Does adjunctive clindamycin have a role in Staphylococcus aureus bacteremia? A protocol for the adjunctive treatment domain of the S. aureus Network Adaptive Platform (SNAP) randomized controlled trial.

INTRODUCTION: The use of adjunctive antibiotics directed against exotoxin production in Staphylococcus aureus bacteremia (SAB) is widespread, and is recommended in many guidelines, but there is limited evidence underpinning this. Existing guidelines are based on the theoretical premise of toxin suppression, as many strains of S. aureus produce toxins such as leucocidins (e.g., Panton-Valentine Leucocidin (PVL), toxic shock syndrome toxin 1 (TSST-1), exfoliative toxins, and various enterotoxins). Many clinicians therefore believe that limiting exotoxin production release by S. aureus could reduce its virulence and improve clinical outcomes. Clindamycin, a protein synthesis inhibitor antibiotic, is commonly used for this purpose. We report the domain-specific protocol, embedded in a large adaptive, platform trial, seeking to definitively answer this question. METHODS AND ANALYSIS: The Staphylococcus aureus Network Adaptive Platform (SNAP) trial is a pragmatic, randomized, multi-center adaptive platform trial that aims to compare different SAB therapies, simultaneously, for 90-day mortality. The adjunctive treatment domain aims to test the effectiveness of adjunctive antibiotics, initially comparing clindamycin to no adjunctive antibiotic, but future adaptations may include other agents. Individuals will be randomized to receive either five days of adjunctive clindamycin (or lincomycin) or no adjunctive antibiotic therapy alongside standard of care antibiotics. Most participants with SAB (within 72hr of index blood culture and not contraindicated) will be eligible to participate in this domain. Prespecified analyses are defined in the statistical appendix to the core protocol and domain-specific secondary analyses will be adjusted for resistance to clindamycin, disease phenotype (complicated or uncomplicated SAB) and PVL-positive isolate.

Genomic investigation and clinical correlates of the in vitro ß-lactam: NaHCO3 responsiveness phenotype among methicillin-resistant Staphylococcus aureus isolates from a randomized clinical trial.

NaHCO3 responsiveness is a novel phenotype where some methicillin-resistant Staphylococcus aureus (MRSA) isolates exhibit significantly lower minimal inhibitory concentrations (MIC) to oxacillin and/or cefazolin in the presence of NaHCO3. NaHCO3 responsiveness correlated with treatment response to ß-lactams in an endocarditis animal model. We investigated whether treatment of NaHCO3-responsive strains with ß-lactams was associated with faster clearance of bacteremia. The CAMERA2 trial (Combination Antibiotics for Methicillin-Resistant Staphylococcus aureus) randomly assigned participants with MRSA bloodstream infections to standard therapy, or to standard therapy plus an anti-staphylococcal ß-lactam (combination therapy). For 117 CAMERA2 MRSA isolates, we determined by broth microdilution the MIC of cefazolin and oxacillin, with and without 44 mM of NaHCO3. Isolates exhibiting ≥4-fold decrease in the MIC to cefazolin or oxacillin in the presence of NaHCO3 were considered "NaHCO3-responsive" to that agent. We compared the rate of persistent bacteremia among participants who had infections caused by NaHCO3-responsive and non-responsive strains, and that were assigned to combination treatment with a ß-lactam. Thirty-one percent (36/117) and 25% (21/85) of MRSA isolates were NaHCO3-responsive to cefazolin and oxacillin, respectively. The NaHCO3-responsive phenotype was significantly associated with sequence type 93, SCCmec type IVa, and mecA alleles with substitutions in positions -7 and -38 in the regulatory region. Among participants treated with a ß-lactam, there was no association between the NaHCO3-responsive phenotype and persistent bacteremia (cefazolin, P = 0.82; oxacillin, P = 0.81). In patients from a randomized clinical trial with MRSA bloodstream infection, isolates with an in vitro ß-lactam-NaHCO3-responsive phenotype were associated with distinctive genetic signatures, but not with a shorter duration of bacteremia among those treated with a ß-lactam.

Immune reconstitution inflammatory syndrome (IRIS) in a patient with neuro pulmonary nocardiosis following hematopoietic cells transplantation (HCT).

Immune reconstitution inflammatory syndrome (IRIS) is increasingly reported in various HIV negative patients with immunosuppression, but the relationship with hematopoietic cell transplantation (HCT) is not well defined. We report a case of IRIS in a patient infected with pulmonary and CNS Nocardiosis following HCT due to primary myelofibrosis.

Tofacitinib reduced death or respiratory failure at 28 d in patients hospitalized with COVID-19 pneumonia.

SOURCE CITATION: Guimarães PO, Quirk D, Furtado RH, et al. Tofacitinib in patients hospitalized with Covid-19 pneumonia. N Engl J Med. 2021;385:406-15. 34133856.

Spotted Fever Group Rickettsioses in Israel, 2010-2019.

In a multicenter, nationwide, retrospective study of patients hospitalized with spotted fever group rickettsiosis in Israel during 2010-2019, we identified 42 cases, of which 36 were autochthonous. The most prevalent species was the Rickettsia conorii Israeli tick typhus strain (n = 33, 79%); infection with this species necessitated intensive care for 52% of patients and was associated with a 30% fatality rate. A history of tick bite was rare, found for only 5% of patients; eschar was found in 12%; and leukocytosis was more common than leukopenia. Most (72%) patients resided along the Mediterranean shoreline. For 3 patients, a new Rickettsia variant was identified and had been acquired in eastern, mountainous parts of Israel. One patient had prolonged fever before admission and clinical signs resembling tickborne lymphadenopathy. Our findings suggest that a broad range of Rickettsia species cause spotted fever group rickettsiosis in Israel.

Plasmodium malariae in Israeli Travelers: A Nationwide Study.

BACKGROUND: Little is known about Plasmodium malariae, a relatively rare cause of malaria in returned travelers. Recently, polymerase chain reaction (PCR) use for malaria diagnosis has enhanced specificity of P. malariae detection. The study objective was to describe the unique aspects of P. malariae diagnosis and clinical course in travelers. METHODS: Malaria is a reportable disease in Israel. All PCR-proven P. malariae monoinfections in Israeli travelers between January 2008 and January 2017 were retrieved from the Ministry of Health Reference Parasitology Laboratory. Data regarding method and timing of diagnosis, clinical characteristics, and laboratory testing were collected from patient charts. RESULTS: Eighteen patients with P. malariae were included. All cases were acquired in Africa. During the study period, the relative proportion of P. malariae increased (2%-10% of all malaria cases). Malaria was identified by blood smear in 10 of 18 patients (56%) on admission, and by rapid antigen test in 5 of 18 (29%) patients only, while P. malariae speciation was correctly identified by smear in 2 of 18 (11%) patients. Though all patients reported fever, only 4 of 18 (22%) described a quartan fever course. In 7 of 18 (39%) patients, malaria was contracted despite prophylactic treatment. Five patients had prolonged prepatent periods (median, 55 days), all of whom received prior prophylaxis. CONCLUSIONS: The relative proportion of P. malariae is on the rise. Diagnosis in routine clinical settings is inadequate due to the low sensitivity and specificity of blood smears. PCR should be considered when clinical suspicion is high. Prophylaxis failure, which caused delayed clinical presentation, was documented.

Combination of Antistaphylococcal ß-Lactam With Standard Therapy Compared to Standard Therapy Alone for the Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia: A Post Hoc Analysis of the CAMERA2 Trial Using a Desirability of Outcome Ranking Approach.

Background: Desirability of outcome ranking (DOOR) is an emerging approach to clinical trial outcome measurement using an ordinal scale to incorporate efficacy and safety endpoints. Methods: We applied a previously validated DOOR endpoint to a cohort of CAMERA2 trial participants with methicillin-resistant Staphylococcus aureus bacteremia (MRSAB). Participants were randomly assigned to standard therapy, or to standard therapy plus an antistaphylococcal ß-lactam (combination therapy). Each participant was assigned a DOOR category, within which they were further ranked according to their hospital length of stay (LOS) and duration of intravenous antibiotic treatment. We calculated the probability and the generalized odds ratio of participants receiving combination therapy having worse outcomes than those receiving standard therapy. Results: Participants assigned combination therapy had a 54.5% (95% confidence interval [CI], 48.9%-60.1%; P = .11) probability and a 1.2-fold odds (95% CI, .95-1.50; P = .12) of having a worse outcome than participants on standard therapy. When further ranked according to LOS and duration of antibiotic treatment, participants in the combination group had a 55.6% (95% CI, 49.5%-61.7%) and 55.3% (95% CI, 49.2%-61.4%) probability of having a worse outcome than participants in the standard treatment group, respectively. Conclusions: When considering both efficacy and safety, treatment of MRSAB with a combination of standard therapy and a ß-lactam likely results in a worse clinical outcome than standard therapy. However, a small benefit of combination therapy cannot be excluded. Most likely the toxicity of combination therapy outweighed any benefit from faster clearance of bacteremia.

Unlocking the DOOR-how to design, apply, analyse, and interpret desirability of outcome ranking endpoints in infectious diseases clinical trials.

BACKGROUND: Desirability of outcome ranking (DOOR) outcomes, with or without response adjusted for antibiotic risk (RADAR), are increasingly used in infectious diseases randomized clinical trials (RCTs), with the advantage of being able to combine multiple clinical outcomes and antibiotic duration in a single metric. However, it remains poorly understood, and there is considerable heterogeneity in its use. OBJECTIVES: In this scoping review, we explain how to design, use and analyse a DOOR endpoint, and highlight several pitfalls and potential improvements that can be made to DOOR/RADAR. SOURCES: The Ovid MEDLINE database was searched for terms related to DOOR in English-language articles published up to 31 December 2022. Articles discussing DOOR methodology and/or reporting clinical trial analyses (as either primary, secondary, or post-hoc analysis) using a DOOR outcome were included. CONTENT: Seventeen articles were included in the final review, of which nine reported DOOR analyses of 12 RCTs. Eight articles discussed DOOR methodology. We synthesised information from these articles and discuss (a) how to develop a DOOR scale, (b) how to conduct a DOOR/RADAR analysis, (c) use in clinical trials, (d) use of alternative tiebreakers apart from RADAR, (e) partial credit analyses, and (f) criticisms and pitfalls of DOOR/RADAR. IMPLICATIONS: DOOR is an important innovation for RCTs in infectious diseases. We highlight potential areas of methodological improvement for future research. There remains considerable heterogeneity in its implementation, and further collaborative efforts, with a more diverse range of perspectives, should be made to develop consensus scales for use in prospective studies.

Host test based on tumor necrosis factor-related apoptosis-inducing ligand, interferon gamma-induced protein-10 and C-reactive protein for differentiating bacterial and viral respiratory tract infections in adults: diagnostic accuracy study.

OBJECTIVES: To assess the performance of a test (called BV), integrating the blood levels of three immune proteins into a score, to differentiate bacterial from viral infection among adults with suspected lower respiratory tract infection (LRTI). METHODS: Prospective diagnostic accuracy study, enrolling febrile adults >18 years with LRTI signs or symptoms for less than 7 days presenting to several hospitals' emergency departments in Israel. The main exclusion criterion was immunodeficiency. Reference standard diagnosis (bacterial/viral/indeterminate) was based on three experts independently reviewing comprehensive patient data including follow-up data. BV generated three results: viral infection or other nonbacterial condition (0 ≤ score < 35), equivocal (35 ≤ score ≤ 65) and bacterial infection including co-infection (65 < score ≤ 100). BV performance was assessed against the reference standard with indeterminate reference standard and equivocal BV cases removed. RESULTS: Of 490 enrolled patients, 415 met eligibility criteria (median age 56 years, interquartile range 35). The reference standard classified 104 patients as bacterial, 210 as viral and 101 as indeterminate. BV was equivocal in 9.6% (30/314). Excluding indeterminate reference standard diagnoses and equivocal BV results, BV's sensitivity for bacterial infection was 98.1% (101/103; 95% confidence interval 95.4-100), specificity 88.4% (160/181; 83.7-93.1) and negative predictive value 98.8% (160/162; 97.1-100). DISCUSSION: BV exhibited high diagnostic performance for febrile adults with suspected LRTI among patients with reference standard diagnoses of bacterial or viral LRTI.

How I manage a patient with MRSA bacteraemia.

BACKGROUND: Staphylococcus aureus bloodstream infections are common and associated with a high mortality of 15-25%. Methicillin-resistant S. aureus (MRSA) bloodstream infection accounts for 10-40% of cases, and has an even higher mortality. Despite being the 'bread and butter' of clinical infectious diseases practice, robust evidence to guide optimal management is often lacking and there is wide variation in practice. OBJECTIVES: To provide a real-world example of a case of MRSA bacteraemia and the thought processes of the authors as key management decision points are reached. SOURCES: The discussion is based on recent literature searches of relevant topics. In making recommendations, randomized clinical trial data have been prioritized and highlighted, and where these are not available recommendations are based on the experience and opinions of the authors. CONTENT: For a patient with MRSA bacteraemia and a primary bone and joint infection the following points are discussed: empirical antibiotic choice for suspected S. aureus bacteraemia; directed antibiotic choice for MRSA; monitoring and dosing of vancomycin; the role of combination therapy when bacteraemia is persistent; and the duration of therapy and role of switching to oral antibiotics. IMPLICATIONS: While broad principles of aggressive source control and appropriate choice and duration of antibiotics are important, the heterogeneity of S. aureus bacteraemia means that a tailored rather than algorithmic approach to management is often required. Further randomized controlled trials are needed to strengthen the evidence base for the management of MRSA bacteraemia.

Immunogenicity trends 1 and 3 months after second BNT162B2 vaccination among healthcare workers in Israel.

OBJECTIVES: We evaluated the antibody response to the BNT162B2 vaccine among healthcare workers (HCWs) to identify factors associated with decreased immunogenicity. METHODS: This prospective cohort study included consenting HCWs who completed a questionnaire regarding background illnesses, medications, and post-vaccination allergic reactions or rash. All HCWs were tested for anti-spike antibodies (LIAISON SARS-CoV-2 S1/S2 IgG assay) 1 and 3 months after the second vaccine dose. A multivariate mixed linear model was adjusted to participants' data and fit to predict antibody levels after the second BNT162B2 vaccine dose, based on antibody levels at 1 month and the slope between 3 months and 1 month. Multivariate analyses identified factors associated with lower antibody levels. RESULTS: In total 1506 HCWs were tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies. Older age was associated with lower mean antibody levels (-1.22 AU/mL, p < 0.001, 95%CI -1.43 to -1.01). In addition, male sex (-22.16 AU/mL, p < 0.001, 95%CI -27.93 to -16.39), underlying condition (-10.86 AU/mL, p 0.007, 95%CI -18.81 to -2.91) and immunosuppressive treatment (-28.57 AU/mL, p 0.002, 95%CI -46.85 to -10.29) were associated with significantly lower mean antibody levels. Allergic reactions after vaccine administration or peri-vaccination glucocorticosteroid treatment were not correlated with antibody levels. CONCLUSIONS: Most HCWs had measurable antibodies at 3 months. Risk factors for lower antibody levels were older age, male sex, underlying condition, and immunosuppressive treatment. These factors may be considered when planning booster doses during vaccine shortages.

In vivo fitness of carbapenem-resistant Acinetobacter baumannii strains in murine infection is associated with treatment failure in human infections.

OBJECTIVES: Mortality among patients with carbapenem-resistant Acinetobacter baumannii (CRAB) infections varies between studies. We examined whether in vivo fitness of CRAB strains is associated with clinical outcomes in patients with CRAB infections. METHODS: Isolates were collected from patients enrolled in the AIDA trial with hospital-acquired pneumonia, bloodstream infections and/or urinary tract infections caused by CRAB. The primary outcome was 14-day clinical failure, defined as failure to meet all criteria: alive; haemodynamically stable; improved or stable Sequential Organ Failure Assessment (SOFA) score; improved or stable oxygenation; and microbiological cure of bacteraemia. The secondary outcome was 14-day mortality. We tested in vivo growth using a neutropenic murine thigh infection model. Fitness was defined based on the CFU count 24 hours after injection of an inoculum of 105 CFU. We used mixed-effects logistic regression to test the association between fitness and the two outcomes. RESULTS: The sample included 266 patients; 215 (80.8%) experienced clinical failure. CRAB fitness ranged from 5.23 to 10.08 log CFU/g. The odds of clinical failure increased by 62% for every 1-log CFU/g increase in fitness (OR 1.62, 95% CI 1.04-2.52). After adjusting for age, Charlson score, SOFA score and acquisition in the intensive care unit, fitness remained significant (adjusted OR 1.63, 95% CI 1.03-2.59). CRAB fitness had a similar effect on 14-day mortailty, although the association was not statistically significant (OR 1.56, 95% CI 0.95-2.57). It became significant after adjusting for age, Charlson score, SOFA score and recent surgery (adjusted OR 1.88, 95% CI 1.09-3.25). CONCLUSIONS: In vivo CRAB fitness was associated with clinical failure in patients with CRAB infection.

The Impact of Nosocomial Bloodstream Infections on Mortality: A Retrospective Propensity-Matched Cohort Study.

BACKGROUND: The mortality toll of nosocomial infections drives infection control efforts. We aimed to assess the contemporary mortality associated with nosocomial bloodstream infections (BSIs). METHODS: Retrospective propensity-matched cohort study conducted in 1 hospital in Israel between January 2010-December 2020. Adults >18 years old with nosocomial BSI were matched to controls using nearest neighbor matching of the propensity score for nosocomial BSI. We assessed all-cause mortality at 30 days, 90 days, and survival up to 1 year starting on the BSI day or matched hospital-day among controls; and the functional and cognitive change between admission and discharge using the Norton score among patients discharged alive. Residual differences between matched groups were addressed through Cox regression for 1-year survival. RESULTS: A total of 1361 patients with nosocomial BSI were matched to 1361 patients without BSI. Matching achieved similar patient groups, with small differences remaining in the Charlson score and albumin and hemoglobin levels. At 90 days, mortality was higher among patients with BSI (odds ratio [OR], 3.36 [95% confidence interval {CI}, 2.77-4.07]). ORs were higher when the BSI was caused by multidrug-resistant bacteria (OR, 5.22 [95% CI, 3.3-8.26]) and with inappropriate empirical antibiotics in the first 24 hours (OR, 3.85 [95% CI, 2.99-4.94]). Following full adjustment, the hazard ratio for 1-year mortality with nosocomial BSI was 2.28 (95% CI, 1.98-2.62). The Norton score declined more frequently among patients with BSI (OR, 2.27 [95% CI, 1.81-2.86]). CONCLUSIONS: Nosocomial BSIs incur a highly significant mortality toll, particularly when caused by multidrug-resistant bacteria. Among hospital survivors, BSIs are associated with functional decline.

ß-lactam antibiotics vs. vancomycin for the early treatment of enterococcal bacteraemia: A retrospective cohort study.

BACKGROUND: The efficacy of vancomycin compared with ampicillin for enterococcal infections is unknown. This study aimed to compare their efficacy among patients with enterococcal bacteraemia. METHODS: Retrospective cohort study including adults aged >16 years with enterococcal bacteraemia, treated with ß-lactam antibiotics active against Enterococcus spp. or vancomycin. Treatment classification was based on the first antibiotic used for >4 days in the 7 days after blood culture collection. Subgroup analyses for patients with penicillin-susceptible enterococcal bacteraemia and patients with monomicrobial penicillin-susceptible enterococcal bacteraemia were performed. The dependent variable was 30-day all-cause mortality. The propensity score (PS) for vancomycin treatment was calculated. Univariate and multi-variate analyses adjusted for PS were performed. RESULTS: In total, 516 patients with enterococcal bacteraemia were included. Mortality was similar for patients treated with ß-lactams (123/315, 39%) and vancomycin (82/201, 40.8%). Independent factors significantly associated with mortality included healthcare-associated or hospital-acquired infection, age, female sex, Charlson Comorbidity Index, dialysis, SOFA score and low albumin. After adjustment for these factors and PS, the odds ratio (OR) for death in patients treated with vancomycin was 0.95 [95% confidence interval (CI) 0.56-1.59]. Results were similar among patients with penicillin-susceptible enterococcal bacteraemia and patients with monomicrobial penicillin-susceptible enterococcal bacteraemia (n=237, adjusted OR 0.59, 95% CI 0.25-1.43). CONCLUSION: No difference in mortality was observed following treatment with a ß-lactam or vancomycin among patients with enterococcal bacteraemia. Vancomycin is not recommended for the treatment of penicillin-susceptible enterococcal infections; however, when needed, it is not inferior to ß-lactams and the addition of a ß-lactam is not necessary.

Standard pre-travel consultation versus shorter consultation combined with smartphone support: a randomized controlled trial.

Immediate and long-term recalls of a pre-travel consultation are suboptimal. We aimed to assess the role of online consultation for travellers.We randomized travellers into two study groups. In the intervention arm, each traveller was given a short pre-travel consultation of 8-12 minutes, combined with the option of smartphone support before and during the trip. In the control arm, each traveller was given a standard length pre-travel consultation of 18-22 minutes. Endpoints included knowledge about potential risks, travellers' satisfaction, time allocated to each traveller and clinical events.We enrolled 75 patients in the intervention group and 74 patients in the control group. Online consultation was used 33 times, by 24 travellers, both before and during the trip. Important health hazards that were addressed included animal and insect bites (8), treatment of diarrhea (4), malaria prophylaxis (2) and altitude sickness prophylaxis (5). Other consultations consisted mainly of reassurances of worried travellers and provision of data. Knowledge about travel-related risks was higher in the control group before travelling (8.86 ± 1.12 vs 8.34 ± 1.32, P = 0.014), and there was a trend towards higher levels of knowledge also during the trip (8.29 ± 1.35 vs 7.89 ± 1.39, P = 0.06). Travellers' satisfaction before and during the trip was similar in both groups: median 10 (10, 10) in both groups before traveling (P = 0.51) and median 9 (8, 10) in both groups during the trip (P = 0.71). In the intervention group, time allocated to each traveller was <12 minutes. There were no differences in the number of clinical events (P > 0.2 for all comparisons).Online WhatsApp support addressed several important travel-related hazards but, when combined with a shortened pre-travel consultation, was associated with a lower level of knowledge about health risks. Therefore, such smartphone support should augment, rather than replace, pre-travel consultation.

Pocket-size point-of-care ultrasound in rural Uganda - A unique opportunity "to see", where no imaging facilities are available.

BACKGROUND: In the developing world, only a small minority of patients have access to radiological services. Over the past decade, technological developments of ultrasound equipment have led to the emergence of point-of-care ultrasonography (POCUS), which is widely used by healthcare professionals of nearly all specialties. We hypothesized that physicians with only basic POCUS training, but with telemedicine support, can use POCUS successfully in rural hospitals in sub-Saharan Africa. METHOD: During a 14-day voluntary clinical work session in a rural hospital in central Uganda, bedside ultrasound scans were performed by use of a pocket-size portable machine by a physician who underwent a five-day training period. All the POCUS studies were reviewed by radiologists and cardiologists abroad with the use of telemedicine. RESULTS: During the study period, 30% of patients received a POCUS-augmented physical examination. 16 out of 23 patients (70%) had positive findings; in 20 of them (87%), the management was changed. The technique was successfully used on trauma casualties, patients suffering from shock, patients with cardiorespiratory symptoms, and patients undergoing invasive procedures. CONCLUSIONS: In a very resource-limited environment, POCUS conducted by basically trained primary care physicians with telemedicine support is a powerful diagnostic tool in a variety of medical conditions.

The epidemiology of typhoid fever in the Dhulikhel area, Nepal: A prospective cohort study.

INTRODUCTION: Typhoid fever (TF) continues to cause considerable morbidity and mortality in Nepal, but only limited epidemiologic data is available about TF outside Kathmandu. METHODS: As part of an interventional trial, we performed a prospective cohort study of bacteremic TF patients in Dhulikhel Hospital between October 2012 and October 2014. Demographic, epidemiological, clinical, and microbiologic data were recorded. RESULTS: 116 bacteremic typhoid patients were included in the study. Most were young, healthy, adults (mean age 27.9±12 years), 41.4% of whom were female. More than 70% of patients were employed in non-manual services or were university students. Salmonella Typhi accounted for 64/115 (55.7%) of all isolates, while Salmonella Paratyphi accounted for 51/115 (44.3%), of which 42 were Paratyphi A and 9 Paratyphi B. A significant proportion of TF cases occurred also during the dry season (48/116, 41.6%). The clinical presentation of Salmonella Typhi and Paratyphi infections was similar, except for a greater proportion of arthralgia in patients with Salmonella Typhi. Most Salmonella Typhi and Paratyphi isolates were resistant to nalidixic acid and susceptible to older antibiotics. One Salmonella Paratyphi isolate was resistant to ceftriaxone. CONCLUSIONS: TF remains common in the Dhulikhel area, even among those with a high level of education. Public health measures aimed at reducing the incidence of TF in the Dhulikhel area are warranted. The relative burden of TF caused by Salmonella Paratyphi is rising; a vaccine with activity against Salmonella Paratyphi is needed. Since Salmonella Paratyphi B was more prevalent in this cohort than in large cohorts of patients from Kathmandu, it is likely that there are significant regional variations in the epidemiology of TF outside Kathmandu.