Oriol Gasch

Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT): a retrospective cohort study

BACKGROUND The best available treatment against carbapenemase-producing Enterobacteriaceae (CPE) is unknown. The objective of this study was to investigate the effect of appropriate therapy and of appropriate combination therapy on mortality of patients with bloodstream infections (BSIs) due to CPE. METHODS In this retrospective cohort study, we included patients with clinically significant monomicrobial BSIs due to CPE from the INCREMENT cohort, recruited from 26 tertiary hospitals in ten countries. Exclusion criteria were missing key data, death sooner than 24 h after the index date, therapy with an active antibiotic for at least 2 days when blood cultures were taken, and subsequent episodes in the same patient. We compared 30 day all-cause mortality between patients receiving appropriate (including an active drug against the blood isolate and started in the first 5 days after infection) or inappropriate therapy, and for patients receiving appropriate therapy, between those receiving active monotherapy (only one active drug) or combination therapy (more than one). We used a propensity score for receiving combination therapy and a validated mortality score (INCREMENT-CPE mortality score) to control for confounders in Cox regression analyses. We stratified analyses of combination therapy according to INCREMENT-CPE mortality score (0-7 [low mortality score] vs 8-15 [high mortality score]). INCREMENT is registered with ClinicalTrials.gov, number NCT01764490. FINDINGS Between Jan 1, 2004, and Dec 31, 2013, 480 patients with BSIs due to CPE were enrolled in the INCREMENT cohort, of whom we included 437 (91%) in this study. 343 (78%) patients received appropriate therapy compared with 94 (22%) who received inappropriate therapy. The most frequent organism was Klebsiella pneumoniae (375 [86%] of 437; 291 [85%] of 343 patients receiving appropriate therapy vs 84 [89%] of 94 receiving inappropriate therapy) and the most frequent carbapenemase was K pneumoniae carbapenemase (329 [75%]; 253 [74%] vs 76 [81%]). Appropriate therapy was associated with lower mortality than was inappropriate therapy (132 [38·5%] of 343 patients died vs 57 [60·6%] of 94; absolute difference 22·1% [95% CI 11·0-33·3]; adjusted hazard ratio [HR] 0·45 [95% CI 0·33-0·62]; p<0·0001). Among those receiving appropriate therapy, 135 (39%) received combination therapy and 208 (61%) received monotherapy. Overall mortality was not different between those receiving combination therapy or monotherapy (47 [35%] of 135 vs 85 [41%] of 208; adjusted HR 1·63 [95% CI 0·67-3·91]; p=0·28). However, combination therapy was associated with lower mortality than was monotherapy in the high-mortality-score stratum (30 [48%] of 63 vs 64 [62%] of 103; adjusted HR 0·56 [0·34-0·91]; p=0·02), but not in the low-mortality-score stratum (17 [24%] of 72 vs 21 [20%] of 105; adjusted odds ratio 1·21 [0·56-2·56]; p=0·62). INTERPRETATION Appropriate therapy was associated with a protective effect on mortality among patients with BSIs due to CPE. Combination therapy was associated with improved survival only in patients with a high mortality score. Patients with BSIs due to CPE should receive active therapy as soon as they are diagnosed, and monotherapy should be considered for those in the low-mortality-score stratum. FUNDING Spanish Network for Research in Infectious Diseases, European Development Regional Fund, Instituto de Salud Carlos III, and Innovative Medicines Initiative.

A Multinational, Preregistered Cohort Study of β-Lactam/β-Lactamase Inhibitor Combinations for Treatment of Bloodstream Infections Due to Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae

ABSTRACT The spread of extended-spectrum-β-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-E) is leading to increased carbapenem consumption. Alternatives to carbapenems need to be investigated. We investigated whether β-lactam/β-lactamase inhibitor (BLBLI) combinations are as effective as carbapenems in the treatment of bloodstream infections (BSI) due to ESBL-E. A multinational, retrospective cohort study was performed. Patients with monomicrobial BSI due to ESBL-E were studied; specific criteria were applied for inclusion of patients in the empirical-therapy (ET) cohort (ETC; 365 patients), targeted-therapy (TT) cohort (TTC; 601 patients), and global cohort (GC; 627 patients). The main outcome variables were cure/improvement rate at day 14 and all-cause 30-day mortality. Multivariate analysis, propensity scores (PS), and sensitivity analyses were used to control for confounding. The cure/improvement rates with BLBLIs and carbapenems were 80.0% and 78.9% in the ETC and 90.2% and 85.5% in the TTC, respectively. The 30-day mortality rates were 17.6% and 20% in the ETC and 9.8% and 13.9% in the TTC, respectively. The adjusted odds ratio (OR) (95% confidence interval [CI]) values for cure/improvement rate with ET with BLBLIs were 1.37 (0.69 to 2.76); for TT, they were 1.61 (0.58 to 4.86). Regarding 30-day mortality, the adjusted OR (95% CI) values were 0.55 (0.25 to 1.18) for ET and 0.59 (0.19 to 1.71) for TT. The results were consistent in all subgroups studied, in a stratified analysis according to quartiles of PS, in PS-matched cases, and in the GC. BLBLIs, if active in vitro, appear to be as effective as carbapenems for ET and TT of BSI due to ESLB-E regardless of the source and specific species. These data may help to avoid the overuse of carbapenems. (This study has been registered at ClinicalTrials.gov under registration no. NCT01764490.)

Emergence of resistance to daptomycin in a cohort of patients with methicillin-resistant Staphylococcus aureus persistent bacteraemia treated with daptomycin

4 Theoretically estimated AUC 24 /MIC ratios against VRE susceptible to linezolid, according to the EUCAST clinical breakpoint (MIC¼ 4 mg/L), 1 were in the recommended range for the effective treatment of severe infections with linezolid (AUC 24 /MIC ratio of 80 –120) 6 in both cases (.93.76 and .250.96, respectively). In addition , biliary trough levels (C min) of linezolid were above the EUCAST clinical breakpoint against VRE in both cases (7.42 and 37.53 mg/L, respectively), this ensuring a theoretical T .MIC of .100%. The wide interindividual pharmacokinetic variability of linezolid observed between the two patients (patient 1: V ss 31. 5 L, CL 4.2 L/h and t 1/2 5.2 h; patient 2: V ss 67.1 L, CL 1.6 L/h and t 1/2 29.1 h) confirmed previous observations in critically ill patients during treatment with linezolid. 8 This variability is expected to potentially impact more on tolerability than on efficacy. Notably, patient 2 experienced hyperlactacidaemia (an increase in lactate level of 6.2 mmol/L during linezolid treatment), which could have been related to drug overexposure potentially favoured by drug –drug interactions and renal impairment. 8 However, it should not be overlooked that linezolid has generally been shown to be safe and effective in LTx patients. 9 The therapeutic drug monitoring of plasma C min may represent a valuable tool for the optimal management of linezolid in these cases, 8 and has recently been shown to improve safety outcomes in long-term treatment. 10 We recognize that the absence of real biliary pharmacokinetic/ pharmacodynamic data may be a limitation. However, these data confirm the potentially valuable role of linezolid in the treatment of cholangitis due to multidrug-resistant Enterococcus in LTx patients, since they meet the recommendations of good biliary penetration that are given in the Tokyo guidelines. References 1 Asín E, Isla A, Canut A et al. Comparison of antimicrobial pharmacokinetic/pharmacodynamic breakpoints with EUCAST and CLSI clinical breakpoints for Gram-positive bacteria. 4 Cremaschi E, Maggiore U, Maccari C et al. Linezolid levels in a patient with biliary tract sepsis, severe hepatic failure and acute kidney injury on sustained low-efficiency dialysis (SLED). 5 Pea F, Viale P, Lugano M et al. Biliary penetration and pharmacodynamic exposure of linezolid in liver transplant patients. 6 Rayner CR, Forrest A, Meagher AK et al. Clinical pharmacodynamics of linezolid in seriously ill patients treated in a compassionate use programme. 7 Pea F, Viale P, Lugano M et …

Epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection: secular trends over 19 years at a university hospital.

Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) is a cause of concern in health systems all over the world, due to the high incidence rates and the associated undesirable outcomes. In our tertiary 900-bed university hospital, all episodes of MRSA-BSI have been prospectively followed up since the identification of the first episode in 1990. We conducted the current study to report changes in the epidemiology of MRSA-BSI over the 19-year period between 1990 and 2008, comparing 4 periods (1990-1994, 1995-1999, 2000-2004, and 2005-2008). Overall, 524 patients developed MRSA-BSI. Cumulative incidence was 10.0 episodes/100,000 patient days (range, 1.3-17.4). Although no trend in the incidence rate was observed between the 4 consecutive periods, significant upward trends in patient age and comorbidities, health care acquisition, and non-intravascular catheter source were all identified (p < 0.05). While the Iberian clone (ST247/SCCmecI) was dominant during the first and second periods, almost all the strains isolated in the subsequent periods belonged to Clonal Complex 5 (ST125/SCCmecIV and ST228/SCCmecI). A significant downward trend in vancomycin geometric minimum inhibitory concentration (MIC) was also observed from 2.04 mg/L to 0.88 mg/L, coinciding with the clonal replacement and the reduction in the hospital vancomycin prescription. Therefore, no MRSA vancomycin MIC creep was observed since higher MICs were associated with strains belonging to the Iberian clone. Glycopeptides were the most frequently used antibiotics for MRSA-BSI during all 4 periods. No differences in MRSA-BSI outcomes were found, and the mortality rate at 30 days was close to 29% in each of the 4 periods.In conclusion, we identified significant changes in demographic and clinical characteristics and in the molecular epidemiology of MRSA-BSI during the study period, but found no significant trends in cumulative incidence or in overall mortality rate.Abbreviations: BSI = bloodstream infection, CLSI = Clinical and Laboratory Standards Institute, EARSS = European Antimicrobial Resistance Surveillance System, hVISA = heterogeneous vancomycin-intermediate Staphylococcus aureus, ICU = intensive care unit, MIC = minimum inhibitory concentration, MRSA = methicillin-resistant Staphylococcus aureus, MSSA = methicillin-susceptible Staphylococcus aureus, NCCLS = National Committee for Clinical Laboratory Standards, PFGE = pulsed-field gel electrophoresis, RP = resistance pattern, SCCmec = staphylococcal cassette chromosome mec, ST = multilocus sequence typing.

Efficacy and Safety of Fosfomycin Plus Imipenem as Rescue Therapy for Complicated Bacteremia and Endocarditis Due to Methicillin-Resistant Staphylococcus aureus: A Multicenter Clinical Trial

BACKGROUND There is an urgent need for alternative rescue therapies in invasive infections caused by methicillin-resistant Staphylococcus aureus (MRSA). We assessed the clinical efficacy and safety of the combination of fosfomycin and imipenem as rescue therapy for MRSA infective endocarditis and complicated bacteremia. METHODS The trial was conducted between 2001 and 2010 in 3 Spanish hospitals. Adult patients with complicated MRSA bacteremia or endocarditis requiring rescue therapy were eligible for the study. Treatment with fosfomycin (2 g/6 hours IV) plus imipenem (1 g/6 hours IV) was started and monitored. The primary efficacy endpoints were percentage of sterile blood cultures at 72 hours and clinical success rate assessed at the test-of-cure visit (45 days after the end of therapy). RESULTS The combination was administered in 12 patients with endocarditis, 2 with vascular graft infection, and 2 with complicated bacteremia. Therapy had previously failed with vancomycin in 9 patients, daptomycin in 2, and sequential antibiotics in 5. Blood cultures were negative 72 hours after the first dose of the combination in all cases. The success rate was 69%, and only 1 of 5 deaths was related to the MRSA infection. Although the combination was safe in most patients (94%), a patient with liver cirrhosis died of multiorgan failure secondary to sodium overload. There were no episodes of breakthrough bacteremia or relapse. CONCLUSIONS Fosfomycin plus imipenem was an effective and safe combination when used as rescue therapy for complicated MRSA bloodstream infections and deserves further clinical evaluation as initial therapy in these infections.

Multiple myeloma and hyperammonemic encephalopathy: review of 27 cases.

Hyperammonemic encephalopathy is a rarely reported complication of multiple myeloma (MM). We describe an illustrative case of hyperammonemia in the setting of an immunoglobulin (Ig) D-lambda MM, and perform a systematic review of the English-written literature. Our search yielded 26 more cases. Median age was 64 years, and 54% of patients were male. All presented with progressive impairment of their level of consciousness. Median ammonium concentration was 109 micromol/L (interquartile range, 73-149 micromol/L). Most were IgA type (10 cases), and there were 2 cases of IgD type. Most cases were aggressive or chemotherapy-resistant forms of MM. Eight patients were diagnosed with MM at the same time as the episode of hyperammonemia. Only 1 patient had signs of portal hypertension as a result of concomitant hyperdynamic heart failure. Determination of amino acid in 10 patients showed high levels of glycine, low levels of tyrosine, and a low Fischer ratio. Two patients did not receive chemotherapy and died. Twenty-two out of 25 patients who received chemotherapy against MM showed a decrease in ammonium blood concentration, and of those, 15 survived the episode (68%). Overall mortality was 44%. In conclusion, hyperammonemia is a severe complication of MM, associated with a high mortality. It should be considered in any patient with MM and a low level of consciousness. Chemotherapy directed against MM seems to be the most effective measure in order to achieve normal ammonium levels and clinical improvement.

Diagnosis and treatment of bacteremia and endocarditis due to Staphylococcus aureus. A clinical guideline from the Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC)

Both bacteremia and infective endocarditis caused by Staphylococcus aureus are common and severe diseases. The prognosis may darken not infrequently, especially in the presence of intracardiac devices or methicillin-resistance. Indeed, the optimization of the antimicrobial therapy is a key step in the outcome of these infections. The high rates of treatment failure and the increasing interest in the influence of vancomycin susceptibility in the outcome of infections caused by both methicillin-susceptible and -resistant isolates has led to the research of novel therapeutic schemes. Specifically, the interest raised in recent years on the new antimicrobials with activity against methicillin-resistant staphylococci has been also extended to infections caused by susceptible strains, which still carry the most important burden of infection. Recent clinical and experimental research has focused in the activity of new combinations of antimicrobials, their indication and role still being debatable. Also, the impact of an appropriate empirical antimicrobial treatment has acquired relevance in recent years. Finally, it is noteworthy the impact of the implementation of a systematic bundle of measures for improving the outcome. The aim of this clinical guideline is to provide an ensemble of recommendations in order to improve the treatment and prognosis of bacteremia and infective endocarditis caused by S. aureus, in accordance to the latest evidence published.

Ertapenem for the treatment of bloodstream infections due to ESBL-producing Enterobacteriaceae: a multinational pre-registered cohort study

OBJECTIVES Data about the efficacy of ertapenem for the treatment of bloodstream infections (BSI) due to ESBL-producing Enterobacteriaceae (ESBL-E) are limited. We compared the clinical efficacy of ertapenem and other carbapenems in monomicrobial BSI due to ESBL-E. METHODS A multinational retrospective cohort study (INCREMENT project) was performed (ClinicalTrials.gov identifier: NCT01764490). Patients given monotherapy with ertapenem or other carbapenems were compared. Empirical and targeted therapies were analysed. Propensity scores were used to control for confounding; sensitivity analyses were performed in subgroups. The outcome variables were cure/improvement rate at day 14 and all-cause 30 day mortality. RESULTS The empirical therapy cohort (ETC) and the targeted therapy cohort (TTC) included 195 and 509 patients, respectively. Cure/improvement rates were 90.6% with ertapenem and 75.5% with other carbapenems (P = 0.06) in the ETC and 89.8% and 82.6% (P = 0.02) in the TTC, respectively; 30 day mortality rates were 3.1% and 23.3% (P = 0.01) in the ETC and 9.3% and 17.1% (P = 0.01) in the TTC, respectively. Adjusted ORs (95% CI) for cure/improvement with empirical and targeted ertapenem were 1.87 (0.24-20.08; P = 0.58) and 1.04 (0.44-2.50; P = 0.92), respectively. For the propensity-matched cohorts it was 1.18 (0.43-3.29; P = 0.74). Regarding 30 day mortality, the adjusted HR (95% CI) for targeted ertapenem was 0.93 (0.43-2.03; P = 0.86) and for the propensity-matched cohorts it was 1.05 (0.46-2.44; P = 0.90). Sensitivity analyses were consistent except for patients with severe sepsis/septic shock, which showed a non-significant trend favouring other carbapenems. CONCLUSIONS Ertapenem appears as effective as other carbapenems for empirical and targeted therapy of BSI due to ESBL-E, but further studies are needed for patients with severe sepsis/septic shock.

Daptomycin plus fosfomycin versus daptomycin monotherapy in treating MRSA: protocol of a multicentre, randomised, phase III trial

Introduction Despite the availability of new antibiotics such as daptomycin, methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia continues to be associated with high clinical failure rates. Combination therapy has been proposed as an alternative to improve outcomes but there is a lack of clinical studies. The study aims to demonstrate that combination of daptomycin plus fosfomycin achieves higher clinical success rates in the treatment of MRSA bacteraemia than daptomycin alone. Methods and analysis A multicentre open-label, randomised phase III study. Adult patients hospitalised with MRSA bacteraemia will be randomly assigned (1:1) to group 1: daptomycin 10 mg/kg/24 h intravenous; or group 2: daptomycin 10 mg/kg/24 h intravenous plus fosfomycin 2 gr/6 g intravenous. The main outcome will be treatment response at week 6 after stopping therapy (test-of-cure (TOC) visit). This is a composite variable with two values: Treatment success: resolution of clinical signs and symptoms (clinical success) and negative blood cultures (microbiological success) at the TOC visit. Treatment failure: if any of the following conditions apply: (1) lack of clinical improvement at 72 h or more after starting therapy; (2) persistent bacteraemia (positive blood cultures on day 7); (3) therapy is discontinued early due to adverse effects or for some other reason based on clinical judgement; (4) relapse of MRSA bacteraemia before the TOC visit; (5) death for any reason before the TOC visit. Assuming a 60% cure rate with daptomycin and a 20% difference in cure rates between the two groups, 103 patients will be needed for each group (α:0.05, ß: 0.2). Statistical analysis will be based on intention to treat, as well as per protocol and safety analysis. Ethics and dissemination The protocol was approved by the Spanish Medicines and Healthcare Products Regulatory Agency (AEMPS). The sponsor commits itself to publishing the data in first quartile peer-review journals within 12 months of the completion of the study. Trial registration number NCT01898338.

Community-acquired Capnocytophaga canimorsus meningitis in adults: report of one case with a subacute course and deafness, and literature review

INTRODUCTION An adult with community-acquired Capnocytophaga canimorsus meningitis presented with a subacute course, deafness, and a predominantly lymphocytic CSF cell count. METHODS Eighteen reported cases of C. canimorsus meningitis in adults were analyzed. RESULTS In about half the cases, CSF contained less than 1,000 leukocytes/microL or lymphocyte percentages 30%. These figures differ from those usually seen in meningitis caused by the classic meningeal pathogens. CONCLUSIONS C. canimorsus should be included among the causes of sporadic lymphocytic meningitis in adults, in particular if the presentation involves deafness.