Hospitalized Patients With Severe Coronavirus Disease 2019 During the Omicron Wave in Israel: Benefits of a Fourth Vaccine Dose.

BACKGROUND: Waning immunity and an increased incidence of coronavirus disease 2019 (COVID-19) during the Omicron outbreak led the Israeli Ministry of Health to recommend a fourth vaccine dose for high-risk individuals. In this study, we assessed its effect for hospitalized patients with severe breakthrough COVID-19. METHODS: In this multicenter cohort study of hospitalized adults with severe COVID-19 in Israel, from 15 to 31 January 2022, cases were divided according to the number of vaccinations received. Poor outcome was defined as mechanical ventilation or in-hospital death and was compared between 3- and 4-dose vaccinees using logistic regression. RESULTS: Included were 1049 patients, median age 80 years. Among them, 394 were unvaccinated, 386 and 88 had received 3 or 4 doses, respectively. The 3-dose group was older, included more males, and immunosuppressed patients but with similar outcomes, 49% vs 51% compared with unvaccinated patients (P = .72). Patients who received 4 doses were similarly older and immunosuppressed but had better outcomes compared with unvaccinated patients, 34% vs 51% (P < .01). We examined independent predictors for poor outcome in patients who received either 3 or 4 doses a median of 161 days or 14 days before diagnosis, respectively. Receipt of the fourth dose was associated with protection (odds ratio, 0.51; 95% confidence interval, .3-.87), as was remdesivir. Male sex, chronic renal failure, and dementia were associated with poor outcomes. CONCLUSIONS: Among hospitalized patients with severe breakthrough COVID-19, a recent fourth dose was associated with significant protection against mechanical ventilation or death compared with 3 doses.

The Effect of Macrolides on Mortality in Bacteremic Pneumococcal Pneumonia: A Retrospective, Nationwide Cohort Study, Israel, 2009-2017.

BACKGROUND: Previous cohort studies of pneumonia patients reported lower mortality with advanced macrolides. Our aim was to characterize antibiotic treatment patterns and assess the role of quinolones or macrolides in empirical therapy. MATERIALS: An historical cohort, 1 July 2009 to 30 June 2017, included, through active surveillance, all culture-confirmed bacteremic pneumococcal pneumonia (BPP) among adults in Israel. Cases without information on antibiotic treatment were excluded. Logistic regression analysis was used to assess independent predictors of in-hospital mortality. RESULTS: A total of 2016 patients with BPP were identified. The median age was 67.2 years (interquartile range [IQR] 53.2-80.6); 55.1% were men. Lobar pneumonia was present in 1440 (71.4%), multi-lobar in 576 (28.6%). Median length of stay was 6 days (IQR 4-11). A total of 1921 cases (95.3%) received empiric antibiotics with anti-pneumococcal coverage: ceftriaxone, in 1267 (62.8%). Coverage for atypical bacteria was given to 1159 (57.5%), 64% of these, with macrolides. A total of 372 (18.5%) required mechanical ventilation, and 397 (19.7%) died. Independent predictors of mortality were age (odds ratio [OR] 1.051, 95% confidence interval [CI] 1.039, 1.063), being at high-risk for pneumococcal disease (OR 2.040, 95% CI 1.351, 3.083), multi-lobar pneumonia (OR 2.356, 95% CI 1.741, 3.189). Female sex and macrolide therapy were predictors of survival: (OR 0.702, 95% CI .516, .955; and OR 0.554, 95% CI .394, .779, respectively). Either azithromycin or roxithromycin treatment for as short as two days was predictor of survival. Quinolone therapy had no effect. CONCLUSIONS: Empirical therapy with macrolides reduced odds for mortality by 45%. This effect was evident with azithromycin and with roxithromycin. The effect did not require a full course of therapy.

Estimating the impact of cefuroxime versus cefazolin and amoxicillin/clavulanate use on future collateral resistance: a retrospective comparison.

BACKGROUND: Quantitative estimates of collateral resistance induced by antibiotic use are scarce. OBJECTIVES: To estimate the effects of treatment with amoxicillin/clavulanate or cefazolin, compared with cefuroxime, on future resistance to ceftazidime among hospitalized patients. METHODS: A retrospective analysis of patients with positive bacterial cultures hospitalized in an Israeli hospital during 2016-19 was conducted. Patients were restricted to those treated with amoxicillin/clavulanate, cefazolin or cefuroxime and re-hospitalized with a positive bacterial culture during the following year. Matching was performed using exact, Mahalanobis and propensity score matching. Each patient in the amoxicillin/clavulanate and cefazolin groups was matched to a single patient from the cefuroxime group, yielding 185:185 and 298:298 matched patients. Logistic regression and the g-formula (standardization) were used to estimate the OR, risk difference (RD) and number needed to harm (NNH). RESULTS: Cefuroxime induced significantly higher resistance to ceftazidime than amoxicillin/clavulanate or cefazolin; the marginal OR was 1.76 (95% CI = 1.16-2.83) compared with amoxicillin/clavulanate and 1.98 (95% CI = 1.41-2.8) compared with cefazolin and the RD was 0.118 (95% CI = 0.031-0.215) compared with amoxicillin/clavulanate and 0.131 (95% CI = 0.058-0.197) compared with cefazolin. We also estimated the NNH; replacing amoxicillin/clavulanate or cefazolin with cefuroxime would yield ceftazidime resistance in 1 more patient for every 8.5 (95% CI = 4.66-32.14) or 7.6 (95% CI = 5.1-17.3) patients re-hospitalized in the following year, respectively. CONCLUSIONS: Our results indicate that treatment with amoxicillin/clavulanate or cefazolin is preferable to cefuroxime, in terms of future collateral resistance. The results presented here are a first step towards quantitative estimations of the ecological damage caused by different antibiotics.

Hospitalised patients with breakthrough COVID-19 following vaccination during two distinct waves in Israel, January to August 2021: a multicentre comparative cohort study.

BackgroundChanging patterns of vaccine breakthrough can clarify vaccine effectiveness.AimTo compare breakthrough infections during a SARS-CoV-2 Delta wave vs unvaccinated inpatients, and an earlier Alpha wave.MethodsIn an observational multicentre cohort study in Israel, hospitalised COVID-19 patients were divided into three cohorts: breakthrough infections in Comirnaty-vaccinated patients (VD; Jun-Aug 2021) and unvaccinated cases during the Delta wave (ND) and breakthrough infections during an earlier Alpha wave (VA; Jan-Apr 2021). Primary outcome was death or ventilation.ResultsWe included 343 VD, 162 ND and 172 VA patients. VD were more likely older (OR: 1.06; 95% CI: 1.05-1.08), men (OR: 1.6; 95% CI: 1.0-2.5) and immunosuppressed (OR: 2.5; 95% CI: 1.1-5.5) vs ND. Median time between second vaccine dose and admission was 179 days (IQR: 166-187) in VD vs 41 days (IQR: 28-57.5) in VA. VD patients were less likely to be men (OR: 0.6; 95% CI: 0.4-0.9), immunosuppressed (OR: 0.3; 95% CI: 0.2-0.5) or have congestive heart failure (OR: 0.6; 95% CI: 0.3-0.9) vs VA. The outcome was similar between all cohorts and affected by age and immunosuppression and not by vaccination, variant or time from vaccination.ConclusionsVaccination was protective during the Delta variant wave, as suggested by older age and greater immunosuppression in vaccinated breakthrough vs unvaccinated inpatients. Nevertheless, compared with an earlier post-vaccination period, breakthrough infections 6 months post-vaccination occurred in healthier patients. Thus, waning immunity increased vulnerability during the Delta wave, which suggests boosters as a countermeasure.

Improving urinary tract infection treatment through a multifaceted antimicrobial stewardship intervention in the emergency department.

BACKGROUND: Urinary tract infection (UTI) is frequently encountered in the emergency department (ED). We assessed an antibiotic stewardship intervention tailored for the ED. The primary objective was improving overall adherence to agent choice and treatment duration. The secondary objective was a decrease in fluoroquinolone prescription. METHODS: This pre-post study included patients discharged from the ED with a UTI diagnosis. The intensive intervention period lasted three months and involved dissemination of guidelines, short lectures, incorporation of order sets into electronic ED charts and weekly personal audit and feedback. The following 11-month phase was a booster period consisting of monthly text messages of the treatment protocol. Assessment of adherence to the protocol was compared between the three-month pre-intervention period and the last two months of the intensive intervention period, as well as with the last two months of the booster period. RESULTS: A total of 177 patients were included in the pre-intervention period, 156 in the intervention period, and 94 in the late follow-up assessing the booster period. Median age was 49 (18-94) years, 78.2% were female, 84.8% had cystitis. During the intervention period, protocol adherence with antibiotic selection and duration increased from 41% to 84% (p < 0.001). Adherence remained high in the late follow-up period (73.4% vs. 41%, p < 0.001). Fluoroquinolone use decreased from 19.1% pre-intervention, to 5% in the intervention and 7.4% in the late follow-up periods (p < 0.001). CONCLUSIONS: An antibiotic stewardship intervention in a busy ED resulted in adherence to treatment protocols, including a decrease in fluoroquinolone use. A monthly reminder preserved most of the effect for a year.

Nosocomial outbreak caused by the SARS-CoV-2 Delta variant in a highly vaccinated population, Israel, July 2021.

A nosocomial outbreak of SARS-CoV-2 Delta variant infected 42 patients, staff and family members; 39 were fully vaccinated. The attack rate was 10.6% (16/151) among exposed staff and reached 23.7% (23/97) among exposed patients in a highly vaccinated population, 16-26 weeks after vaccination (median: 25 weeks). All cases were linked and traced to one patient. Several transmissions occurred between individuals wearing face masks. Fourteen of 23 patients became severely sick or died, raising a question about possible waning immunity.

Risk factors for surgical site infections following open versus laparoscopic colectomies: a cohort study.

BACKGROUND: Surgical site infections (SSIs) are among the most common healthcare-associated infections. Evaluating risk factors for SSIs among patients undergoing laparoscopic and open colorectal resections can aid in selecting appropriate candidates for each modality. METHODS: A cohort of all consecutive patients undergoing elective colorectal resections during 2008-2017 in a single center was analyzed. SSIs were prospectively assessed by infection control personnel. Patient data were collected from electronic medical records. Risk factors for SSIs were compared between patients who underwent laparoscopic and open surgeries. A multivariate analysis was performed for significant variables. RESULTS: During the study period, 865 patients underwent elective colorectal resection: 596 laparoscopic and 269 open surgeries. Mean age was 68.2 ± 15.1 years, weight 72.5 ± 18.3 kg and 441 (51%) were men. The most common indication for surgery was malignancy, in 767 patients (88.7%) with inflammatory bowel diseases and diverticulitis following (4.5% and 3.9%, respectively). Patients undergoing laparoscopic surgery were younger, had fewer comorbidities, shorter pre-operative hospitalizations, lower risk index scores, and lower rates of SSI, compared with open surgery. Independent risk factors for SSI following laparoscopic surgery were chronic obstructive pulmonary disease [odds ratio (OR) 2.655 95% CI (1.267, 5.565)], risk index ≥ 2 [OR 2.079, 95% CI (1.041,4.153)] and conversion of laparoscopic to open surgery [OR 2.056 95%CI (1.212, 3.486)]. Independent risk factors for SSI following open surgery were immunosuppression [OR 3.378 95% CI (1.071, 10.655)], chronic kidney disease [OR 2.643 95% CI (1.008, 6.933)], and need for a second dose of prophylactic antibiotics [OR 2.519 95%CI (1.074, 5.905)]. CONCLUSIONS: Risk factors for SSIs differ between laparoscopic and open colorectal resections. Knowledge of specific risk factors may inform patient selection for these modalities.

Healthcare-associated Pneumocystis jirovecii Pneumonia (PJP) Infection in HIV-negative Adults: a Multicenter Study.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection in immunocompromised patients. Clusters of PJP, especially among organ transplant recipients in clinic settings were described. Data regarding nosocomial PJP infection among inpatients are limited. OBJECTIVES: To assess the magnitude and characteristics of inpatient healthcare-associated PJP infection (HCA-PJP) in HIV-negative patients. METHODS: A retrospective chart review of hospitalized PJP patients was performed to identify HCA-PJP. The study was performed at six medical centers in Israel from 2006 to 2016. HCA-PJP was defined as cases of hospital-onset or those with documented contact with a PJP patient. We reviewed and cross-matched temporal and spatial co-locations of patients. Clinical laboratory characteristics and outcomes were compared. RESULTS: Seventy-six cases of PJP were identified. Median age was 63.7 years; 64% men; 44% hematological malignancies; 18% inflammatory diseases; and 61% steroid usage. Thirty-two patients (42%) were defined as HCA-PJP: 18/32 (23.6%) were hospitalized at onset and 14/32 (18.4%) had a previous encounter with a PJP patient. Time from onset of symptoms to diagnosis was shorter in HCA-PJP vs. community-PJP (3.25 vs. 11.23 days, P = 0.009). In multivariate analysis, dyspnea at presentation (odds ratio [OR] 16.79, 95% confidence interval [95%CI] 1.78-157.95) and a tendency toward higher rate of ventilator support (72% vs. 52%, P = 0.07, OR 5.18, 95%CI 0.7-30.3) were independently associated with HCA-PJP, implying abrupt disease progression in HCA-PJP. CONCLUSIONS: HCA-PJP was common. A high level of suspicion for PJP among selected patients with nosocomial respiratory infection is warranted. Isolation of PJP patients should be considered.

Quinolone Consumption by Mothers Increases Their Children's Risk of Acquiring Quinolone-Resistant Bacteriuria.

BACKGROUND: Quinolone resistance has been documented in the pediatric population, although their use is limited in children. This study investigated the effect of maternal quinolone use on gram-negative bacterial resistance to quinolones in their offspring. METHODS: We conducted a population-based, unmatched case-control study during 2010-2017. Cases were all children aged 0.5-17 years with community acquired, gram-negative quinolone-resistant bacteriuria. Controls were similar children with quinolone-sensitive bacteriuria. Only the first positive urine cultures for each child were included. Data on quinolones dispensed to the mother, any antibiotics dispensed to the children, age, sex, ethnicity, and prior hospitalizations were collected. Children with previous quinolone use were excluded. RESULTS: The study population consisted of 40 204 children. Quinolone resistance was detected in 2182 (5.3%) urine cultures. The median age was 5 years, with 93.7% females and 77.6% Jewish. A total of 26 937 (65%) of the children received any antibiotic and 1359 (3.2%) of the mothers received quinolones in the 6 months preceding bacteriuria. Independent risk factors were quinolone dispensed to the mothers (odds ratio [OR], 1.50 [95% confidence interval {CI}, 1.22-1.85]), Arab ethnicity (OR, 1.99 [95% CI, 1.81-2.19]), and antibiotic dispensed to the child (OR, 1.54 [95% CI, 1.38-1.71]). Compared with children aged 12-17 years, younger children had 1.33-1.43 increased odds for quinolone-resistant bacteriuria. CONCLUSIONS: Quinolone prescription to mothers was linked to increased risk of community-acquired, quinolone-resistant bacteria in their offspring, by about 50%. This is another example of the deleterious ecological effects of antibiotic use and should be considered when prescribing antibiotics.

Antibiotic treatment for invasive nonpregnancy-associated listeriosis and mortality: a retrospective cohort study.

Little evidence exists addressing the clinical value of adding gentamicin to ampicillin for invasive listeriosis. A multicenter retrospective observational study of nonpregnant adult patients with invasive listeriosis (primary bacteremia, central nervous system (CNS) disease, and others) in 11 hospitals in Israel between the years 2008 and 2014 was conducted. We evaluated the effect of penicillin-based monotherapy compared with early combination therapy with gentamicin, defined as treatment started within 48 h of culture results and continued for a minimum of 7 days. Patients who died within 48 h of the index culture were excluded. The primary outcome was 30-day all-cause mortality. A total of 190 patients with invasive listeriosis were included. Fifty-nine (30.6%) patients were treated with early combination therapy, 90 (46.6%) received monotherapy, and 44 (22.8%) received other treatments. Overall 30-day mortality was 20.5% (39/190). Factors associated with mortality included lower baseline functional status, congestive heart failure, and higher sequential organ failure assessment score. Source of infection, treatment type, and time from culture taken date to initiation of effective therapy were not associated with mortality. In multivariable analysis, monotherapy was not significantly associated with increased 30-day mortality compared with early combination therapy (OR 1.947, 95% CI 0.691-5.487). Results were similar in patients with CNS disease (OR 3.037, 95% CI 0.574-16.057) and primary bacteremia (OR 2.983, 95% CI 0.575-15.492). In our retrospective cohort, there was no statistically significant association between early combination therapy and 30-day mortality. A randomized controlled trial may be necessary to assess optimal treatment.

Antibiotic Exposure in the Community and Resistance Patterns of Escherichia coli Community-Acquired Bloodstream Infection.

BACKGROUND: Increasing antibiotic resistance in the community results in greater use of empiric broad spectrum antibiotics for patients at hospital admission. As a measure of antibiotic stewardship it is important to identify a patient population that can receive narrow spectrum antibiotics. OBJECTIVES: To evaluate resistance patterns of Escherichia coli bloodstream infection (BSI) from strictly community-acquired infection and the impact of recent antibiotic use on this resistance. METHODS: This single center, historical cohort study of adult patients with E. coli BSI was conducted from January 2007 to December 2011. Patients had no exposure to any healthcare facility and no chronic catheters or chronic ulcers. Data on antibiotic use during the previous 90 days was collected and relation to resistance patterns was assessed. RESULTS: Of the total number of patients, 267 BSI cases met the entry criteria; 153 patients (57%) had bacteria sensitive to all antibiotics. Among 189 patients with no antibiotic exposure, 61% of isolates (116) were pan-sensitive. Resistance to any antibiotic appeared in 114 patients and 12 were extended-spectrum beta-lactamase (ESBL) producers. Quinolone use was the main driver of resistance to any antibiotic and to ESBL resistance patterns. In a multivariate analysis, older age (odds ratio 1.1) and quinolone use (odds ratio 7) were independently correlated to ESBL. CONCLUSIONS: At admission, stratification by patient characteristics and recent antibiotic use can help personalize primary empirical therapy.

Economic evaluation of universal prenatal HIV screening compared with current 'at risk' policy in a very low prevalence country.

OBJECTIVES: Our objective was to economically evaluate universal HIV prenatal screening in Israel, a very low prevalence country (0.1%), compared with the current policy of testing only women belonging to high-risk (HR) groups. DESIGN: A cost-effectiveness analytical model was constructed. Life expectancies, direct medical costs and utility weights of an HIV-positive newborn and a healthy newborn were derived from the literature. Screening was assessed using fourth-generation combo tests. Structural uncertainties were discussed with leading Israeli HIV experts. Univariate and multivariate sensitivity analyses were conducted to account for uncertainty of the model's parameters. RESULTS: Under the current policy, about 2700 women are tested annually identifying 27 HIV-positive women. With the universal screening, 171 000 women would be tested yearly identifying 37 as HIV positive. The analysis included the increased life expectancy of vertically infected children based on current standards of care. Over the lifetime expectancy, universal screening is projected to grant 15 additional quality-adjusted life years and save $177 521 when compared with the current HR only policy. CONCLUSIONS: Universal prenatal HIV screening is projected to be cost saving in Israel, despite a very low HIV prevalence in the general population.

Increased Prevalence of Diabetes Mellitus in a Non-Obese Adult Population: HIV-Infected Ethiopians.

BACKGROUND: Diabetes mellitus (DM) is a metabolic sequel in people infected with HIV, especially following the advent of HAART. This may be a particular concern in immigrants due to lifestyle changes. OBJECTIVES: To characterize the prevalence of DM in HIV-infected Ethiopians in Israel, and to define the risk factors. METHODS: We retrospectively screened the records of 173 HIV-infected Ethiopians and 69 HIV-infected non-Ethiopian HIV patients currently registered at the HIV Clinic of Meir Medical Center. Data were also retrieved from 1323 non-HIV Ethiopians treated in the hospital between 2007 and 2012. The presence of DM was determined by family physician diagnosis as recorded in the hospital database or by the presence of one or more of the following: fasting glucose > 127 mg/dl, hA1C > 6.5% (> 48 mmol/mol), or blood glucose > 200 mg/dl. Population data and risk factors for DM were analyzed by univariate and multivariate analyses. RESULTS: Among HIV-infected Ethiopian subjects, the prevalence of DM was 31% (54/173) compared to 4% (3/69) in HIV-infected non-Ethiopians and 8% (102/1323) in non-HIV-infected Ethiopians (P < 0.0001). The relatively increased prevalence of DM was age independent, but most noticeable in those under the median age (< 42 years). Body mass index (BMI) was a predictor for DM (OR 1.263, CI 1.104-1.444, P = 0.001), although its values did not vary between the two ethnic groups. CONCLUSIONS: HIV-infected Ethiopians are more likely to develop DM at low BMI values compared to non-Ethiopians. This observation questions the relevance of accepted BMI values in this population and suggests that preventive measures against DM be routinely taken in these subjects.

Characteristics of SCCmec IV and V Methicillin-Resistant Staphylococcus aureus (MRSA) in Israel.

BACKGROUND: Isolation of methicillin-resistant Staphylococcus aureus (MRSA) in healthy individuals is not common in Israel. In our hospital, about 30% of MRSA isolates were SCCmec types IV and V. OBJECTIVES: To identify the demographic and clinical characteristics of patients carrying MRSA SCCmec type IV or V, and to compare them with each other and with those of patients with SCCmec types I-III. METHODS: We conducted a case-control study that included 501 patients from whom MRSA was isolated: 254 with SCCmec type I, II, or III, and 243 isolates from SCCmec types IV or V. RESULTS: MRSA was isolated from surveillance cultures in 75% of patients and from a clinical site in 25%. The majority of our study population was elderly, from nursing homes, and with extensive exposure to health care. First, we compared characteristics of patients identified through screening. Statistically significant predictors of SCCmec V vs. IV were Arab ethnicity (OR 7.44, 95% CI 1.5-37.9) and hospitalization in the year prior to study inclusion (OR 5.7, 95% CI 1.9-16.9). No differences were found between patients with SCCmec types I-III and patients with SCCmec type IV or V. Analysis of the subset of patients who had clinical cultures yielded similar results. CONCLUSIONS: SCCmec types IV and V were common in the hospital setting although rare in the community. It seems that in Israel, SCCmec IV and V are predominantly health care-associated MRSA.

An international multicenter study comparing COVID-19 omicron outcomes in patients with hematological malignancies treated with obinutuzumab versus rituximab.

OBJECTIVES: Hematological malignancy (HM) patients treated with anti-CD20 monoclonal antibodies are at higher risk for severe COVID-19. A previous single-center study showed worse outcomes in patients treated with obinutuzumab compared to rituximab. We examined this hypothesis in a large international multicenter cohort. METHODS: We included HM patients from 15 centers, from five countries treated with anti-CD20, comparing those treated with obinutuzumab (O-G) to rituximab (R-G) between December 2021 and June 2022, when Omicron lineage was dominant. RESULTS: We collected data on 1048 patients. Within the R-G (n = 762, 73%), 191 (25%) contracted COVID-19 compared to 103 (36%) in the O-G. COVID-19 patients in the O-G were younger (61 ± 11.7 vs. 64 ± 14.5, p = 0.039), had more indolent HM diagnosis (aggressive lymphoma: 3.9% vs. 67.0%, p < 0.001), and most were on maintenance therapy at COVID-19 diagnosis (63.0% vs. 16.8%, p < 0.001). Severe-critical COVID-19 occurred in 31.1% of patients in the O-G and 22.5% in the R-G. In multivariable analysis, O-G had a 2.08-fold increased risk for severe-critical COVID-19 compared to R-G (95% CI 1.13-3.84), adjusted for Charlson comorbidity index, sex, and tixagevimab/cilgavimab (T-C) prophylaxis. Further analysis comparing O-G to R-G demonstrated increased hospitalizations (51.5% vs. 35.6% p = 0.008), ICU admissions (12.6% vs. 5.8%, p = 0.042), but the nonsignificant difference in COVID-19-related mortality (n = 10, 9.7% vs. n = 12, 6.3%, p = 0.293). CONCLUSIONS: Despite younger age and a more indolent HM diagnosis, patients receiving obinutuzumab had more severe COVID-19 outcomes than those receiving rituximab. Our findings underscore the need to evaluate the risk-benefit balance when considering obinutuzumab therapy for HM patients during respiratory viral outbreaks.

[Metabolic bone disorders in HIV patients].

The life expectancy of HIV patients has increased dramatically since the introduction of combination antiretroviral therapy. This led to an increase in the incidence of non-AIDS related diseases, such as liver diseases, malignancies and metabolic disorders. Increased incidence of osteoporosis and bone fractures was found in HIV patients compared to the general population. The causes were multifactorial, combining traditional risk factors (such as age, sex, low weight, smoking, steroid treatment, vitamin D deficiency), with risk factors associated with the viral infection itself (increased bone loss and decreased bone formation), and to a lesser extent from the antiretroviral treatment itself. An association between bone density loss and antiviral drugs such as Tenofovir, and different protease inhibitors, was found in several studies, but no definite evidence of an increased risk of bone fractures was found. Current American guidelines recommend screening for low bone density only HIV patients who are over 50 years of age with a risk factor for osteoporosis. European guidelines recommend screening all HIV patients older than 50 years. HIV patients at risk for fractures should be treated according to local guidelines in the general population. Currently, no recommendations exist to change any specific antiretroviral therapy in case of osteoporosis, unless there are specific circumstances.

[Variability of management for patients hospitalized with 2009 A/H1N1 influenza in three Israeli hospitals].

OBJECTIVES: To assess uniformity of criteria for hospitalization and management of inpatients with documented 2009 A/H1N1 influenza, at a time when national guidelines for management were issued by the public health authorities. METHODS: This was a prospective observational cohort study. We included all adults with laboratory-confirmed pandemic 2009 A/H1N1 influenza in three hospitals in central Israel admitted between 22/7/2009 and 15/2/2010. We compared baseline data, results and treatment management between the three hospitals. Chi-square, ANOVA and Kruskal-WalLis tests were performed. RESULTS: Overall, 496 patients with documented 2009 A/H1N1 influenza were included; the mean age was 44 years (range 19-93). Of all the patients sampled, PCR for influenza was positive in 21.2% [178/840], 27.4% [124/453] and 18.6% [194/1043] in the three hospitals. Differences between hospitals in baseline patient characteristics were few. Significant differences were observed with regard to disease characteristics at admission, including temperature, respiratory symptoms, hypoxia, pulmonary infiltrates (33.7% [60/178], 19.4% [24/124] and 38.7% [75/194]), all influenza complications and severity of illness score (p < 0.05 for all). Differences were observed with regard to oseltamivir treatment, ranging from 79.5% to 98.9% of inpatients. Antibiotic treatment was common (overall 71%) but differences between hospitals were observed with regard to the antibiotic regimens used. The ratio of infectious disease physicians to hospital-bed ratio was low and variable (0.35, and 0.35 per 100 beds). CONCLUSIONS: There was significant variability between hospitals in the hospitalization and management of patients hospitalized with 2009 A/H1N1 influenza.

Prediction of ciprofloxacin resistance in hospitalized patients using machine learning.

BACKGROUND: Ciprofloxacin is a widely used antibiotic that has lost efficiency due to extensive resistance. We developed machine learning (ML) models that predict the probability of ciprofloxacin resistance in hospitalized patients. METHODS: Data were collected from electronic records of hospitalized patients with positive bacterial cultures, during 2016-2019. Susceptibility results to ciprofloxacin (n = 10,053 cultures) were obtained for Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Pseudomonas aeruginosa, Proteus mirabilis and Staphylococcus aureus. An ensemble model, combining several base models, was developed to predict ciprofloxacin resistant cultures, either with (gnostic) or without (agnostic) information on the infecting bacterial species. RESULTS: The ensemble models' predictions are well-calibrated, and yield ROC-AUCs (area under the receiver operating characteristic curve) of 0.737 (95%CI 0.715-0.758) and 0.837 (95%CI 0.821-0.854) on independent test-sets for the agnostic and gnostic datasets, respectively. Shapley additive explanations analysis identifies that influential variables are related to resistance of previous infections, where patients arrived from (hospital, nursing home, etc.), and recent resistance frequencies in the hospital. A decision curve analysis reveals that implementing our models can be beneficial in a wide range of cost-benefits considerations of ciprofloxacin administration. CONCLUSIONS: This study develops ML models to predict ciprofloxacin resistance in hospitalized patients. The models achieve high predictive ability, are well calibrated, have substantial net-benefit across a wide range of conditions, and rely on predictors consistent with the literature. This is a further step on the way to inclusion of ML decision support systems into clinical practice.

Ciprofloxacin is an antibiotic commonly used to treat various infections. Due to the frequent use of ciprofloxacin, bacteria have developed high rates of resistance to it, which means they continue to grow, reducing the effectiveness of treatment. The aim of this study was to develop computer code to predict ciprofloxacin resistance in hospitalized patients. We used data from medical records and tests of whether particular bacteria could be killed by antibiotics from a large hospital in Israel to develop the computer code. The computational model accurately predicted resistance. This model could enable antibiotic treatment to be more appropriately targeted to patients that would benefit from it and reduce the amount of bacteria resistant to ciprofloxacin.

The time-varying association between previous antibiotic use and antibiotic resistance.

OBJECTIVES: The objective of the study was to estimate how the time elapsed from previous antibiotic use is associated with antibiotic resistance. METHODS: Data comprised electronic medical records of all patients in an Israeli hospital who had a positive bacterial culture from 2016 to 2019. These included susceptibility testing results and clinical and demographic data. Mixed-effects time-varying logistic models were fitted to estimate the association between the time elapsed since the last use of aminoglycosides and gentamicin resistance (n = 13 095), cephalosporins and ceftazidime resistance (n = 13 051), and fluoroquinolones and ciprofloxacin resistance (n = 15 364) while adjusting for multiple covariates. RESULTS: For all examined antibiotics, previous antibiotic use had a statistically significant association with resistance (p < 0.001). These associations exhibited a clear decreasing pattern over time, which we present as a flexible function of time. Nonetheless, previous antibiotic use remained a significant risk factor for resistance for at least 180 days when the adjusted ORs were 1.94 (95% CI, 1.40-2.69), 1.33 (95% CI, 1.10-1.61), and 2.25 (95% CI, 1.49-3.41) for gentamicin, ceftazidime, and ciprofloxacin, respectively. DISCUSSION: The association between prior antibiotic use and resistance decreases over time. Commonly used cut-offs for prior antibiotic use can either misclassify patients still at higher risk when too recent or provide a diluted estimate of the effects of antibiotic use on future resistance when too distant. Hence, prior antibiotic use should be considered a time-dependent risk factor for resistance in both epidemiological research and clinical practice.