addition, the prevalence of NGS resistant to both classes of antibiotics was significantly greater in the amoxiclav group at days 8 (P < 0.01) and 45 (P < 0.015).

Activity and diffusion of tigecycline (GAR-936) in experimental enterococcal endocarditis.

The activity of tigecycline (GAR-936), a novel glycylcycline, was investigated in vitro and in experimental endocarditis due to the susceptible Enterococcus faecalis JH2-2 strain, its VanA type transconjugant BM4316, and a clinical VanA type strain, E. faecium HB217 resistant to tetracycline. MICs of GAR-936 were 0.06 micro g/ml for the three strains. In vitro pharmacodynamic studies demonstrated a bacteriostatic effect of GAR-936 that was not enhanced by increasing concentrations to more than 1 micro g/ml and a postantibiotic effect ranging from 1 to 4.5 h for concentrations of 1- to 20-fold the MIC. Intravenous injection of [(14)C]GAR-936 to five rabbits with enterococcal endocarditis sacrificed 30 min, 4 h, or 12 h after the end of the infusion evidenced a lower clearance of GAR-936 from aortic vegetations than from serum and a homogeneous diffusion of GAR-936 into the vegetations. In rabbits with endocarditis, GAR-936 (14 mg/kg of body weight twice a day [b.i.d.]) given intravenously for 5 days was bacteriostatic against both strains of E. faecalis. Against E. faecium HB217, bacterial counts in vegetations significantly decreased during therapy (P < 0.01), and the effect was similar with GAR-936 at 14 mg/kg b.i.d., 14 mg/kg once a day (o.d.), and 7 mg/kg o.d., which provided concentrations in serum constantly above the MIC. Mean serum elimination half-life ranged from 3.3 to 3.6 h. No GAR-936-resistant mutants were selected in vivo with any regimen. We concluded that the combination of prolonged half-life, significant postantibiotic effect, and good and homogeneous diffusion into the vegetations may account for the in vivo activity of GAR-936 against enterococci susceptible or resistant to glycopeptides and tetracyclines, even when using a o.d. regimen in rabbits.

Intrapulmonary pharmacokinetics of telithromycin, a new ketolide, in healthy Japanese volunteers.

The concentrations of telithromycin, a new ketolide antimicrobial agent, in alveolar macrophages (AMs) and bronchoalveolar epithelial lining fluid (ELF) were determined in order to investigate the transfer of the drug into target tissue, relative to plasma, following multiple oral doses of telithromycin. Twenty-four healthy male Japanese volunteers were randomly allocated to four groups. Each subject was given 600 or 800 mg of telithromycin once daily for 5 days, followed by bronchoalveolar lavage (BAL) 2 or 8 h after the last dose (group A and B: 600 mg, 2 and 8 h BAL time point; group C and D: 800 mg, 2 and 8 h BAL time point). The mean concentrations of the drug in AMs and ELF were 34.54 and 4.92 mg/liter in group A, 50.97 and 2.26 mg/liter in group B, 25.47 and 4.24 mg/liter in group C, and 108.22 and 4.31 mg/liter in group D, respectively, which markedly exceeded concentrations in plasma. These results demonstrated good transfer of telithromycin into AMs and ELF, suggesting good efficacy against common respiratory pathogens, including intracellular pathogens and atypical microorganisms.

Combination of quinupristin-dalfopristin (Synercid) and rifampin is highly synergistic in experimental Staphylococcus aureus joint prosthesis infection.

We compared the efficacies of quinupristin-dalfopristin (Q-D; 30 mg/kg of body weight every 8 h) and vancomycin (60 mg/kg twice daily), alone or in combination with rifampin (10 mg/kg twice daily), in a rabbit model of methicillin-resistant Staphylococcus aureus knee prosthesis infection. In contrast to vancomycin, Q-D significantly reduced the mean log(10) CFU per gram of bone versus that for the controls. The combination of rifampin with either Q-D or vancomycin was significantly more effective than monotherapy.