Browsing by Subject "Bacterial Infections"
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Item Open Access Antibiotic resistance-the need for global solutions.(Lancet Infect Dis, 2013-12) Laxminarayan, Ramanan; Duse, Adriano; Wattal, Chand; Zaidi, Anita KM; Wertheim, Heiman FL; Sumpradit, Nithima; Vlieghe, Erika; Hara, Gabriel Levy; Gould, Ian M; Goossens, Herman; Greko, Christina; So, Anthony D; Bigdeli, Maryam; Tomson, Göran; Woodhouse, Will; Ombaka, Eva; Peralta, Arturo Quizhpe; Qamar, Farah Naz; Mir, Fatima; Kariuki, Sam; Bhutta, Zulfiqar A; Coates, Anthony; Bergstrom, Richard; Wright, Gerard D; Brown, Eric D; Cars, OttoThe causes of antibiotic resistance are complex and include human behaviour at many levels of society; the consequences affect everybody in the world. Similarities with climate change are evident. Many efforts have been made to describe the many different facets of antibiotic resistance and the interventions needed to meet the challenge. However, coordinated action is largely absent, especially at the political level, both nationally and internationally. Antibiotics paved the way for unprecedented medical and societal developments, and are today indispensible in all health systems. Achievements in modern medicine, such as major surgery, organ transplantation, treatment of preterm babies, and cancer chemotherapy, which we today take for granted, would not be possible without access to effective treatment for bacterial infections. Within just a few years, we might be faced with dire setbacks, medically, socially, and economically, unless real and unprecedented global coordinated actions are immediately taken. Here, we describe the global situation of antibiotic resistance, its major causes and consequences, and identify key areas in which action is urgently needed.Item Open Access Challenges in the Diagnosis and Management of Bacterial Lung Infections in Solid Organ Recipients: A Narrative Review.(International journal of molecular sciences, 2020-02) Carugati, Manuela; Morlacchi, Letizia Corinna; Peri, Anna Maria; Alagna, Laura; Rossetti, Valeria; Bandera, Alessandra; Gori, Andrea; Blasi, Francesco; Working Group, IfaltRespiratory infections pose a significant threat to the success of solid organ transplantation, and the diagnosis and management of these infections are challenging. The current narrative review addressed some of these challenges, based on evidence from the literature published in the last 20 years. Specifically, we focused our attention on (i) the obstacles to an etiologic diagnosis of respiratory infections among solid organ transplant recipients, (ii) the management of bacterial respiratory infections in an era characterized by increased antimicrobial resistance, and (iii) the development of antimicrobial stewardship programs dedicated to solid organ transplant recipients.Item Restricted Changing epidemiology of serious bacterial infections in febrile infants without localizing signs.(PLoS One, 2010-08-27) Watt, Kevin; Waddle, Erica; Jhaveri, RaviOBJECTIVE: Historically, management of infants with fever without localizing signs (FWLS) has generated much controversy, with attempts to risk stratify based on several criteria. Advances in medical practice may have altered the epidemiology of serious bacterial infections (SBIs) in this population. We conducted this study to test the hypothesis that the rate of SBIs in this patient population has changed over time. PATIENTS AND METHODS: We performed a retrospective review of all infants meeting FWLS criteria at our institution from 1997-2006. We examined all clinical and outcome data and performed statistical analysis of SBI rates and ampicillin resistance rates. RESULTS: 668 infants met criteria for FWLS. The overall rate of SBIs was 10.8%, with a significant increase from 2002-2006 (52/361, 14.4%) compared to 1997-2001 (20/307, 6.5%) (p = 0.001). This increase was driven by an increase in E. coli urinary tract infections (UTI), particularly in older infants (31-90 days). CONCLUSIONS: We observed a significant increase in E. coli UTI among FWLS infants with high rates of ampicillin resistance. The reasons are likely to be multifactorial, but the results themselves emphasize the need to examine urine in all febrile infants <90 days and consider local resistance patterns when choosing empiric antibiotics.Item Open Access Complications of implantable venous access devices in patients with sickle cell disease.(American journal of hematology, 2011-10) Shah, N; Landi, D; Shah, R; Rothman, J; De Castro, LM; Thornburg, CDImplantable venous access devices (VADs) are used in sickle cell disease (SCD) for patients with poor venous access to facilitate chronic blood transfusions and manage acute complications. We attempted to define the frequency of bloodstream infections (BSI) and thrombosis in adults and children with SCD and VADs. We performed a single-institution, retrospective review of VAD-associated infection and thrombosis in patients with SCD. Thirty-two patients (median age 20 years, range, 1-59) had 86 VADs placed (median, 2.7 VADs per patient, range, 1-7) with a total of 41,292 catheter days (median, 1,376 days; range, 323-3,999). Mean catheter lifespan in adults (691 days ± 123) was not significantly higher than children (614 days ± 154). A total of 66 VAD-associated BSI (1.59 infections per 1,000 catheter days) occurred in 17 of 32 (53%) patients. Children with VADs had fewer BSI (3 of 10; 30%) than adults (14 of 22; 64%, P = 0.08). 24 catheter-associated thromboses (0.49 thromboses per 1,000 catheter days) occurred in 10 of 32 (41%) of patients. Children also had fewer VAD-associated-thrombosis (1 of 10; 10%) than adults (9 of 22; 40%, P = 0.08). In conclusion, the use of VADs in SCD was linked to a significant rate of infection and thrombosis.Item Open Access Cyanoacrylate dressings: are they microbiologically impermeable?(The Journal of hospital infection, 2010-06) Rocos, B; Blom, AW; Bowker, KItem Open Access Discriminating Bacterial and Viral Infection Using a Rapid Host Gene Expression Test.(Critical care medicine, 2021-10) Tsalik, Ephraim L; Henao, Ricardo; Montgomery, Jesse L; Nawrocki, Jeff W; Aydin, Mert; Lydon, Emily C; Ko, Emily R; Petzold, Elizabeth; Nicholson, Bradly P; Cairns, Charles B; Glickman, Seth W; Quackenbush, Eugenia; Kingsmore, Stephen F; Jaehne, Anja K; Rivers, Emanuel P; Langley, Raymond J; Fowler, Vance G; McClain, Micah T; Crisp, Robert J; Ginsburg, Geoffrey S; Burke, Thomas W; Hemmert, Andrew C; Woods, Christopher W; Antibacterial Resistance Leadership GroupObjectives
Host gene expression signatures discriminate bacterial and viral infection but have not been translated to a clinical test platform. This study enrolled an independent cohort of patients to describe and validate a first-in-class host response bacterial/viral test.Design
Subjects were recruited from 2006 to 2016. Enrollment blood samples were collected in an RNA preservative and banked for later testing. The reference standard was an expert panel clinical adjudication, which was blinded to gene expression and procalcitonin results.Setting
Four U.S. emergency departments.Patients
Six-hundred twenty-three subjects with acute respiratory illness or suspected sepsis.Interventions
Forty-five-transcript signature measured on the BioFire FilmArray System (BioFire Diagnostics, Salt Lake City, UT) in ~45 minutes.Measurements and main results
Host response bacterial/viral test performance characteristics were evaluated in 623 participants (mean age 46 yr; 45% male) with bacterial infection, viral infection, coinfection, or noninfectious illness. Performance of the host response bacterial/viral test was compared with procalcitonin. The test provided independent probabilities of bacterial and viral infection in ~45 minutes. In the 213-subject training cohort, the host response bacterial/viral test had an area under the curve for bacterial infection of 0.90 (95% CI, 0.84-0.94) and 0.92 (95% CI, 0.87-0.95) for viral infection. Independent validation in 209 subjects revealed similar performance with an area under the curve of 0.85 (95% CI, 0.78-0.90) for bacterial infection and 0.91 (95% CI, 0.85-0.94) for viral infection. The test had 80.1% (95% CI, 73.7-85.4%) average weighted accuracy for bacterial infection and 86.8% (95% CI, 81.8-90.8%) for viral infection in this validation cohort. This was significantly better than 68.7% (95% CI, 62.4-75.4%) observed for procalcitonin (p < 0.001). An additional cohort of 201 subjects with indeterminate phenotypes (coinfection or microbiology-negative infections) revealed similar performance.Conclusions
The host response bacterial/viral measured using the BioFire System rapidly and accurately discriminated bacterial and viral infection better than procalcitonin, which can help support more appropriate antibiotic use.Item Open Access Etiologies of illness among patients meeting integrated management of adolescent and adult illness district clinician manual criteria for severe infections in northern Tanzania: implications for empiric antimicrobial therapy.(Am J Trop Med Hyg, 2015-02) Rubach, Matthew P; Maro, Venance P; Bartlett, John A; Crump, John AWe describe the laboratory-confirmed etiologies of illness among participants in a hospital-based febrile illness cohort study in northern Tanzania who retrospectively met Integrated Management of Adolescent and Adult Illness District Clinician Manual (IMAI) criteria for septic shock, severe respiratory distress without shock, and severe pneumonia, and compare these etiologies against commonly used antimicrobials, including IMAI recommendations for emergency antibacterials (ceftriaxone or ampicillin plus gentamicin) and IMAI first-line recommendations for severe pneumonia (ceftriaxone and a macrolide). Among 423 participants hospitalized with febrile illness, there were 25 septic shock, 37 severe respiratory distress without shock, and 109 severe pneumonia cases. Ceftriaxone had the highest potential utility of all antimicrobials assessed, with responsive etiologies in 12 (48%) septic shock, 5 (14%) severe respiratory distress without shock, and 19 (17%) severe pneumonia illnesses. For each syndrome 17-27% of participants had etiologic diagnoses that would be non-responsive to ceftriaxone, but responsive to other available antimicrobial regimens including amphotericin for cryptococcosis and histoplasmosis; anti-tuberculosis therapy for bacteremic disseminated tuberculosis; or tetracycline therapy for rickettsioses and Q fever. We conclude that although empiric ceftriaxone is appropriate in our setting, etiologies not explicitly addressed in IMAI guidance for these syndromes, such as cryptococcosis, histoplasmosis, and tetracycline-responsive bacterial infections, were common.Item Open Access Etiology of severe non-malaria febrile illness in Northern Tanzania: a prospective cohort study.(PLoS Negl Trop Dis, 2013) Crump, John A; Morrissey, Anne B; Nicholson, William L; Massung, Robert F; Stoddard, Robyn A; Galloway, Renee L; Ooi, Eng Eong; Maro, Venance P; Saganda, Wilbrod; Kinabo, Grace D; Muiruri, Charles; Bartlett, John AINTRODUCTION: The syndrome of fever is a commonly presenting complaint among persons seeking healthcare in low-resource areas, yet the public health community has not approached fever in a comprehensive manner. In many areas, malaria is over-diagnosed, and patients without malaria have poor outcomes. METHODS AND FINDINGS: We prospectively studied a cohort of 870 pediatric and adult febrile admissions to two hospitals in northern Tanzania over the period of one year using conventional standard diagnostic tests to establish fever etiology. Malaria was the clinical diagnosis for 528 (60.7%), but was the actual cause of fever in only 14 (1.6%). By contrast, bacterial, mycobacterial, and fungal bloodstream infections accounted for 85 (9.8%), 14 (1.6%), and 25 (2.9%) febrile admissions, respectively. Acute bacterial zoonoses were identified among 118 (26.2%) of febrile admissions; 16 (13.6%) had brucellosis, 40 (33.9%) leptospirosis, 24 (20.3%) had Q fever, 36 (30.5%) had spotted fever group rickettsioses, and 2 (1.8%) had typhus group rickettsioses. In addition, 55 (7.9%) participants had a confirmed acute arbovirus infection, all due to chikungunya. No patient had a bacterial zoonosis or an arbovirus infection included in the admission differential diagnosis. CONCLUSIONS: Malaria was uncommon and over-diagnosed, whereas invasive infections were underappreciated. Bacterial zoonoses and arbovirus infections were highly prevalent yet overlooked. An integrated approach to the syndrome of fever in resource-limited areas is needed to improve patient outcomes and to rationally target disease control efforts.Item Open Access Imaging of musculoskeletal bacterial infections by [124I]FIAU-PET/CT.(PLoS One, 2007-10-10) Diaz, Luis A; Foss, Catherine A; Thornton, Katherine; Nimmagadda, Sridhar; Endres, Christopher J; Uzuner, Ovsev; Seyler, Thorsten M; Ulrich, Slif D; Conway, Janet; Bettegowda, Chetan; Agrawal, Nishant; Cheong, Ian; Zhang, Xiaosong; Ladenson, Paul W; Vogelstein, Barry N; Mont, Michael A; Zhou, Shibin; Kinzler, Kenneth W; Vogelstein, Bert; Pomper, Martin GBACKGROUND: Traditional imaging techniques for the localization and monitoring of bacterial infections, although reasonably sensitive, suffer from a lack of specificity. This is particularly true for musculoskeletal infections. Bacteria possess a thymidine kinase (TK) whose substrate specificity is distinct from that of the major human TK. The substrate specificity difference has been exploited to develop a new imaging technique that can detect the presence of viable bacteria. METHODOLOGY/PRINCIPAL FINDINGS: Eight subjects with suspected musculoskeletal infections and one healthy control were studied by a combination of [(124)I]FIAU-positron emission tomography and CT ([(124)I]FIAU-PET/CT). All patients with proven musculoskeletal infections demonstrated positive [(124)I]FIAU-PET/CT signals in the sites of concern at two hours after radiopharmaceutical administration. No adverse reactions with FIAU were observed. CONCLUSIONS/SIGNIFICANCE: [(124)I]FIAU-PET/CT is a promising new method for imaging bacterial infections.Item Open Access Prospective Validation of a Rapid Host Gene Expression Test to Discriminate Bacterial From Viral Respiratory Infection.(JAMA network open, 2022-04) Ko, Emily R; Henao, Ricardo; Frankey, Katherine; Petzold, Elizabeth A; Isner, Pamela D; Jaehne, Anja K; Allen, Nakia; Gardner-Gray, Jayna; Hurst, Gina; Pflaum-Carlson, Jacqueline; Jayaprakash, Namita; Rivers, Emanuel P; Wang, Henry; Ugalde, Irma; Amanullah, Siraj; Mercurio, Laura; Chun, Thomas H; May, Larissa; Hickey, Robert W; Lazarus, Jacob E; Gunaratne, Shauna H; Pallin, Daniel J; Jambaulikar, Guruprasad; Huckins, David S; Ampofo, Krow; Jhaveri, Ravi; Jiang, Yunyun; Komarow, Lauren; Evans, Scott R; Ginsburg, Geoffrey S; Tillekeratne, L Gayani; McClain, Micah T; Burke, Thomas W; Woods, Christopher W; Tsalik, Ephraim L; Antibacterial Resistance Leadership GroupImportance
Bacterial and viral causes of acute respiratory illness (ARI) are difficult to clinically distinguish, resulting in the inappropriate use of antibacterial therapy. The use of a host gene expression-based test that is able to discriminate bacterial from viral infection in less than 1 hour may improve care and antimicrobial stewardship.Objective
To validate the host response bacterial/viral (HR-B/V) test and assess its ability to accurately differentiate bacterial from viral infection among patients with ARI.Design, setting, and participants
This prospective multicenter diagnostic study enrolled 755 children and adults with febrile ARI of 7 or fewer days' duration from 10 US emergency departments. Participants were enrolled from October 3, 2014, to September 1, 2019, followed by additional enrollment of patients with COVID-19 from March 20 to December 3, 2020. Clinical adjudication of enrolled participants identified 616 individuals as having bacterial or viral infection. The primary analysis cohort included 334 participants with high-confidence reference adjudications (based on adjudicator concordance and the presence of an identified pathogen confirmed by microbiological testing). A secondary analysis of the entire cohort of 616 participants included cases with low-confidence reference adjudications (based on adjudicator discordance or the absence of an identified pathogen in microbiological testing). Thirty-three participants with COVID-19 were included post hoc.Interventions
The HR-B/V test quantified the expression of 45 host messenger RNAs in approximately 45 minutes to derive a probability of bacterial infection.Main outcomes and measures
Performance characteristics for the HR-B/V test compared with clinical adjudication were reported as either bacterial or viral infection or categorized into 4 likelihood groups (viral very likely [probability score <0.19], viral likely [probability score of 0.19-0.40], bacterial likely [probability score of 0.41-0.73], and bacterial very likely [probability score >0.73]) and compared with procalcitonin measurement.Results
Among 755 enrolled participants, the median age was 26 years (IQR, 16-52 years); 360 participants (47.7%) were female, and 395 (52.3%) were male. A total of 13 participants (1.7%) were American Indian, 13 (1.7%) were Asian, 368 (48.7%) were Black, 131 (17.4%) were Hispanic, 3 (0.4%) were Native Hawaiian or Pacific Islander, 297 (39.3%) were White, and 60 (7.9%) were of unspecified race and/or ethnicity. In the primary analysis involving 334 participants, the HR-B/V test had sensitivity of 89.8% (95% CI, 77.8%-96.2%), specificity of 82.1% (95% CI, 77.4%-86.6%), and a negative predictive value (NPV) of 97.9% (95% CI, 95.3%-99.1%) for bacterial infection. In comparison, the sensitivity of procalcitonin measurement was 28.6% (95% CI, 16.2%-40.9%; P < .001), the specificity was 87.0% (95% CI, 82.7%-90.7%; P = .006), and the NPV was 87.6% (95% CI, 85.5%-89.5%; P < .001). When stratified into likelihood groups, the HR-B/V test had an NPV of 98.9% (95% CI, 96.1%-100%) for bacterial infection in the viral very likely group and a positive predictive value of 63.4% (95% CI, 47.2%-77.9%) for bacterial infection in the bacterial very likely group. The HR-B/V test correctly identified 30 of 33 participants (90.9%) with acute COVID-19 as having a viral infection.Conclusions and relevance
In this study, the HR-B/V test accurately discriminated bacterial from viral infection among patients with febrile ARI and was superior to procalcitonin measurement. The findings suggest that an accurate point-of-need host response test with high NPV may offer an opportunity to improve antibiotic stewardship and patient outcomes.Item Open Access Systematic comparison of published host gene expression signatures for bacterial/viral discrimination.(Genome medicine, 2022-02-21) Bodkin, Nicholas; Ross, Melissa; McClain, Micah T; Ko, Emily R; Woods, Christopher W; Ginsburg, Geoffrey S; Henao, Ricardo; Tsalik, Ephraim LBackground
Measuring host gene expression is a promising diagnostic strategy to discriminate bacterial and viral infections. Multiple signatures of varying size, complexity, and target populations have been described. However, there is little information to indicate how the performance of various published signatures compare to one another.Methods
This systematic comparison of host gene expression signatures evaluated the performance of 28 signatures, validating them in 4589 subjects from 51 publicly available datasets. Thirteen COVID-specific datasets with 1416 subjects were included in a separate analysis. Individual signature performance was evaluated using the area under the receiving operating characteristic curve (AUC) value. Overall signature performance was evaluated using median AUCs and accuracies.Results
Signature performance varied widely, with median AUCs ranging from 0.55 to 0.96 for bacterial classification and 0.69-0.97 for viral classification. Signature size varied (1-398 genes), with smaller signatures generally performing more poorly (P < 0.04). Viral infection was easier to diagnose than bacterial infection (84% vs. 79% overall accuracy, respectively; P < .001). Host gene expression classifiers performed more poorly in some pediatric populations (3 months-1 year and 2-11 years) compared to the adult population for both bacterial infection (73% and 70% vs. 82%, respectively; P < .001) and viral infection (80% and 79% vs. 88%, respectively; P < .001). We did not observe classification differences based on illness severity as defined by ICU admission for bacterial or viral infections. The median AUC across all signatures for COVID-19 classification was 0.80 compared to 0.83 for viral classification in the same datasets.Conclusions
In this systematic comparison of 28 host gene expression signatures, we observed differences based on a signature's size and characteristics of the validation population, including age and infection type. However, populations used for signature discovery did not impact performance, underscoring the redundancy among many of these signatures. Furthermore, differential performance in specific populations may only be observable through this type of large-scale validation.Item Open Access Validation of a Host Gene Expression Test for Bacterial/Viral Discrimination in Immunocompromised Hosts.(Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2021-08) Mahle, Rachael E; Suchindran, Sunil; Henao, Ricardo; Steinbrink, Julie M; Burke, Thomas W; McClain, Micah T; Ginsburg, Geoffrey S; Woods, Christopher W; Tsalik, Ephraim LBackground
Host gene expression has emerged as a complementary strategy to pathogen detection tests for the discrimination of bacterial and viral infection. The impact of immunocompromise on host-response tests remains unknown. We evaluated a host-response test discriminating bacterial, viral, and noninfectious conditions in immunocompromised subjects.Methods
An 81-gene signature was measured using real-time-polymerase chain reaction in subjects with immunocompromise (chemotherapy, solid-organ transplant, immunomodulatory agents, AIDS) with bacterial infection, viral infection, or noninfectious illness. A regularized logistic regression model trained in immunocompetent subjects was used to estimate the likelihood of each class in immunocompromised subjects.Results
Accuracy in the 136-subject immunocompetent training cohort was 84.6% for bacterial versus nonbacterial discrimination and 80.8% for viral versus nonviral discrimination. Model validation in 134 immunocompromised subjects showed overall accuracy of 73.9% for bacterial infection (P = .04 relative to immunocompetent subjects) and 75.4% for viral infection (P = .30). A scheme reporting results by quartile improved test utility. The highest probability quartile ruled-in bacterial and viral infection with 91.4% and 84.0% specificity, respectively. The lowest probability quartile ruled-out infection with 90.1% and 96.4% sensitivity for bacterial and viral infection, respectively. Performance was independent of the type or number of immunocompromising conditions.Conclusions
A host gene expression test discriminated bacterial, viral, and noninfectious etiologies at a lower overall accuracy in immunocompromised patients compared with immunocompetent patients, although this difference was only significant for bacterial infection classification. With modified interpretive criteria, a host-response strategy may offer clinically useful diagnostic information for patients with immunocompromise.Item Open Access WHO guidelines for antimicrobial treatment in children admitted to hospital in an area of intense Plasmodium falciparum transmission: prospective study.(BMJ, 2010-03-30) Nadjm, Behzad; Amos, Ben; Mtove, George; Ostermann, Jan; Chonya, Semkini; Wangai, Hannah; Kimera, Juma; Msuya, Walii; Mtei, Frank; Dekker, Denise; Malahiyo, Rajabu; Olomi, Raimos; Crump, John A; Whitty, Christopher JM; Reyburn, HughOBJECTIVES: To assess the performance of WHO's "Guidelines for care at the first-referral level in developing countries" in an area of intense malaria transmission and identify bacterial infections in children with and without malaria. DESIGN: Prospective study. SETTING: District hospital in Muheza, northeast Tanzania. PARTICIPANTS: Children aged 2 months to 13 years admitted to hospital for febrile illness. MAIN OUTCOME MEASURES: Sensitivity and specificity of WHO guidelines in diagnosing invasive bacterial disease; susceptibility of isolated organisms to recommended antimicrobials. RESULTS: Over one year, 3639 children were enrolled and 184 (5.1%) died; 2195 (60.3%) were blood slide positive for Plasmodium falciparum, 341 (9.4%) had invasive bacterial disease, and 142 (3.9%) were seropositive for HIV. The prevalence of invasive bacterial disease was lower in slide positive children (100/2195, 4.6%) than in slide negative children (241/1444, 16.7%). Non-typhi Salmonella was the most frequently isolated organism (52/100 (52%) of organisms in slide positive children and 108/241 (45%) in slide negative children). Mortality among children with invasive bacterial disease was significantly higher (58/341, 17%) than in children without invasive bacterial disease (126/3298, 3.8%) (P<0.001), and this was true regardless of the presence of P falciparum parasitaemia. The sensitivity and specificity of WHO criteria in identifying invasive bacterial disease in slide positive children were 60.0% (95% confidence interval 58.0% to 62.1%) and 53.5% (51.4% to 55.6%), compared with 70.5% (68.2% to 72.9%) and 48.1% (45.6% to 50.7%) in slide negative children. In children with WHO criteria for invasive bacterial disease, only 99/211(47%) of isolated organisms were susceptible to the first recommended antimicrobial agent. CONCLUSIONS: In an area exposed to high transmission of malaria, current WHO guidelines failed to identify almost a third of children with invasive bacterial disease, and more than half of the organisms isolated were not susceptible to currently recommended antimicrobials. Improved diagnosis and treatment of invasive bacterial disease are needed to reduce childhood mortality.Item Open Access Zoonotic causes of febrile illness in malaria endemic countries: a systematic review.(The Lancet. Infectious diseases, 2020-02) Halliday, Jo EB; Carugati, Manuela; Snavely, Michael E; Allan, Kathryn J; Beamesderfer, Julia; Ladbury, Georgia AF; Hoyle, Deborah V; Holland, Paul; Crump, John A; Cleaveland, Sarah; Rubach, Matthew PFever is one of the most common reasons for seeking health care globally and most human pathogens are zoonotic. We conducted a systematic review to describe the occurrence and distribution of zoonotic causes of human febrile illness reported in malaria endemic countries. We included data from 53 (48·2%) of 110 malaria endemic countries and 244 articles that described diagnosis of 30 zoonoses in febrile people. The majority (17) of zoonoses were bacterial, with nine viruses, three protozoa, and one helminth also identified. Leptospira species and non-typhoidal salmonella serovars were the most frequently reported pathogens. Despite evidence of profound data gaps, this Review reveals widespread distribution of multiple zoonoses that cause febrile illness. Greater understanding of the epidemiology of zoonoses in different settings is needed to improve awareness about these pathogens and the management of febrile illness.