Michal Chowers

Effectiveness and safety of colistin: prospective comparative cohort study

BACKGROUND Colistin has re-entered clinical use by necessity. We aimed to assess its effectiveness and safety compared with newer antibiotics. METHODS This was a single-centre, prospective cohort study. Inclusion criteria were microbiologically documented pneumonia, urinary tract infection, surgical site infection, meningitis or bacteraemia treated appropriately with colistin versus imipenem, meropenem or ampicillin/sulbactam (comparators). All consecutive patients were included, only once, between May 2006 and July 2009. The primary outcome was 30 day mortality. Multivariable and Cox regression survival analyses were used to adjust comparisons between groups. Odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals are reported. RESULTS Two hundred patients treated with colistin and 295 patients treated with comparators were included. Treatment with colistin was associated with older age, admission from healthcare facilities, mechanical ventilation and lower rate of early appropriate antibiotic treatment. The 30 day mortality was 39% (78/200) for colistin versus 28.8% (85/295) for comparators; unadjusted OR 1.58 (1.08-2.31). In the adjusted analysis the OR was 1.44 (0.91-2.26) overall and 1.99 (1.06-3.77) for bacteraemic patients (n = 220). At the end of follow-up, treatment with colistin was significantly associated with cumulative mortality; adjusted HR 1.27 (1.01-1.60) overall and 1.65 (1.18-2.31) among patients with bacteraemia. Nephrotoxicity at the end of treatment was more frequent with colistin; OR adjusted for other risk factors for nephrotoxicity 3.31 (1.54-7.08). Treatment with colistin was followed by increased incidence of Proteus spp. infections during a 3 month follow-up. CONCLUSIONS The need for colistin treatment is associated with poorer survival. Adjusted analyses suggest that colistin is less effective and more toxic than beta-lactam antibiotics.

Genetic variation at NNRTI resistance-associated positions in patients infected with HIV-1 subtype C.

Objective: Genetic differences between subtypes of HIV-1, even when not associated with key resistance mutations, are known to affect baseline susceptibility to specific antiretroviral drugs and resistance-development pathways. We studied the prevalence and patterns of non-nucleoside reverse transcriptase inhibitor (NNRTI)-associated mutations in HIV-1 subtype C-infected patients. Method: We analysed the genetic variation at sites associated with NNRTI and nucleoside reverse transcriptase inhibitor resistance in subtype C- versus B-infected patients, both drug-naive and -experienced. We extended the comparison to subtype B records from the Stanford database. Results: A total of 150 subtype B and 341 subtype C-infected patients were studied. No significant differences were found in treatment and clinical parameters between the groups. In NNRTI-naive patients, changes in NNRTI positions were present in 9.3% of subtype B- versus 33.1% of subtype C-infected patients (P < 0.001). Differences were seen in both drug-naive (subtype B, 10.0% versus subtype C, 50.1%; P < 0.021) and drug-experienced NNRTI-naive patients (subtype B, 9.0% versus subtype C, 23.8%; P < 0.001). In NNRTI experienced patients, the number of A98G/S changes was significantly higher in subtype C patients treated with either efavirenz or nevirapine (P < 0.0001), and V106M was higher in efavirenz-treated subtype C-infected patients (P < 0.0001). The average mutation rates were 1.26 and 1.67 per patient for subtypes B and C, respectively (P = 0.036). The frequency of nucleoside associated mutations, but not M184V, in treated patients was significantly higher in subgroup B-infected patients (P = 0.028). Conclusion: Collectively, these data indicate that genetic variation at NNRTI resistance-associated positions such as V106M and A98S is substantially greater in subtype C-infected patients than in subtype B-infected patients. The natural structure of each subtype probably affects the frequency and pattern of drug resistance mutations selected under treatment.

Assessment, Diagnosis, and Treatment of HIV-Associated Neurocognitive Disorder: A Consensus Report of the Mind Exchange Program

Many practical clinical questions regarding the management of human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) remain unanswered. We sought to identify and develop practical answers to key clinical questions in HAND management. Sixty-six specialists from 30 countries provided input into the program, which was overseen by a steering committee. Fourteen questions were rated as being of greatest clinical importance. Answers were drafted by an expert group based on a comprehensive literature review. Sixty-three experts convened to determine consensus and level of evidence for the answers. Consensus was reached on all answers. For instance, good practice suggests that all HIV patients should be screened for HAND early in disease using standardized tools. Follow-up frequency depends on whether HAND is already present or whether clinical data suggest risk for developing HAND. Worsening neurocognitive impairment may trigger consideration of antiretroviral modification when other causes have been excluded. The Mind Exchange program provides practical guidance in the diagnosis, monitoring, and treatment of HAND.

National Multicenter Study of Predictors and Outcomes of Bacteremia upon Hospital Admission Caused by Enterobacteriaceae Producing Extended-Spectrum β-Lactamases

ABSTRACT Extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae are pathogens that may lead to a spectrum of clinical syndromes. We aimed to identify predictors and outcomes of ESBL bacteremia upon hospital admission (UHA) in a nationwide prospective study. Thus, a multicenter prospective study was conducted in 10 Israeli hospitals. Adult patients with bacteremia due to Enterobacteriaceae diagnosed within 72 h of hospitalization were included. Patients with ESBL producers (cases) were compared to those with non-ESBL producers (controls), and a 1:1 ratio was attempted in each center. A case-control study to identify predictors and a cohort study to identify outcomes were conducted. Bivariate and multivariate logistic regressions were used for analyses. Overall, 447 patients with bacteremia due to Enterobacteriaceae were recruited: 205 cases and 242 controls. Independent predictors of ESBL were increased age, multiple comorbid conditions, poor functional status, recent contact with health care settings, invasive procedures, and prior receipt of antimicrobial therapy. In addition, patients presenting with septic shock and/or multiorgan failure were more likely to have ESBL infections. Patients with ESBL producers suffered more frequently from a delay in appropriate antimicrobial therapy (odds ratio [OR], 4.7; P, <0.001) and had a higher mortality rate (OR, 3.5; P, <0.001). After controlling for confounding variables, both ESBL production (OR, 2.3; P, 9.1) and a delay in adequate therapy (OR, 0.05; P, 0.001) were significant predictors for mortality and other adverse outcomes. We conclude that among patients with bacteremia due to Enterobacteriaceae UHA, those with ESBL producers tend to be older and chronically ill and to have a delay in effective therapy and severe adverse outcomes. Efforts should be directed to improving the detection of patients with ESBL bacteremia UHA and to providing immediate appropriate therapy.

Impact of Quinolone Restriction on Resistance Patterns of Escherichia coli Isolated from Urine by Culture in a Community Setting

BACKGROUND Decreased antimicrobial susceptibility after increased antibiotic use is a known phenomenon. Restoration of susceptibility once antimicrobial use is decreased is not self-evident. Our objective was to evaluate, in a community setting, the impact of quinolone restriction on the antimicrobial resistance of E. coli urine isolates. METHODS We conducted a retrospective, quasi-experimental ecological study to assess the proportion of quinolone-susceptible E. coli urine isolates in the periods before, during, and after a nationwide restriction on ciprofloxacin use was implemented. We used an interrupted time interval analysis for outcome evaluation. RESULTS We found a significant decline in quinolone consumption, measured as defined daily doses (DDDs) per month, between the preintervention and intervention periods (point estimate, -1827.3 DDDs per month; 95% confidence interval [CI], -2248.8 to -1405.9 DDDs per month; p < .001). This decline resulted in a significant decrease in E. coli nonsusceptibility to quinolones, from a mean of 12% in the preintervention period to a mean of 9% in the intervention period (odds ratio, 1.35; p = .014). The improved susceptibility pattern reversed immediately when quinolone consumption rose. Moreover, a highly significant inverse relationship was found between the level of quinolone use (regardless of intervention period) and the susceptibility of E. coli urine isolates to quinolone (odds ratio, 1.70; 95% CI, 1.26-2.28). During the months of highest quinolone use (8321 DDDs per month), the proportion of nonsusceptibility was 14%, whereas during the months of lowest quinolone use (4027 DDDs per month), the proportion of nonsusceptibility was 9%. An average decrease in resistance of 1.16% was observed for each decrease of 1000 DDDs. CONCLUSION Reducing quinolone consumption can lead to an immediate increase in the susceptibility of E. coli urine isolates to quinolones.

Antibiotic Exposure as a Risk Factor for Fluconazole-Resistant Candida Bloodstream Infection

ABSTRACT Recent exposure to azoles is an important risk factor for infection with fluconazole-resistant Candida spp., but little is known about the role of antibacterial drug exposure in the emergence of drug-resistant Candida. We did a prospective nationwide surveillance study of candidemia in Israel and analyzed the propensity score-adjusted association between antifungal and antibacterial drug exposure and bloodstream infection with C. glabrata and fluconazole-resistant Candida isolates. Four hundred forty-four episodes of candidemia (450 Candida isolates, 69 [15%] C. glabrata isolates, and 38 [8.5%] fluconazole-resistant isolates) from 18 medical centers in Israel were included. C. glabrata bloodstream infection was strongly associated with recent metronidazole exposure (odds ratio [OR], 3.2; P < 0.001). Infection with a fluconazole-resistant isolate was associated with exposure to carbapenems, trimethoprim-sulfamethoxazole, clindamycin, and colistin (odds ratio, 2.8; P = 0.01). The inclusion of antibacterial drug exposure in a multivariable model significantly enhanced the models predictive accuracy for fluconazole-resistant Candida bloodstream infection. Our findings may be relevant to the selection of empirical antifungal treatment and broaden the scope of antibiotic-associated collateral damage.

Benefit of early treatment with oseltamivir in hospitalized patients with documented 2009 influenza A (H1N1): retrospective cohort study

BACKGROUND We assessed the association between early oseltamivir treatment and influenza complications in hospitalized patients. METHODS A retrospective cohort study, including adults with laboratory-confirmed 2009 influenza A (H1N1) in three hospitals in Israel, was performed between July 2009 and January 2010, when admission was limited to high-risk patients. We compared patients treated with oseltamivir early versus late (>48 h after symptom onset). We analysed risk factors for complications, defined as radiographic pneumonia, hypoxia, mechanical ventilation, intensive care unit admission, haemodynamic support or in-hospital death. Risk factors for complications on univariate analysis were entered into a multivariable logistic regression analysis. Odds ratios (ORs) with 95% confidence intervals (CI) are reported. RESULTS Four hundred and forty-nine inpatients treated with oseltamivir were included, 189 (42.1%) of whom were treated early. Influenza complications occurred significantly more frequently among patients treated late with oseltamivir [150/260 (57.7%) versus 67/189 (35.4%), P < 0.001]. Late oseltamivir remained significantly associated with complications in the adjusted analysis (OR 2.37, 95% CI 1.52-3.70). Other independent risk factors included dyspnoea, disease severity on admission, lower sodium and treatment at one hospital; rhinorrhoea was protective. In an analysis adjusted for the propensity for early treatment the association remained significant (OR 2.21, 95% CI 1.41-3.46). Initiation of oseltamivir >48 h after admission was associated with a higher rate of complications documented after admission (OR 4.09, 95% CI 1.55-10.80). Severe complications (excluding hypoxia and uncomplicated pneumonia) occurred more frequently with late oseltamivir (adjusted OR 3.28,95% CI 1.56-6.89). CONCLUSIONS Initiation of oseltamivir within 48 h of symptom onset was associated with fewer complications in patients hospitalized with 2009 influenza A (H1N1).

Active Surveillance for Methicillin‐Resistant Staphylococcus aureus (MRSA) Decreases the Incidence of MRSA Bacteremia

OBJECTIVES To evaluate the influence of performance of active surveillance cultures for methicillin-resistant Staphylococcus aureus (MRSA) on the incidence of nosocomial MRSA bacteremia in an endemic hospital. DESIGN Before-after trial. SETTING A 700-bed hospital. PATIENTS All patients admitted to the hospital who were at high risk for MRSA bacteremia. INTERVENTION Performance of surveillance cultures for detection of MRSA were recommended for all patients at high risk, and contact isolation was implemented for patients with positive results of culture. Each MRSA-positive patient received one course of eradication treatment. We compared the total number of surveillance cultures, the percentage of surveillance cultures with positive results, and the number of MRSA bacteremia cases before the intervention (from January 2002 through February 2003) after the start of the intervention (from July 2003 through October 2004). RESULTS The number of surveillance cultures performed increased from a mean of 272.57 cultures/month before the intervention to 865.83 cultures/month after the intervention. The percentage of surveillance cultures with positive results increased from 3.13% before to 5.22% after the intervention (P < .001). The mean number of MRSA bacteremia cases per month decreased from 3.6 cases before the intervention to 1.8 cases after the intervention (P < 0.001). CONCLUSIONS Active surveillance culture is important for identifying hidden reservoirs of MRSA. Contact isolation can prevent new colonization and infection and lead to a significant reduction of morbidity and healthcare costs.

Risk behaviors and spectrum of diseases among elderly travelers: a comparison of younger and older adults.

BACKGROUND Elderly travel to the developing world is increasing. Little information is available regarding risk behaviors and health during and after travel in this population. METHODS We compared the risk factors and occurrence of travel-related diseases in two populations of Israelis, travelers aged 60 years and older and travelers in the age group of 20 to 30 years. Only people traveling for less than a month were included. Pre-travel, each person received routine counseling regarding travel-associated health risks, was immunized, and given anti-malarial prescriptions as needed. Travelers were surveyed by telephone 6 to 12 months following travel about underlying medical conditions, current medications, and travel history. Risk and preventive behaviors, compliance with anti-malarial prophylaxis, and history of illness during and after travel were assessed. RESULTS Of patients who visited the clinic from January to June 2008, 191/208 (91%) travelers aged 60 and older and 203/291 (69%) travelers aged 20 to 30 years were contacted by phone and recruited. Fewer elderly travelers drank open drinks, compared to young travelers (8% vs 35%, p < 0.01), and fewer purchased street food compared to young travelers (16.2% vs 37.9%, p < 0.01). More elderly travelers were fully compliant with their anti-malarial chemoprophylaxis regimen (60.7% vs 33.8%, p < 0.01). More elderly travelers took organized tours (61% vs 2%, p < 0.001). Young travelers more often backpacked (50.7% vs 10.4%, p < 0.001). Illness, most commonly diarrhea, was reported by 18.8% of elderly travelers compared to 34.0% of the young travelers (p = 0.001). In a logistic regression model only travel to East Asia (OR 4.66) (95%CI 1.93-11.22) and traveling under basic conditions (OR 1.94) (95% CI 1.42-3.29) remained significantly associated with illness, irrespective of age. CONCLUSIONS Because elderly travelers tend to comply with health-related recommendations better and use less risky travel modes, their risk for illness during travel was lower. Traveling to East Asia and travel mode are associated with illness during travel, irrespective of age.

Human gastrin: A Helicobacter pylori–specific growth factor

Abstract Background & Aims: Helicobacter pylori resides within the gastric mucosa, a niche hostile to other microorganisms. Human gastrin levels are elevated after infection and return to normal after eradication. The aim of this study was to test the direct effect of gastrin on the growth of H. pylori. Methods: H. pylori and control bacteria were grown with gastrin or control peptides and growth rate was determined. 125 I-labeled gastrin was used to determine uptake. Results: Human gastrin stimulated H. pylori growth in a specific, dose-dependent manner. Gastrin shortened the lag time, increased growth rate in the logarithmic phase, and increased final bacterial concentration at the stationary phase. These effects were shown over a wide concentration range, including physiological luminal and serum levels. Labeled gastrin uptake was inhibited by unlabeled gastrin. Controls consisting of cholecystokinin and pentagastrin inhibited gastrin uptake but did not stimulate growth. In contrast, somatostatin and epidermal growth factor had no effect on either gastrin uptake or bacterial growth. These results suggest a structurally restricted, receptor-mediated, gastrin-specific effect. Conclusions: Human gastrin is a specific growth factor for H. pylori and may have a role in the adaptation of H. pylori to its unique habitat. GASTROENTEROLOGY 1999;117:1113-1118