Warren Lowman

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.)

Antimicrobial Susceptibility Testing and Profiling of Nocardia Species and Other Aerobic Actinomycetes from South Africa: Comparative Evaluation of Broth Microdilution versus the Etest

ABSTRACT Nocardiosis is an underrecognized clinical entity in South Africa, for which interspecies epidemiological and clinical differences are poorly understood. The taxonomical state of flux and the lack of a simple antimicrobial susceptibility testing method are partly responsible. Definitive identification is molecularly based, which further complicates the study of this ubiquitous organism, as this methodology is beyond the scope of most routine diagnostic laboratories. The Etest methodology has been proposed as an alternative to the reference broth microdilution method, although there have been a limited number of comparative studies. We profiled 51 clinical isolates of aerobic actinomycetes, including 39 Nocardia species, using sequence-based (16S rRNA) identification. Broth microdilution and Etests were done concurrently on all isolates. The overall level of categorical and essential agreement for broth microdilution and Etest for the Nocardia isolates ranged from 67.5 to 100% and 46.2 to 81.6%, respectively. Very major errors were seen with amikacin, amoxicillin-clavulanate, ciprofloxacin, clarithromycin, and imipenem. For Nocardia species, uniform susceptibility to co-trimoxazole, amikacin, and linezolid was demonstrated, with a 48.8% susceptibility rate to imipenem. Nocardia farcinica (20.5%) and Nocardia cyriacigeorgica (15.4%) were the most commonly identified species among the 82% of isolates identified to species level using 16S rRNA sequences. Furthermore, drug susceptibility patterns demonstrated limited concordance with species identification. Our results suggest that, in a routine diagnostic setting, the Etest is not an acceptable alternative to the reference method of broth microdilution for antimicrobial susceptibility testing. Given the diversity and limited understanding of this group of organisms, further widespread evaluation of clinical isolates, from both clinical and diagnostic perspectives, is warranted.

NDM-1 has arrived: first report of a carbapenem resistance mechanism in South Africa

The New Delhi Metallo-β-lactamase (NDM) resistance mechanism in Enterobacteriaceae threatens to render serious Gram-negative infections untreatable. The NDM-1 enzyme hydrolyses all available penicillin, cephalosporin and carbapenem antibiotics, and is commonly accompanied by additional resistance mechanisms to multiple antibiotic classes. Initially identified as a significant healthcare risk on the Indian sub-continent, it has rapidly become a global problem, posing significant diagnostic and management challenges. Here we report the first laboratory-confirmed case of NDM-1 in South Africa.

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.

A case of community-acquired Acinetobacter baumannii meningitis - has the threat moved beyond the hospital?

Acinetobacter baumannii is a prolific nosocomial pathogen renowned for its multidrug-resistant nature. We report a case of community-acquired meningitis due to A. baumannii. The case highlights the potential pathogenicity of this organism and raises concerns that this highly adaptable organism may soon evolve into a significant community pathogen, too.

Prevalence and trends of Staphylococcus aureus bacteraemia in hospitalized patients in South Africa, 2010 to 2012 : laboratory-based surveillance mapping of antimicrobial resistance and molecular epidemiology

Introduction We aimed to obtain an in-depth understanding on recent antimicrobial resistance trends and molecular epidemiology trends of S. aureus bacteraemia (SAB). Methods Thirteen academic centres in South Africa were included from June 2010 until July 2012. S. aureus susceptibility testing was performed on the MicroScan Walkaway. Real-time PCR using the LightCycler 480 II was done for mecA and nuc. SCCmec and spa-typing were finalized with conventional PCR. We selected one isolate per common spa type per province for multilocus sequence typing (MLST). Results S. aureus from 2709 patients were included, and 1231 (46%) were resistant to methicillin, with a significant decline over the three-year period (p-value = 0.003). Geographical distribution of MRSA was significantly higher in Gauteng compared to the other provinces (P<0.001). Children <5 years were significantly associated with MRSA with higher rates compared to all other age groups (P = 0.01). The most prevalent SCCmec type was SCCmec type III (531 [41%]) followed by type IV (402 [31%]). Spa-typing discovered 47 different spa-types. The five (87%) most common spa-types were t037, t1257, t045, t064 and t012. Based on MLST, the commonest was ST612 clonal complex (CC8) (n = 7) followed by ST5 (CC5) (n = 4), ST36 (CC30) (n = 4) and ST239 (CC8) (n = 3). Conclusions MRSA rate is high in South Africa. Majority of the isolates were classified as SCCmec type III (41%) and type IV (31%), which are typically associated with hospital and community- acquired infections, respectively. Overall, this study reveals the presence of a variety of hospital-acquired MRSA clones in South Africa dominance of few clones, spa 037 and 1257. Monitoring trends in resistance and molecular typing is recommended to detect changing epidemiological trends in AMR patterns of SAB.

Antimicrobial treatment and outcomes of critically ill patients with OXA-48like carbapenemase-producing Enterobacteriaceae infections☆☆☆

We report on the clinical characteristics, antimicrobial therapy, and outcomes of 20 critically ill patients with severe OXA-48like infections. Carbapenem-based therapy demonstrated improved survival (odds ratio = 5.0) as compared with non-carbapenem therapy. Risk factors for mortality included Acute Physiology and Chronic Health Evaluation III score and length of stay, highlighting the significant influence of comorbidities and severity of underlying illness on outcomes.

Development and validation of the INCREMENT-ESBL predictive score for mortality in patients with bloodstream infections due to extended-spectrum-β-lactamase-producing Enterobacteriaceae

Background. Bloodstream infections (BSIs) due to ESBL-producing Enterobacteriaceae (ESBL-E) are frequent yet outcome prediction rules for clinical use have not been developed. The objective was to define and validate a predictive risk score for 30 day mortality. Methods. A multinational retrospective cohort study including consecutive episodes of BSI due to ESBL-E was performed; cases were randomly assigned to a derivation cohort (DC) or a validation cohort (VC). The main outcome variable was all-cause 30 day mortality. A predictive score was developed using logistic regression coefficients for the DC, then tested in the VC. Results. The DC and VC included 622 and 328 episodes, respectively. The final multivariate logistic regression model for mortality in the DC included age >50 years (OR = 2.63; 95% CI: 1.18–5.85; 3 points), infection due to Klebsiella spp. (OR = 2.08; 95% CI: 1.21–3.58; 2 points), source other than urinary tract (OR = 3.6; 95% CI: 2.02–6.44; 3 points), fatal underlying disease (OR = 3.91; 95% CI: 2.24–6.80; 4 points), Pitt score >3 (OR = 3.04; 95 CI: 1.69–5.47; 3 points), severe sepsis or septic shock at presentation (OR = 4.8; 95% CI: 2.72–8.46; 4 points) and inappropriate early targeted therapy (OR = 2.47; 95% CI: 1.58–4.63; 2 points). The score showed an area under the receiver operating curve (AUROC) of 0.85 in the DC and 0.82 in the VC. Mortality rates for patients with scores of < 11 and ≥11 were 5.6% and 45.9%, respectively, in the DC, and 5.4% and 34.8% in the VC. Conclusions. We developed and validated an easy-to-collect predictive scoring model for all-cause 30 day mortality useful for identifying patients at high and low risk of mortality.

Two echinocandin-resistant Candida glabrata FKS mutants from South Africa.

Echinocandins are recommended as first-line agents to treat invasive infections caused by Candida glabrata since this organism is inherently less susceptible to azoles. However, resistance to echinocandins has been described in C. glabrata due to amino acid changes in the hotspot regions of the FKS1 and FKS2 genes. In this report, we describe the first two South African C. glabrata isolates with echinocandin resistance mediated by mutations in the FKS2 gene. Both isolates were cultured from urine specimens from private-sector patients.