Use of antibiotics and factors associated with treatment failure among 152,245 patients with pneumonia treated in the community - a retrospective cohort study.

This study aims to evaluate risk factors associated with treatment failure and the antibiotics prescribed by primary care physicians in a large patient cohort treated for pneumonia in the community. A retrospective cohort study based on the databases of Maccabi Healthcare Services that provide healthcare to a quarter of the Israeli population. Included patients were > 12 years and diagnosed with pneumonia in the outpatient setting. Cohort 1 included patients with community-acquired pneumonia (CAP), whereas cohort 2 included patients with a documented pneumonia diagnosis following hospital discharge. Treatment failure (TF) was defined as either the use of a second line antibiotic OR hospital admission within 3-14 days OR death within 30 days of diagnosis. Risk factors for TF in the study cohorts were analyzed using multivariable logistic regression. During the study period, 148,376 patients were included in cohort 1 and 3,869 patients in cohort 2, with mean ages of 46.5 ± 20.3 and 63.8 ± 19.5 years, respectively. The most commonly used antibiotics were cephalosporins (36%) and macrolides (35.5%). TF occurred in 12% of cohort 1 and was associated with older age, comorbid conditions, use of non-respiratory fluoroquinolones, and penicillin. Atypical coverage (either macrolides or tetracyclines) was associated with a lower risk of failure. Among cohort 2, TF was higher (16.4%, p < 0.001) and was associated with older age, prior cancer, and congestive heart failure. Treatment failure was associated with comorbid conditions and increasing age. Among young patients with CAP and no comorbid conditions, macrolides or tetracyclines may suffice.

From hydroxychloroquine to ivermectin: what are the anti-viral properties of anti-parasitic drugs to combat SARS-CoV-2?

BACKGROUND: Nearly a year into the COVID-19 pandemic, we still lack effective anti-SARS-CoV-2 drugs with substantial impact on mortality rates except for dexamethasone. As the search for effective antiviral agents continues, we aimed to review data on the potential of repurposing antiparasitic drugs against viruses in general, with an emphasis on coronaviruses. METHODS: We performed a review by screening in vitro and in vivo studies that assessed the antiviral activity of several antiparasitic agents: chloroquine, hydroxychloroquine (HCQ), mefloquine, artemisinins, ivermectin, nitazoxanide (NTZ), niclosamide, atovaquone and albendazole. RESULTS: For HCQ and chloroquine we found ample in vitro evidence of antiviral activity. Cohort studies that assessed the use of HCQ for COVID-19 reported conflicting results, but randomized controlled trials (RCTs) demonstrated no effect on mortality rates and no substantial clinical benefits of HCQ used either for prevention or treatment of COVID-19. We found two clinical studies of artemisinins and two studies of NTZ for treatment of viruses other than COVID-19, all of which showed mixed results. Ivermectin was evaluated in one RCT and few observational studies, demonstrating conflicting results. As the level of evidence of these data is low, the efficacy of ivermectin against COVID-19 remains to be proven. For chloroquine, HCQ, mefloquine, artemisinins, ivermectin, NTZ and niclosamide, we found in vitro studies showing some effects against a wide array of viruses. We found no relevant studies for atovaquone and albendazole. CONCLUSIONS: As the search for an effective drug active against SARS-CoV-2 continues, we argue that pre-clinical research of possible antiviral effects of compounds that could have antiviral activity should be conducted. Clinical studies should be conducted when sufficient in vitro evidence exists, and drugs should be introduced into widespread clinical use only after being rigorously tested in RCTs. Such a search may prove beneficial in this pandemic or in outbreaks yet to come.

The use of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for rapid bacterial identification in patients with smear-positive bacterial meningitis.

OBJECTIVES: To assess the potential of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) in rapid identification of bacteria from smear-positive cerebrospinal fluid (CSF) in a cohort of patients with meningitis. METHODS: Single-centre observational study, including adults and children with community-acquired or postneurosurgical bacterial meningitis. Meningitis was defined using established criteria. Samples of CSF that had a positive CSF Gram stain were directly examined by MALDI-TOF-MS. Identification was considered accurate when identical to the CSF culture or PCR results (species and genus level). Laboratory workers performing the MALDI-TOF-MS and interpreting its results were blinded to the direct smear results, except for the fact that it was positive. MALDI-TOF-MS results were not conveyed to clinicians. RESULTS: MALDI-TOF-MS was tested on 44 CSF samples; ten samples were obtained from patients with community-acquired meningitis, and 34 samples were from patients with postneurosurgical meningitis. The assay identified bacteria correctly in 17/21 of the samples with Gram-negative rods observed on the direct smear, all obtained from patients who had undergone neurosurgery, (sensitivity 81%, 95% CI 64.2%-97.7%). In the postneurosurgical group, Gram-positive cocci were identified correctly in only 1/11 (9.1%) of the samples, and Candida species were not identified in two samples. Among patients with community-acquired meningitis, the assay did not identify Streptococcus pneumoniae in eight of eight samples, Neisseria meningitidis in one sample (1/1), and Streptococcus agalactiae in one sample (1/1). CONCLUSIONS: We found MALDI-TOF-MS to be useful in the rapid identification of Gram-negative rods directly from smear-positive CSF samples, but not of Gram-positive bacteria.

Duration of viral shedding and factors associated with prolonged shedding among inpatients with influenza treated with oseltamivir: a prospective cohort study.

The purpose of this study was to determine the rate of decline in the diagnostic yield of influenza PCR assay after oseltamivir administration, and to identify risk factors for prolonged shedding. This was a prospective observational study. We included adult inpatients with clinical signs of influenza during the influenza seasons 2015 and 2016, who had positive influenza PCR tests and who were treated with oseltamivir. Clinical follow-up and repeat PCR testing were performed on days 2, 4 and 6 after the first positive test. We defined prolonged shedders as patients who still required hospitalization and had a positive PCR assay on day 4. Risk factors for prolonged shedding were assessed in univariate and multivariate analyses. A total of 215 patients were included in our study. The median age was 64 years and 49.3% were men. The main influenza type was H1N1 (50.1%). Rates of PCR positivity among evaluable patients on days 2, 4 and 6 were 142/215 (66%), 50/78 (64.1%) and 20/30 (66.6%), respectively. Independent risk factors for prolonged shedding (50 patients) included hypoxemia [odds ratio (OR) 2.55, 95% confidence interval (1.3-5.1)] and lower diastolic blood pressure [OR 0.94, 95% CI (0.92-0.97)] on admission. Negative PCR tests taken more than 48 h after initiation of treatment had low diagnostic yield. More severe disease, manifested by hypoxemia and lower blood pressure, is associated with prolonged shedding on oseltamivir treatment.

Expression of CD73 slows down migration of skin dendritic cells, affecting the sensitization phase of contact hypersensitivity reactions in mice.

BACKGROUND: Application of haptens to the skin induces release of immune stimulatory ATP into the extracellular space. This "danger" signal can be converted to immunosuppressive adenosine (ADO) by the action of the ectonucleotidases CD39 and CD73, expressed by skin and immune cells. Thus, the expression and regulation of CD73 by skin derived cells may have crucial influence on the outcome of contact hypersensitivity (CHS) reactions. OBJECTIVE: To investigate the role of CD73 expression during 2,4,6-trinitrochlorobenzene (TNCB) induced CHS reactions. METHODS: Wild type (wt) and CD73 deficient mice were subjected to TNCB induced CHS. In the different mouse strains the resulting ear swelling reaction was recorded along with a detailed phenotypic analysis of the skin migrating subsets of dendritic cells (DC). RESULTS: In CD73 deficient animals the motility of DC was higher as compared to wt animals and in particular after sensitization we found increased migration of Langerin+ DC from skin to draining lymph nodes (LN). In the TNCB model this led to a stronger sensitization as indicated by increased frequency of interferon-γ producing T cells in the LN and an increased ear thickness after challenge. CONCLUSION: CD73 derived ADO production slows down migration of Langerin+ DC from skin to LN. This may be a crucial mechanism to avoid over boarding immune reactions against haptens.

Management of post-neurosurgical meningitis: narrative review.

BACKGROUND: Infections complicating neurosurgery pose unacceptable mortality and morbidity. AIMS: To summarize what is known about the epidemiology, diagnosis and treatment of post-neurosurgical meningitis (PNM). SOURCES: PubMed, references of identified studies and reviews, and personal experience when evidence was lacking. CONTENT: The incidence and pathogen distribution of PNM is highly variable. A shift towards Gram-negative bacteria has been observed with use of antibiotic prophylaxis and antibiotic-coated devices directed mainly against Gram-positive bacteria. However, knowledge of the local epidemiology is necessary to treat PNM. The diagnosis of PNM is difficult because, unlike community-acquired meningitis, symptoms are less specific; patients are ill at baseline and many neurosurgical conditions mimic meningitis and cause cerebrospinal fluid (CSF) abnormalities. Pivotal CSF findings for diagnosis of PNM are the CSF glucose, CSF lactate and Gram stain. CSF leucocyte counts are not specific in PNM. Current diagnostic capabilities leave a non-negligible category of patients with microbiologically negative, uncertain diagnosis of PNM. There is no high-quality evidence on several cardinal issues in PNM management, including the effectiveness of intraventricular or intrathecal (IV/IT) antibiotics, effectiveness of dual antibiotic therapy for multidrug-resistant Gram-negative bacteria; clinical benefit of routine therapeutic drug monitoring; and safest timing of shunt replacement. Some data point to a potential benefit of IV/IT antibiotic treatment, mainly for PNM caused by carbapenem-resistant Gram-negative bacteria. Carbapenem-colistin combination therapy is suggested for PNM caused by carbapenem-resistant Gram-negative bacteria with a carbapenem MIC ≤8 mg/L. IMPLICATIONS: Guiding the optimal management of PNM will necessitate collaborative multicentre efforts and unique study designs.

Pros and cons of circumcision: an evidence-based overview.

Based on three large randomized controlled trials (RCTs) conducted in Africa, it can clearly be stated that circumcision lowers the risk of infection with the human immunodeficiency virus (HIV) and some sexually transmitted infections (STIs) among males in settings of high HIV and STI endemicity. Similar effects on STI risk may exist for females, although this may result from an indirect effect of decreasing risk of infection among male partners. It is unknown whether circumcision prevents HIV acquisition in men who have sex with men (MSM), although there might be a protective effect for men who engage mainly in insertive anal intercourse. When the effects of adult circumcision on sexual function and satisfaction of men are examined, high-quality evidence strongly supports lack of harm. Whether circumcision alters sexual satisfaction of female partners is not known as fewer and smaller studies reported conflicting results. Circumcision rarely causes serious complications if practiced by trained practitioners, in a sterile setting, and with a proper follow-up. These conclusions are limited by the lack of high-quality data from areas outside of Africa. RCTs have not been conducted to assess the effects of circumcising infants or MSM. Circumcision has well-proven benefits for people residing in areas with high prevalence of STIs, including HIV, and is not unethical for those who choose to be circumcised or have their children circumcised on religious, social, or cultural grounds. For many others, a definite pro or con recommendation, based on a risk-benefit ratio, cannot be made.

Risk factors associated with death or neurological deterioration among patients with Gram-negative postneurosurgical meningitis.

In a retrospective cohort of 115 patients with Gram-negative postneurosurgical meningitis, factors associated with 30-day mortality or neurological deterioration on multivariate analysis included days from admission to meningitis (OR 1.05 per day, 95% CI 1.02-1.09), decreased level of consciousness (OR 2.69, 95% CI 0.99-7.31), blood glucose level >180 mg/dL (OR 3.70, 95% CI 1.27-10.77), higher creatinine level (OR 4.07 per 1 mg/dL, 95% CI 1.50-11.08), and cerebrospinal fluid glucose <50 mg/dL (OR 5.02, 95% CI 1.71-14.77) at diagnosis. A predictive score triaged patients into three groups with low (4/44, 9.1%), intermediate (16/38, 42.1%) and high (22/33, 66.7%) unfavourable outcome rates. Validation on a different group of 36 patients with Gram-negative postneurosurgical meningitis was acceptable.

Intrathecal or intraventricular therapy for post-neurosurgical Gram-negative meningitis: matched cohort study.

Gram-negative post-operative meningitis due to carbapenem-resistant bacteria (CR-GNPOM) is a dire complication of neurosurgical procedures. We performed a nested propensity-matched historical cohort study aimed at examining the possible benefit of intrathecal or intraventricular (IT/IV) antibiotic treatment for CR-GNPOM. We included consecutive adults with GNPOM in two centres between 2005 and 2014. Patients receiving combined systemic and IT/IV treatment were matched to patients receiving systemic treatment only. Matching was done based on the propensity of the patients to receive IT/IV treatment. We compared patient groups with 30-day mortality defined as the primary outcome. The cohort included 95 patients with GNPOM. Of them, 37 received IT/IV therapy in addition to systemic treatment (22 with colistin and 15 with amikacin), mostly as initial therapy, through indwelling cerebrospinal fluid drains. Variables associated with IT/IV therapy in the propensity score included no previous neurosurgery, time from admission to meningitis, presence of a urinary catheter and GNPOM caused by carbapenem-resistant Gram-negative bacteria. Following propensity matching, 23 patients given IT/IV therapy and 27 controls were analysed. Mortality was significantly lower with IT/IV therapy: 2/23 (8.7%) versus 9/27 (33.3%), propensity-adjusted OR 0.19, 95% CI 0.04-0.99. Death or neurological deterioration at 30 days, 14-day and in-hospital mortality were lower with IT/IV therapy (OR <0.4 for all) without statistically significant differences. Among patients discharged alive, those receiving IT/IV therapy did not experience more neurological deterioration. Serious adverse events with IT/IV therapy were not documented. Our results support the early use of IT antibiotic treatment for CR-GNPOM when a delivery method is available.

Risk factors for and impact of carbapenem-resistant Acinetobacter baumannii colonization and infection: matched case-control study.

The objective of this investigation was to identify risk factors for carbapenem-resistant Acinetobacter baumannii (CRAB) and its association with mortality. A population-based matched case-control study using the computerized database of Clalit Health Services (CHS) in the period between 2007 and 2012 was conducted. Hospitalized patients with CRAB colonization or infection were compared to hospitalized patients without evidence of A. baumannii, matched by age, ward of hospitalization, season, Charlson score, and length of hospitalization. Risk factors for CRAB isolation were searched for using multivariate analysis. Association of CRAB and other risk factors with mortality were assessed in the cohort. A total of 1190 patients with CRAB were matched to 1190 patients without CRAB. Low socioeconomic status was independently associated with CRAB isolation and CRAB bacteremia [odds ratio 2.18, 95% confidence interval (CI) 1.02-5]. Other risk factors were invasive procedures and bacteremia with other pathogens prior to CRAB isolation, and various comorbidities. Among all patients, CRAB isolation was independently associated with increased mortality (hazard ratio 2.33, 95% CI 2.08-2.6). Socioeconomic status is associated with health outcomes. Our population-based study revealed an almost doubled risk for CRAB in patients at lower socioeconomic status and an association with healthcare exposure. CRAB was associated with mortality and might become a risk indicator for complex morbidity and mortality.

The significance of persistent fever in the treatment of suspected bacterial infections among inpatients: a prospective cohort study.

Antibiotic escalations are frequently guided by fever persistence. Unnecessary antibiotic escalation is associated with resistance induction. We examined whether fever persistence is associated with adverse outcomes among medical inpatients with sepsis. In a single-center prospective cohort study, we included consecutive medical inpatients with suspected or documented bacterial infections. Data were collected on days 0, 2, 4, and 30 days from episode onset. We examined the association between fever persistence at 4 days and 30-day mortality on univariate and multivariate analysis. Inappropriate empirical antibiotic treatment (IAET) was defined for patients with microbiologically documented infections (MDIs). Odds ratios (ORs) are presented with 95% confidence intervals (CIs). A total of 1,621 patients were included. Among patients with MDIs, 38/206 (18.4%) given appropriate empiric therapy had continued fever on day 4, compared to 64/231 (27.7%) of patients receiving IAET, OR 0.59, 95% CI 0.37-0.93. Fever persistence was not associated with mortality after adjustment for other risk factors. Among patients with presumed sepsis who did not have MDIs, persistent fever was significantly associated with 30-day mortality on a multivariate analysis, adjusted OR 2.77 (95% CI 1.78-4.31). Other risk factors for mortality included older age, nosocomial infections, malignancy, dyspnea, shock, decreased albumin, and elevated creatinine. For patients with MDIs, fever persistence for up to 4 days is a marker of IAET, but is not associated with mortality, and should not, in itself, trigger antibiotic escalation. For patients without MDIs, fever persistence should trigger careful re-evaluation, as it is associated with mortality.

Modelling in infectious diseases: between haphazard and hazard.

Modelling of infectious diseases is difficult, if not impossible. No epidemic has ever been truly predicted, rather than being merely noticed when it was already ongoing. Modelling the future course of an epidemic is similarly tenuous, as exemplified by ominous predictions during the last influenza pandemic leading to exaggerated national responses. The continuous evolution of microorganisms, the introduction of new pathogens into the human population and the interactions of a specific pathogen with the environment, vectors, intermediate hosts, reservoir animals and other microorganisms are far too complex to be predictable. Our environment is changing at an unprecedented rate, and human-related factors, which are essential components of any epidemic prediction model, are difficult to foresee in our increasingly dynamic societies. Any epidemiological model is, by definition, an abstraction of the real world, and fundamental assumptions and simplifications are therefore required. Indicator-based surveillance methods and, more recently, Internet biosurveillance systems can detect and monitor outbreaks of infections more rapidly and accurately than ever before. As the interactions between microorganisms, humans and the environment are too numerous and unexpected to be accurately represented in a mathematical model, we argue that prediction and model-based management of epidemics in their early phase are quite unlikely to become the norm.

Impact of carbapenem resistance on the outcome of patients' hospital-acquired bacteraemia caused by Klebsiella pneumoniae.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae, especially Klebsiella spp., have become a major health problem recently worldwide. Since 2006 the incidence of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections has increased substantially in Israel. Bloodstream infections (BSIs) caused by these strains have been associated with high rates of treatment failure and mortality. AIM: This study was designed to identify risk factors for carbapenem resistance among patients with healthcare-related (HCR) K. pneumoniae bacteraemia and predictors of mortality associated with HCR-CRKP bacteraemia compared with carbapenem-susceptible K. pneumoniae (CSKP). METHODS: In this retrospective case-control study, all cases of K. pneumoniae bacteraemia during 2006-2008 were identified. Resistance patterns, underlying morbidities, risk factors for drug resistance and mortality rates were compared for patients with CRKP and CSKP bacteraemia. FINDINGS: Two hundred and fourteen patients with CSKP bacteraemia were compared with 103 patients with CRKP bacteraemia. Severe, chronic comorbidities and prior antibiotic use were more frequent among patients with CRKP bacteraemia. On multivariate analysis prior use of macrolides and antibiotic exposure for ≥14 days remained the only independent factors associated with CRKP bacteraemia. Mortality rates of CRKP patients were significantly higher than those of CSKP patients. On multivariate analyses: bedridden status, chronic liver disease, Charlson comorbidity index ≥5, mechanical ventilation, and haemodialysis remained independently associated with mortality among patients with K. pneumoniae bacteraemia. Carbapenem resistance was not a risk factor for mortality. CONCLUSIONS: Previous antibiotic exposure is a risk factor for CRKP-BSI. Mortality among patients with K. pneumoniae bacteraemia is associated with serious comorbidities, but not with carbapenem resistance.

Malaria among patients and aid workers consulting a primary healthcare centre in Leogane, Haiti, November 2010 to February 2011 - a prospective observational study.

Plasmodium falciparum malaria is endemic in Haiti, but epidemiological data are scarce. A total of 61 cases of malaria were diagnosed between November 2010 and February 2011 among 130 Haitian patients with undifferentiated fever. Three additional cases were diagnosed in expatriates not taking the recommended chemoprophylaxis. No cases were diagnosed among aid workers using chemoprophylaxis. In conclusion, malaria is a significant health problem in Leogane, Haiti. Aid workers and visitors should use chemoprophylaxis according to existing guidelines.

Clinical impact of a PCR assay for rapid identification of Klebsiella pneumoniae in blood cultures.

The clinical impact of a rapid PCR identification assay for Klebsiella pneumoniae in positive blood cultures was prospectively evaluated. Multivariate analysis identified the rapid PCR assay as the only significant factor in decreasing the time lapse preceding the initiation of appropriate antimicrobial therapy (hazards ratio, 3.03; confidence interval, 1.62 to 5.68; P, 0.001).

Septic arthritis caused by Mycobacterium kansasii in a prosthetic knee joint.

Mycobacterium kansasii is a relatively common cause of nontuberculous mycobacterial pulmonary infection. Septic arthritis caused by Mycobacterium kansasii, on the other hand, is rare. Reported here for the first time is the case of an 82-year-old patient with an infection of a prosthetic knee joint with Mycobacterium kansasii.