Nazaret Cobos-Trigueros

Influence of Empiric Therapy with a β-Lactam Alone or Combined with an Aminoglycoside on Prognosis of Bacteremia Due to Gram-Negative Microorganisms

ABSTRACT Evidence supporting the combination of aminoglycosides with β-lactams for Gram-negative bacteremia is inconclusive. We have explored the influence on survival of empirical therapy with a β-lactam alone versus that with a β-lactam-aminoglycoside combination by retrospectively analyzing a series of bacteremic episodes due to aerobic or facultative Gram-negative microorganisms treated with single or combination therapy. The outcome variable was a 30-day mortality. Prognostic factors were selected by regression logistic analysis. A total of 4,863 episodes were assessed, of which 678 (14%) received combination therapy and 467 (10%) were fatal. Factors independently associated with mortality included age greater than 65 (odds ratio [OR], 2; 95% confidence interval [CI], 1.6 to 2.6), hospital acquisition (OR, 1.5; 95% CI, 1.2 to 1.9), a rapidly or ultimately fatal underlying disease (OR, 2.5; 95% CI, 2 to 3.2), cirrhosis (OR, 1.9; 95% CI, 1.4 to 2.6), prior corticosteroids (OR, 1.5; 95% CI, 1.1 to 2), shock on presentation (OR, 8.8; 95% CI, 7 to 11), pneumonia (OR, 2.8; 95% CI, 1.9 to 4), and inappropriate empirical therapy (OR, 1.8; 95% CI, 1.3 to 2.5). Subgroup analysis revealed that combination therapy was an independent protective factor in episodes presenting shock (OR, 0.6; 95% CI, 0.4 to 0.9) or neutropenia (OR, 0.5; 95% CI, 0.3 to 0.9). Combination therapy improved the appropriateness of empirical therapy in episodes due to extended-spectrum β-lactamase (ESBL)- or AmpC-producing Enterobacteriaceae and Pseudomonas aeruginosa. In patients with Gram-negative bacteremia, we could not find an overall association between empirical β-lactam-aminoglycoside combination therapy and prognosis. However, a survival advantage cannot be discarded for episodes presenting shock or neutropenia, hence in these situations the use of combination therapy may still be justified. Combination therapy also should be considered for patients at risk of being infected with resistant organisms, if only to increase the appropriateness of empirical therapy.

Influence of Multidrug Resistance and Appropriate Empirical Therapy on the 30-Day Mortality Rate of Pseudomonas aeruginosa Bacteremia

ABSTRACT Infections due to multidrug-resistant (MDR) Pseudomonas aeruginosa are increasing. The aim of our study was to evaluate the influences of appropriate empirical antibiotic therapy and multidrug resistance on mortality in patients with bacteremia due to P. aeruginosa (PAB). Episodes of PAB were prospectively registered from 2000 to 2008. MDR was considered when the strain was resistant to ≥3 antipseudomonal antibiotics. Univariate and multivariate analyses were performed. A total of 709 episodes of PAB were studied. MDR PAB (n = 127 [17.9%]) was more frequently nosocomial and associated with longer hospitalization, bladder catheter use, steroid and antibiotic therapy, receipt of inappropriate empirical antibiotic therapy, and a higher mortality. Factors independently associated with mortality were age (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.002 to 1.033), shock (OR, 6.6; 95% CI, 4 to 10.8), cirrhosis (OR, 3.3; 95% CI, 1.4 to 7.6), intermediate-risk sources (OR, 2.5; 95% CI, 1.4 to 4.3) or high-risk sources (OR, 7.3; 95% CI, 4.1 to 12.9), and inappropriate empirical therapy (OR, 2.1; 95% CI, 1.3 to 3.5). To analyze the interaction between empirical therapy and MDR, a variable combining both was introduced in the multivariate analysis. Inappropriate therapy was significantly associated with higher mortality regardless of the susceptibility pattern, and there was a trend toward higher mortality in patients receiving appropriate therapy for MDR than in those appropriately treated for non-MDR strains (OR, 2.2; 95% CI, 0.9 to 5.4). In 47.9% of MDR PAB episodes, appropriate therapy consisted of monotherapy with amikacin. In conclusion, MDR PAB is associated with a higher mortality than non-MDR PAB. This may be related to a higher rate of inappropriate empirical therapy and probably also to amikacin as frequently the only appropriate empirical therapy given to patients with MDR PAB.

Diagnosis and antimicrobial treatment of invasive infections due to multidrug-resistant Enterobacteriaceae. Guidelines of the Spanish Society of Infectious Diseases and Clinical Microbiology

The spread of multidrug-resistant Enterobacteriaceae related to the production of extended-spectrum β-lactamases and carbapenemases is a serious public health problem worldwide. Microbiological diagnosis and therapy of these infections are challenging and controversial. Clinically relevant questions were selected and the literature was reviewed for each of them. The information from the selected articles was extracted and recommendations were provided and graded according to the strength of the recommendations and quality of the evidence. The document was opened to comments from the members from the Spanish Society of Infectious Diseases and Clinical Microbiology, which were considered for inclusion in the final version. Evidence-based recommendations are provided for the use of microbiological techniques for the detection of extended-spectrum β-lactamases and carbapenemases in Enterobacteriaceae, and for antibiotic therapy for invasive/severe infections caused by these organisms. The absence of randomised controlled trials is noteworthy; thus, recommendations are mainly based on observational studies (that have important methodological limitations), pharmacokinetic and pharmacodynamics models, and data from animal studies. Additionally, areas for future research were identified.

Clinical characteristics and outcome of elderly patients with community-onset bacteremia.

OBJECTIVES To evaluate characteristics and prognostic factors of community-onset bloodstream infection (Co-BSI) in elderly patients (≥65 years). METHODS Analysis of a prospective series of Co-BSI at a tertiary hospital (2005-2011). Predictors of 30-day mortality were established by logistic regression analysis. RESULTS A total of 2605 episodes of Co-BSI were identified and empirical antibiotic treatment was inappropriate in 404 (15.5%). Thirty-day mortality was 11.4% and was independently associated with age (75-84 years OR 1.9, 1.37-2.67; ≥85 OR 2.85, 1.93-4.21), previous hospitalization (OR 1.45, 1.05-2.00), a fatal underlying disease (OR 2.81, 2.10-3.76), neutropenia (OR 2.62, 1.54-4.43), absence of fever (OR 1.99, 1.26-3.12), shock (OR 7.96, 5.83-10.89), inappropriate empirical treatment (OR 1.49, 1.03-2.16), isolation of Staphylococcus aureus (methicillin-resistant OR 2.83, 1.38-5.78; methicillin-susceptible OR 3.24, 1.98-5.32), enterococci (OR 2.02, 1.14-3.59) or Enterobacteriaceae resistant to third-generation cephalosporin (3GCR-E) (OR 1.96, 1.16-3.32) and having endovascular non-catheter (OR 4.64, 2.51-8.59), abdominal (OR 3.65, 2.12-6.27), skin/soft tissue (OR 3.48, 1.90-6.37), respiratory (OR 2.80, 1.75-4.50) or unknown (OR 1.83, 1.17-2.87) source. CONCLUSIONS Age is a prognostic factor and appropriateness of empirical treatment is the only modifiable variable. S. aureus, enterococci and 3GCR-E may be the microorganisms with major prognostic significance; hence efforts should be made to improve their management.

Rapid Diagnosis of Staphylococcal Catheter-Related Bacteraemia in Direct Blood Samples by Real-Time PCR

Catheter-related bacteremia (CRB) is an important cause of morbidity and mortality among hospitalized patients, being staphylococci the main etiologic agents. The objective of this study was to assess the use of a PCR-based assay for detection of staphylococci directly from blood obtained through the catheter to diagnose CRB caused by these microorganisms and to perform a cost-effectiveness analysis. A total of 92 patients with suspected CRB were included in the study. Samples were obtained through the catheter. Paired blood cultures were processed by standard culture methods and 4 ml blood samples were processed by GeneXpert-MRSA assay for the detection of methicillin-susceptible (MSSA) or methicillin-resistant (MRSA) Staphylococcus aureus, and methicillin-resistant coagulase-negative staphylococci (MR-CoNS). Sixteen CRB caused by staphylococci were diagnosed among 92 suspected patients. GeneXpert detected 14 out of 16 cases (87.5%), including 4 MSSA and 10 MR-CoNS in approximately 1 hour after specimen receipt. The sensitivity and specificity of GeneXpert were 87.5% (CI 95%: 60.4–97.8) and 92.1% (CI 95%: 83–96.7), respectively, compared with standard culture methods. The sensitivity of GeneXpert for S. aureus was 100%. Regarding a cost-effectiveness analysis, the incremental cost of using GeneXpert was of 31.1€ per patient while the incremental cost-effectiveness ratio of GeneXpert compared with blood culture alones was about 180€ per life year gained. In conclusion, GeneXpert can be used directly with blood samples obtained through infected catheters to detect S. aureus and MR-CoNS in approximately 1h after sampling. In addition, it is cost-effective especially in areas with high prevalence of staphylococcal CRB.

Usefulness of time-to-positivity in aerobic and anaerobic vials to predict the presence of Candida glabrata in patients with candidaemia

OBJECTIVES To determine whether time-to-positivity (TTP) in aerobic and anaerobic blood culture vials is useful to predict the presence of Candida glabrata in patients with candidaemia. METHODS TTP was recorded for both aerobic and anaerobic vials for each blood culture set of monomicrobial candidaemia. We considered TTP as the shortest time registered for any positive vial. Two diagnostic criteria were evaluated: the cut-off TTP value as obtained from a receiver operating characteristic curve and the detection of growth only or with a shorter TTP in anaerobic vials. RESULTS A total of 157 episodes were analysed of which 19 (12.1%) were due to C. glabrata. The TTP for C. glabrata was longer than that for other species. C. glabrata grew more frequently than other species in anaerobic vials [9/19 (47%) versus 19/138 (14%); P = 0.001] and also more often exclusively or earlier in anaerobic vials [7/19 (37%) versus 5/138 (4%); P < 0.0001]. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of a TTP >56.5 h for predicting the presence of C. glabrata were 47%, 88%, 36% and 92%, respectively. Growth detection only or earlier in anaerobic flasks had a sensitivity of 37%, a specificity of 96%, a PPV of 58% and an NPV of 92%. CONCLUSIONS Using the BACTEC 9240 system, a TTP ≤ 56.5 h is useful to rule out C. glabrata. In addition, in settings with an ~12% prevalence of C. glabrata candidaemia, yeast detection exclusively or earlier in anaerobic vials increases the probability of the presence of C. glabrata to 58%, which may be useful for early treatment optimization.

Macrólidos y cetólidos

Macrolides and ketolides are two families of antibiotics that share the same mechanism of action. They bind to different bases of the peptidyl transferase center of 23S RNA. The antibacterial spectrum of these drugs virtually overlaps, but dissimilarities in the affinity and number of binding sites results in differences in the intensity of their antibacterial effects (bacteriostatic or bactericidal) and their activity against strains with acquired resistance mechanisms. These agents are active against most gram-positive microorganisms and many intracellular microorganisms. Over the last ten years in Spain, the percentage of macrolide-resistant pneumococci and Streptococcus pyogenes strains has increased substantially. Telithromycin, a ketolide, has maintained the activity against these strains. Macrolides and ketolides are metabolized in the liver through CYP3A4 and they can partially block the activity of the enzyme, interfering with the metabolism of other drugs that use the same metabolic pathway. There is little elimination through the urine, with the exception of clarithromycin. High concentrations are reached in the cellular cytoplasm, but they do not diffuse to cerebrospinal fluid. These agents are included among class B drugs for use during pregnancy. Tolerance to macrolides is good and they have few associated adverse effects. The main clinical indication for these drugs is in empirical treatment of mild to moderate, community-acquired, upper and lower respiratory tract infections. Some patients treated with telithromycin developed severe hepatitis; therefore, its use is limited to community-acquired pneumonia in cases with no other available alternative.

In vivo evolution of resistance of Pseudomonas aeruginosa strains isolated from patients admitted to an intensive care unit: mechanisms of resistance and antimicrobial exposure

OBJECTIVES The main objective of this study was to investigate the relationship among the in vivo acquisition of antimicrobial resistance in Pseudomonas aeruginosa clinical isolates, the underlying molecular mechanisms and previous exposure to antipseudomonal agents. METHODS PFGE was used to study the molecular relatedness of the strains. The MICs of ceftazidime, cefepime, piperacillin/tazobactam, imipenem, meropenem, ciprofloxacin and amikacin were determined. Outer membrane protein profiles were assessed to study OprD expression. RT-PCR was performed to analyse ampC, mexB, mexD, mexF and mexY expression. The presence of mutations was analysed through DNA sequencing. RESULTS We collected 17 clonally related paired isolates [including first positive samples (A) and those with MICs increased ≥4-fold (B)]. Most B isolates with increased MICs of imipenem, meropenem and ceftazidime became resistant to these drugs. The most prevalent resistance mechanisms detected were OprD loss (65%), mexB overexpression (53%), ampC derepression (29%), quinolone target gene mutations (24%) and increased mexY expression (24%). Five (29%) B isolates developed multidrug resistance. Meropenem was the most frequently (71%) received treatment, explaining the high prevalence of oprD mutations and likely mexB overexpression. Previous exposure to ceftazidime showed a higher impact on selection of increased MICs than previous exposure to piperacillin/tazobactam. CONCLUSIONS Stepwise acquisition of resistance has a critical impact on the resistance phenotypes of P. aeruginosa, leading to a complex scenario for finding effective antimicrobial regimens. In the clinical setting, meropenem seems to be the most frequent driver of multidrug resistance development, while piperacillin/tazobactam, in contrast to ceftazidime, seems to be the β-lactam least associated with the selection of resistance mechanisms.

Executive summary of the diagnosis and antimicrobial treatment of invasive infections due to multidrug-resistant Enterobacteriaceae. Guidelines of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC)

The spread of multidrug-resistant Enterobacteriaceae related to the production of extended-spectrum β-lactamases (ESBL) and carbapenemases is a serious public health problem worldwide. Microbiological diagnosis and therapy of these infections are challenging and controversial. After the selection of clinically relevant questions, this document provides evidence-based recommendations for the use of microbiological techniques for the detection of ESBL- and carbapenemase-producing Enterobacteriaceae, and for antibiotic therapy for invasive infections caused by these organisms. The absence of randomized-controlled trials is noteworthy, thus recommendations are mainly based on observational studies, that have important methodological limitations, pharmacokinetic and pharmacodynamics models, and data from animal studies. Additionally, areas for future research were identified.

Evaluation of a Mixing versus a Cycling Strategy of Antibiotic Use in Critically-Ill Medical Patients: Impact on Acquisition of Resistant Microorganisms and Clinical Outcomes

Objective To compare the effect of two strategies of antibiotic use (mixing vs. cycling) on the acquisition of resistant microorganisms, infections and other clinical outcomes. Methods Prospective cohort study in an 8-bed intensive care unit during 35- months in which a mixing-cycling policy of antipseudomonal beta-lactams (meropenem, ceftazidime/piperacillin-tazobactam) and fluoroquinolones was operative. Nasopharyngeal and rectal swabs and respiratory secretions were obtained within 48h of admission and thrice weekly thereafter. Target microorganisms included methicillin-resistant S. aureus, vancomycin-resistant enterococci, third-generation cephalosporin-resistant Enterobacteriaceae and non-fermenters. Results A total of 409 (42%) patients were included in mixing and 560 (58%) in cycling. Exposure to ceftazidime/piperacillin-tazobactam and fluoroquinolones was significantly higher in mixing while exposure to meropenem was higher in cycling, although overall use of antipseudomonals was not significantly different (37.5/100 patient-days vs. 38.1/100 patient-days). There was a barely higher acquisition rate of microorganisms during mixing, but this difference lost its significance when the cases due to an exogenous Burkholderia cepacia outbreak were excluded (19.3% vs. 15.4%, OR 0.8, CI 0.5–1.1). Acquisition of Pseudomonas aeruginosa resistant to the intervention antibiotics or with multiple-drug resistance was similar. There were no significant differences between mixing and cycling in the proportion of patients acquiring any infection (16.6% vs. 14.5%, OR 0.9, CI 0.6–1.2), any infection due to target microorganisms (5.9% vs. 5.2%, OR 0.9, CI 0.5–1.5), length of stay (median 5 d for both groups) or mortality (13.9 vs. 14.3%, OR 1.03, CI 0.7–1.3). Conclusions A cycling strategy of antibiotic use with a 6-week cycle duration is similar to mixing in terms of acquisition of resistant microorganisms, infections, length of stay and mortality.