Identification of Francisella tularensis in ascites in the context of typhoidal tularaemia.

Tularaemia is a highly infectious, zoonotic disease caused by Francisella tularensis, which has become increasingly prevalent over the past decade. Depending on the route of infection, different clinical manifestations can be observed. We report a case of typhoidal tularaemia presenting as a febrile illness with gastrointestinal symptoms in a patient in her mid-80s. During the acute illness phase and in the context of alcohol-related liver cirrhosis, the patient developed progressive ascites. During paracentesis, spontaneous bacterial peritonitis was consistently reported. Blood culture revealed Gram-negative bacilli identified as F. tularensis upon microscopic examination. Immediate clinical improvement was observed after adaptation to a pathogen-specific antibiotic regime. Typhoidal tularaemia presents general, non-specific symptoms without the local manifestations seen in other forms of the disease, thus representing a diagnostic challenge. In the case of protracted fever and if the epidemiological context as well as possible exposure are compatible, tularaemia should be considered in the differential diagnosis.

Systematic Review: Clinical Features, Antimicrobial Treatment, and Outcomes of Human Tularemia, 1993-2023.

BACKGROUND: Francisella tularensis, the causative agent of tularemia, is endemic throughout the Northern Hemisphere and requires as few as 10 organisms to cause disease, making this potential bioterrorism agent one of the most infectious bacterial pathogens known. Aminoglycosides, tetracyclines, and, more recently, fluoroquinolones are used for treatment of tularemia; however, data on the relative effectiveness of these and other antimicrobial classes are limited. METHODS: Nine databases, including Medline, Global Health, and Embase, were systematically searched for articles containing terms related to tularemia. Articles with case-level data on tularemia diagnosis, antimicrobial treatment, and patient outcome were included. Patient demographics, clinical findings, antimicrobial administration, and outcome (eg, intubation, fatality) were abstracted using a standardized form. RESULTS: Of the 8878 publications identified and screened, 410 articles describing 870 cases from 1993 to 2023 met inclusion criteria. Cases were reported from 35 countries; more than half were from the United States, Turkey, or Spain. The most common clinical forms were ulceroglandular, oropharyngeal, glandular, and pneumonic disease. Among patients treated with aminoglycosides (n = 452 [52%]), fluoroquinolones (n = 339 [39%]), or tetracyclines (n = 419 [48%]), the fatality rate was 0.7%, 0.9%, and 1.2%, respectively. Patients with pneumonic disease who received ciprofloxacin had no fatalities and the lowest rates of thoracentesis/pleural effusion drainage and intubation compared to those who received aminoglycosides and tetracyclines. CONCLUSIONS: Aminoglycosides, fluoroquinolones, and tetracyclines are effective antimicrobials for treatment of tularemia, regardless of clinical manifestation. For pneumonic disease specifically, ciprofloxacin may have slight advantages compared to other antimicrobials.

Efficacy of Doxycycline and Ciprofloxacin for Treatment of Pneumonic Tularemia in Cynomolgus Macaques.

BACKGROUND: The incidence of pneumonic tularemia is very low; therefore, it is not feasible to conduct clinical efficacy testing of tularemia medical countermeasures (MCMs) in humans. The US Food and Drug Administration's Animal Model Qualification Program under the Drug Development Tools Program is a regulatory pathway for animal models used in MCM efficacy testing and approval under the Animal Rule. The National Institute of Allergy and Infectious Diseases and Biomedical Advanced Research and Development Authority worked together to qualify the cynomolgus macaque model of pneumonic tularemia. METHODS: Using the model parameters and end points defined in the qualified model, efficacy of the antibiotics doxycycline and ciprofloxacin was evaluated in separate studies. Antibiotic administration, aimed to model approved human dosing, was initiated at time points of 24 hours or 48 hours after onset of fever as an indicator of disease. RESULTS: Upon aerosol exposure (target dose of 1000 colony-forming units) to Francisella tularensis SchuS4, 80% of vehicle-treated macaques succumbed or were euthanized. Ciprofloxacin treatment led to 10 of 10 animals surviving irrespective of treatment time. Doxycycline administered at 48 hours post-fever led to 10 of 10 animals surviving, while 9/10 animals survived in the group treated with doxycycline 24 hours after fever. Selected surviving animals in both the placebo and doxycycline 48-hour group showed residual live bacteria in peripheral tissues, while there were no bacteria in tissues from ciprofloxacin-treated macaques. CONCLUSIONS: Both doxycycline and ciprofloxacin were efficacious in treatment of pneumonic tularemia, although clearance of bacteria may be different between the 2 drugs.

Systematic Review of Tularemia During Pregnancy.

BACKGROUND: Tularemia is caused by the gram-negative bacterium Francisella tularensis. Although rare, tularemia during pregnancy has been associated with pregnancy complications; data on efficacy of recommended antimicrobials for treatment are limited. We performed a systematic literature review to characterize clinical manifestations of tularemia during pregnancy and examine maternal, fetal, and neonatal outcomes with and without antimicrobial treatment. METHODS: We searched 9 databases, including Medline, Embase, Global Health, and PubMed Central, using terms related to tularemia and pregnancy. Articles reporting cases of tularemia with ≥1 maternal or fetal outcome were included. RESULTS: Of 5891 articles identified, 30 articles describing 52 cases of tularemia in pregnant patients met inclusion criteria. Cases were reported from 9 countries, and oropharyngeal and ulceroglandular tularemia were the most common presenting forms. A plurality (46%) of infections occurred in the second trimester. Six complications were observed: lymph node aspiration, lymph node excision, maternal bleeding, spontaneous abortion, intrauterine fetal demise, and preterm birth. No deaths among mothers were reported. Of 28 patients who received antimicrobial treatment, 1 pregnancy loss and 1 fetal death were reported. Among 24 untreated patients, 1 pregnancy loss and 3 fetal deaths were reported, including one where F. tularensis was detected in placental and fetal tissues. CONCLUSIONS: Pregnancy loss and other complications have been reported among cases of tularemia during pregnancy. However, risk of adverse outcomes may be lower when antimicrobials known to be effective are used. Without treatment, transplacental transmission appears possible. These data underscore the importance of prompt recognition and treatment of tularemia during pregnancy.

Tularemia Clinical Manifestations, Antimicrobial Treatment, and Outcomes: An Analysis of US Surveillance Data, 2006-2021.

BACKGROUND: Tularemia, a potentially fatal zoonosis caused by Francisella tularensis, has been reported from nearly all US states. Information on relative effectiveness of various antimicrobials for treatment of tularemia is limited, particularly for newer classes such as fluoroquinolones. METHODS: Data on clinical manifestations, antimicrobial treatment, and illness outcome of patients with tularemia are provided voluntarily through case report forms to the US Centers for Disease Control and Prevention by state and local health departments. We summarized available demographic and clinical information submitted during 2006-2021 and evaluated survival according to antimicrobial treatment. We grouped administered antimicrobials into those considered effective for treatment of tularemia (aminoglycosides, fluoroquinolones, and tetracyclines) and those with limited efficacy. Logistic regression models with a bias-reduced estimation method were used to evaluate associations between antimicrobial treatment and survival. RESULTS: Case report forms were available for 1163 US patients with tularemia. Francisella tularensis was cultured from a clinical specimen (eg, blood, pleural fluid) in approximately half of patients (592; 50.9%). Nearly three-quarters (853; 73.3%) of patients were treated with a high-efficacy antimicrobial. A total of 27 patients (2.3%) died. After controlling for positive culture as a proxy for illness severity, use of aminoglycosides, fluoroquinolones, and tetracyclines was independently associated with increased odds of survival. CONCLUSIONS: Most US patients with tularemia received high-efficacy antimicrobials; their use was associated with improved odds of survival regardless of antimicrobial class. Our findings provide supportive evidence that fluoroquinolones are an effective option for treatment of tularemia.

Neuroinvasive Francisella tularensis Infection: Report of 2 Cases and Review of the Literature.

BACKGROUND: Neuroinvasive infection with Francisella tularensis, the causative agent of tularemia, is rare. Establishing clinical suspicion is challenging if risk factors or clinical features classically associated with tularemia are absent. Tularemia is treatable with antibiotics; however, there are limited data to inform management of potentially fatal neuroinvasive infection. METHODS: We collected epidemiologic and clinical data on 2 recent US cases of neuroinvasive F. tularensis infection, and performed a literature review of cases of neuroinvasive F. tularensis infection published after 1950. RESULTS: One patient presented with focal neurologic deficits and brain lesions; broad-range molecular testing on resected brain tissue detected F. tularensis. The other patient presented with meningeal signs; tularemia was suspected based on animal exposure, and F. tularensis grew in cerebrospinal fluid (CSF) culture. Both patients received combination antibiotic therapy and recovered from infection. Among 16 published cases, tularemia was clinically suspected in 4 cases. CSF often displayed lymphocytic pleocytosis. Among cases with available data, CSF culture was positive in 13 of 16 cases, and F. tularensis antibodies were detected in 11 of 11 cases. Treatment typically included an aminoglycoside combined with either a tetracycline or a fluoroquinolone. Outcomes were generally favorable. CONCLUSIONS: Clinicians should consider neuroinvasive F. tularensis infection in patients with meningitis and signs suggestive of tularemia or compatible exposures, lymphocyte-predominant CSF, unrevealing standard microbiologic workup, or lack of response to empiric bacterial meningitis treatment. Molecular testing, culture, and serologic testing can reveal the diagnosis. Favorable outcomes can be achieved with directed antibiotic treatment.

Antimicrobial Susceptibility of Francisella tularensis Isolates in the United States, 2009-2018.

Francisella tularensis is the causative agent of tularemia. We tested the susceptibility of 278 F. tularensis isolates from the United States received during 2009-2018 to 8 antimicrobial drugs (ciprofloxacin, levofloxacin, doxycycline, tetracycline, gentamicin, streptomycin, chloramphenicol, and erythromycin). All isolates were susceptible to all tested drugs.

Treatment Outcome of Severe Respiratory Type B Tularemia Using Fluoroquinolones.

BACKGROUND: Fluoroquinolones lack approval for treatment of tularemia but have been used extensively for milder illness. Here, we evaluated fluoroquinolones for severe illness. METHODS: In an observational study, we identified case-patients with respiratory tularemia from July to November 2010 in Jämtland County, Sweden. We defined severe tularemia by hospitalization for >24 hours and severe bacteremic tularemia by Francisella tularensis subsp. holarctica growth in blood or pleural fluid. Clinical data and drug dosing were retrieved from electronic medical records. Chest images were reexamined. We used Kaplan-Meier curves to evaluate time to defervescence and hospital discharge. RESULTS: Among 67 case-patients (median age, 66 years; 81% males) 30-day mortality was 1.5% (1 of 67). Among 33 hospitalized persons (median age, 71 years; 82% males), 23 had nonbacteremic and 10 had bacteremic severe tularemia. Subpleural round consolidations, mediastinal lymphadenopathy, and unilateral pleural fluid were common on chest computed tomography. Among 29 hospitalized persons with complete outcome data, ciprofloxacin/levofloxacin (n = 12), ciprofloxacin/levofloxacin combinations with doxycycline and/or gentamicin (n = 11), or doxycycline as the single drug (n = 6) was used for treatment. One disease relapse occurred with doxycycline treatment. Treatment responses were rapid, with median fever duration 41.0 hours in nonbacteremic and 115.0 hours in bacteremic tularemia. Increased age-adjusted Charlson comorbidity index predicted severe bacteremic tularemia (odds ratio, 2.7 per score-point; 95% confidence interval, 1.35-5.41). A 78-year-old male with comorbidities and delayed ciprofloxacin/gentamicin treatment died. CONCLUSIONS: Fluoroquinolone treatment is effective for severe tularemia. Subpleural round consolidations and mediastinal lymphadenopathy were typical findings on computed tomography among case-patients in this study.

[Carcinoma, tuberculosis, atypical pneumonia - or may be pulmonary tularemia? Two case reports]. / Karzinom, Tuberkulose, atypische Pneumonie ­ oder vielleicht pulmonale Tularämie? Zwei Fallberichte.

Tularemia is a rare zoonotic disease, endemic in rural areas all over Germany. It's clinical manifestation following inhalation of infectious aerosols may resemble pulmonary neoplasia, other atypical pneumonias or tuberculosis. Here we describe two representative cases with pulmonary tularemia.

Positive Francisella tularensis meningitis outcome despite delayed identification: a case report.

Francisella tularensis is a Gram-negative bacteria, that may cause a zoonotic disease, tularemia. Here, we describe a patient case, where a previously healthy young woman in Northern Finland contacted health care because of fever and headache. Due to the symptoms and lack of further diagnostic tools in primary health care, she was transferred to University Hospital (UH) where ampicillin and ceftriaxone was given empirically. A cerebrospinal fluid sample (CSF) was drawn showing small Gram-negative rods that grew on chocolate agar after 2 days of incubation. Matrix-assisted laser-desorption-ionization time of-flight (Maldi-tof) did not provide identification, but the bacteria was interpreted as sensitive to ciprofloxacin and the treatment was changed to ciprofloxacin. During the time the patient was infected, there were several positive tularemia samples found in the area. Therefore, an in house tularemia nucleic acid method (PCR) was used on the bacterial culture. Additionally, 16S rDNA sequencing was performed and these methods identified the bacteria as F. tularensis. Fortunately, the patient recovered completely with ciprofloxacin and was discharged without any complications. Our case underlines the need to understand the limits of specific diagnostic methods, such as Maldi-tof, used in clinical laboratory settings. It also highlights the need of both clinicians and laboratory staff to be aware of the many clinical presentations of tularemia when working in an endemic area.

Diffuse skin findings secondary to lymph node tularemia in a patient with chronic rheumatoid arthritis on methotrexate.

Tularemia has many atypical presentations which can represent a diagnostic challenge. The history is essential in the investigation of this disease. Bite-induced primary skin lesions should be distinguished from the infrequent immune-mediated secondary skin lesions. Herein, we present an atypical pseudovesicular rash secondary to Francisella tularensis.

Case Studies and Literature Review of Francisella tularensis-Related Prosthetic Joint Infection.

Tularemia is a zoonotic infection caused by Francisella tularensis. Its most typical manifestations in humans are ulceroglandular and glandular; infections in prosthetic joints are rare. We report 3 cases of F. tularensis subspecies holarctica-related prosthetic joint infection that occurred in France during 2016-2019. We also reviewed relevant literature and found only 5 other cases of Francisella-related prosthetic joint infections worldwide, which we summarized. Among those 8 patients, clinical symptoms appeared 7 days to 19 years after the joint placement and were nonspecific to tularemia. Although positive cultures are typically obtained in only 10% of tularemia cases, strains grew in all 8 of the patients. F. tularensis was initially identified in 2 patients by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry; molecular methods were used for 6 patients. Surgical treatment in conjunction with long-term antimicrobial treatment resulted in favorable outcomes; no relapses were seen after 6 months of follow-up.

Tularemia in Pregnant Woman, Serbia, 2018.

Tularemia was diagnosed for a 33-year-old pregnant woman in Serbia after a swollen neck lymph node was detected at gestation week 18. Gentamicin was administered parenterally (120 mg/d for 7 d); the pregnancy continued with no complications and a healthy newborn was delivered. Treatment of tularemia optimizes maternal and infant outcomes.

[A rare and atypical form of tularemia in a context of immunodepression]. / Forme rare et atypique de tularémie dans un contexte d'immunodépression.

INTRODUCTION: We present an original severe case of tularemia with cutaneous damage, lymphadenopathy and pericarditis ; pathology of increasing incidence in Europe due to global warming. OBSERVATION: A 33-years-old women consulted emergency unit for altered general condition, anorexia, hyperthermia at 38,3°C, dyspnea and dry cough evolving for few days. Her only history was Crohn's disease with introduction of an anti-TNF alpha for 3 months. The interrogation found regular forest walks ¼. Treatment with Amoxicillin/clavulanic acid 1g 3 times daily and curative anticoagulation was started after the initial diagnosis of infectious pneumonia associated with pulmonary embolism. The patient reconsulted 2 weeks later for clinical deterioration associated with skin lesions. The chest CT scan showed increased mediastinal lymphadenopathy and a circumferential pericardial effusion ; quantified at 5mm on transthoracic ultrasound. Tularemia serology was positive in IgG at 400IU/mL. Despite an adapted antibiotic therapy with Ciprofloxacin, the patient presented a new brutal clinical deterioration. A pericardiocentesis was performed and the analysis revealed a predominantly neutrophilic exudate and a strongly positive PCR Francisella tularensis. Gentamicin 5mg/kg was associated allowing a resolution of the symptoms. CONCLUSION: Tularemia is one of the pathologies whose atypical presentation with pericarditis (favored by a certain immunodepression) worsens the prognosis. Global warming influences the epidemiology of inoculation diseases, including tularemia, making it more frequent.

Pulmonary tularaemia in a female adolescent with inflammatory bowel disease receiving infliximab: Do not miss the diagnosis.

We report the first described case of pulmonary tularaemia in the pediatric patient receiving infliximab for ulcerative colitis. We highlight the importance of considering Francisella tularensis in diagnostically challenging cases of persistent respiratory symptoms to facilitate early diagnosis and adequate therapy. The TCR-γδ + DN T cells are gaining important role in clinical practice. Polymerase chain reaction assays and serology guarantee early recognition.

Water-borne oculoglandular tularemia: Two complicated cases and a review of the literature.

BACKGROUND: In this study, we presented two cases of late diagnosed complicated oculoglandular tularemia and reviewed the clinical features of oculoglandular tularemia in cases reported in the last ten years. METHOD: Tularemia was diagnosed when serum microagglutination test (MAT) was ≥ 1/160 titer or when there was at least a four-fold increase in MAT titers measured over a two-week interval. We searched the oculoglandular tularemia cases reported in the last 10 years in the PubMed and Google Academic engines. RESULTS: Case 1 (19 M) and case 2 (15 M) had complaints of fever and burning in the eye. In both cases, the diagnosis of tularemia was delayed. Lymph node suppuration developed in both cases. A total of 19 cases of tularemia were found within the search. In the cases of oculoglandular tularemia reported in the last 10 years, submandibular and preauricular lymphadenopathy were most common after ocular findings and fever. The mean time to diagnosis was 41 ± 94 days, and the complication rate was 31.5%. CONCLUSION: Tularemia should definitely be considered in cases of fever and ocular findings, especially in endemic areas. In non-endemic areas, a good anamnesis and clinical suspicion can help diagnose the disease early and reduce the complication rate.