Tularemia treatment: experimental and clinical data

Tularemia is a zoonosis caused by the Gram negative, facultative intracellular bacterium Francisella tularensis. This disease has multiple clinical presentations according to the route of infection, the virulence of the infecting bacterial strain, and the underlying medical condition of infected persons. Systemic infections (e.g., pneumonic and typhoidal form) and complications are rare but may be life threatening. Most people suffer from local infection (e.g., skin ulcer, conjunctivitis, or pharyngitis) with regional lymphadenopathy, which evolve to suppuration in about 30% of patients and a chronic course of infection. Current treatment recommendations have been established to manage acute infections in the context of a biological threat and do not consider the great variability of clinical situations. This review summarizes literature data on antibiotic efficacy against F. tularensis in vitro, in animal models, and in humans. Empirical treatment with beta-lactams, most macrolides, or anti-tuberculosis agents is usually ineffective. The aminoglycosides gentamicin and streptomycin remain the gold standard for severe infections, and the fluoroquinolones and doxycycline for infections of mild severity, although current data indicate the former are usually more effective. However, the antibiotic treatments reported in the literature are highly variable in their composition and duration depending on the clinical manifestations, the age and health status of the patient, the presence of complications, and the evolution of the disease. Many patients received several antibiotics in combination or successively. Whatever the antibiotic treatment administered, variable but high rates of treatment failures and relapses are still observed, especially in patients treated more then 2–3 weeks after disease onset. In these patients, surgical treatment is often necessary for cure, including drainage or removal of suppurative lymph nodes or other infectious foci. It is currently difficult to establish therapeutic recommendations, particularly due to lack of comparative randomized studies. However, we have attempted to summarize current knowledge through proposals for improving tularemia treatment which will have to be discussed by a group of experts. A major factor in improving the prognosis of patients with tularemia is the early administration of appropriate treatment, which requires better medical knowledge and diagnostic strategy of this disease.


Introduction
Francisella tularensis is a Gram-negative, facultative intracellular bacterium.Only two subspecies cause tularemia: subsp.tularensis (type A) in Northern America, and subsp.holarctica (type B) in the whole Northern hemisphere and southern Australia (Sjöstedt, 2007;Jackson et al., 2012).F. tularensis subsp.mediasiatica is restricted to specific areas in Central Europe and Russia and has never been isolated from humans (Ellis et al., 2002;Timofeev et al., 2017).F. tularensis is highly virulent and belongs to the category A of potential bioterrorism agents of the Centers for Diseases Control and Prevention (CDC, USA) [CDC | Bioterrorism Agents/Diseases (by category) | Emergency Preparedness & Response, 2019].Type A and type B strains are split into clades and subclades, the major clades being A1, A2, B4, B6, B12, and B16 (Johansson et al., 2004;Vogler et al., 2009).
Francisella tularensis has been detected in more than 200 animal species, including most mammals and arthropod vectors (Ixodidae ticks, and mosquitoes in Sweden and Finland) (Telford and Goethert, 2020).This bacterium can also survive for prolonged periods in the hydrotelluric environment (Hennebique et al., 2019).Human infection with F. tularensis can occur through the skin (e.g., skin wound after contact with an infected animal, and arthropod bites), the conjunctiva, the oral route (e.g., ingestion of contaminated food or water), or the respiratory route (inhalation of a contaminated aerosol).After a short incubation period (usually 3-5 days), infected persons usually develop a flu-like illness (Tärnvik and Chu, 2007;Hepburn and Simpson, 2008;Maurin and Gyuranecz, 2016).Then, the disease may evolve to six classical forms: the ulceroglandular (UG) and glandular (GL) forms, a regional lymphadenopathy, with or without detectable skin inoculation lesion, respectively; the oculoglandular (OG) form, a conjunctivitis with satellite lymphadenopathy; the oropharyngeal (OP) form, a pharyngitis with regional lymphadenopathy; the pneumonic (PN) form, an acute, subacute, or chronic pneumonia; and the typhoidal (TY) form, mimicking typhoid.Many complications may occur (e.g., soft tissue infection, meningitis, endocarditis, and prosthetic joint infection), sometimes as inaugural presentations of the disease (Tärnvik and Chu, 2007;Hepburn and Simpson, 2008;Maurin and Gyuranecz, 2016).The global death rate of tularemia is less than 1% for type B infections and about 2-3% for type A, but can be up to 30% for untreated acute type A pneumonia (Dennis et al., 2001).
Human tularemia mostly occur as sporadic cases but outbreaks caused by one or several F. tularensis clones are regularly reported (Pérez-Castrillón et al., 2001;Reintjes et al., 2002;Celebi et al., 2006;Kantardjiev et al., 2006;Svensson et al., 2009;Hauri et al., 2010;Larssen et al., 2011;Johansson et al., 2014).The number of reported tularemia cases has increased in recent years in most endemic countries.The European Center for Disease Control and Prevention (ECDC) reported 641 confirmed human tularemia cases in Europe in 2020 (incidence, 0.15 per 100,000 persons per year), most of which occurred in Sweden and Finland.In the USA, 1984 human tularemia cases were reported from 2011 to 2019 (average incidence, 0.07 cases per 100,000 person per year), predominantly in Arkansas, Missouri, Oklahoma, and Kansas (Bishop et al., 2023).Tularemia is a significant public health problem since the 2000's in Turkey (Erdem et al., 2014).
Tularemia diagnosis can be established serologically or by culture or PCR detection of F. tularensis from clinical samples (Tärnvik and Chu, 2007;Hepburn and Simpson, 2008;Maurin, 2020;Wawszczak et al., 2022).Culture and PCR tests may allow an early and specific diagnosis of tularemia.Depending on the clinical presentation, F. tularensis can be grown or PCR-detected from various clinical samples including blood, skin eschar, conjunctival or pharyngeal exudates, lymph node samples, cerebrospinal fluid, sputum, and osteoarticular samples.However, the sensitivity of F. tularensis culture rapidly decreases over time and this bacterium is isolated in only about 10% of tularemia cases.PCR tests usually remain positive for longer time.For example, they are usually positive for lymph node samples collected after several weeks evolution of tularemia while culture is usually negative.However, in many patients, clinical samples other than blood and serum samples are not available for PCR testing.Therefore, tularemia diagnosis remains often based on serology.Significant titers of specific antibodies are usually detected only 2-3 weeks after disease onset.False positive results may arise from long term persistence (months to years) of antibodies in persons with past tularemia infection and from serological cross reactions.Therefore, two serum samples taken at least 2 weeks apart should be tested to increase specificity.Tularemia diagnosis is usually considered confirmed in patients with compatible epidemiological and clinical data and F. tularensis detection by culture or PCR, or a seroconversion or a 4-fold increase of antibody titers at 2 weeks or more interval.In the same context, a single positive serum sample correspond to a probable tularemia case.
Tularemia diagnostic and treatment delay is the rule in most endemic countries, due to poor specificity of clinical symptoms and late medical consultation of patients with mild diseases.No vaccine against tularemia is authorized in humans or animals.Prophylaxis is based on protective measures against sources of infection (e.g., animals, arthropods, drinking water and food, hydrotelluric environment).Appropriate recommendations should be provided by physicians to people living in tularemia endemic areas and at high risk of F. tularensis infections due to their occupation (e.g., farmers, veterinarians, butchers, landscapers) or leisure activities (e.g., hunting, trapping, walking).Only aminoglycosides, tetracyclines and fluoroquinolones are considered in the firstline treatment of tularemia.However, the current international recommendations for tularemia treatment have been primarily developed to deal with emergency situations in the context of bioterrorism (Dennis et al., 2001;Bossi et al., 2004).This review updates data we previously published on antibiotic susceptibilities of F. tularensis (Caspar and Maurin, 2017) and summarizes the current literature on efficacy of antibiotics in F. tularensisinfected animal models and tularemia patients.Our objective is to highlight the variability and complexity of clinical situations encountered in patients with tularemia, which should lead to new therapeutic recommendations to reduce the disabling and chronic nature of this disease, as well as the risk of severe complications.Although this study does not allow us to propose new therapeutic recommendations, we have attempted to provide Data on antibiotic susceptibility of F. tularensis to antibiotics have been previously reviewed by Caspar and Maurin (2017).Therefore, the present review will only summarize the most significant data, adding those published in more recent years.

Methods
Francisella tularensis antibiotic susceptibility has been mainly evaluated using the broth microdilution (BMD) and the E-test strips (E-test) methods, and less frequently the antibiotic agar dilution method (Caspar and Maurin, 2017).The BMD method from the Clinical and Laboratory Standards Institute (CLSI) is currently the best standardized method (Clinical And Laboratory Standards Institute, 2005, 2016).Experimental conditions include the use of cation-adjusted Mueller Hinton broth (caMHB) supplemented with 2% defined growth supplement (e.g., Polyvitex R or IsoVitalex R ), a 5 × 10 5 cfu/ml bacterial inoculum, and a 48 h incubation of cultures at 37 • C in aerobic atmosphere (or 5% CO 2 atmosphere for capnophilic strains).In Tables 1-4 we have summarized data obtained with the BMD method using CaMHB medium or the E-test strips method.Some publications reporting high MICs suggesting acquired resistance to antibiotics in F. tularensis but without genetic confirmation were not considered (Baker et al., 1985;Scheel et al., 1993;Martínez-Martínez et al., 2021).

Bacteriostatic activity (MIC and MIC90)
The beta-lactams are poorly active against F. tularensis with MIC90 (i.e., MIC inhibiting 90% of the tested strains) highest than the maximum concentration tested (i.e., > 32-256 mg/L) for penicillins, cephalosporins, monobactams, and carbapenems (Table 1).A few F. tularensis strains displayed low MICs, e.g., 4 mg/L for penicillin A, 0.03 mg/L for ceftriaxone, 0.047 mg/L for imipenem, and 0.094 mg/L for meropenem (Tomaso et al., 2005;Hotta et al., 2013;Heine et al., 2017).In the above studies, the percentage of strains with MICs lower than 2 mg/L among those tested varied from 4 % (Tomaso et al., 2005) up to 66.6% (Hotta et al., 2013) for imipenem, and was 50% for ceftriaxone (Hotta et al., 2013).These two studies used the E-test method.The last study did not specify the distribution of strains according to the MIC (Heine et al., 2017).These data are difficult to interpret until we further understand the mechanisms of beta-lactam resistance in F. tularensis (see below).
The activity of the macrolides depends on the F. tularensis clade (Table 4).Type B biovar (bv) II strains (currently clade B12) are naturally highly resistant to the macrolides, with erythromycin and azithromycin MICs > 256 mg/L.The other A and B clades display lower MICs to the macrolides although variables between studies.Overall, using the BMD method, erythromycin MIC and MIC90 ranges were 0.5-8 mg/L and 1-4 mg/L, respectively.Azithromycin was more effective, with MIC ranges of 0.125-2 mg/L.No macrolide CLSI susceptibility breakpoint is available for F. tularensis.Chloramphenicol and rifampicin are considered less effective against F. tularensis, although no CLSI breakpoint is available for this species (Table 4).Moreover, rapid resistance to rifampicin may occur through mutations in the RNA polymerase encoding gene (Bhatnagar et al., 1994;Zaw et al., 2018).
Although we did not find MICs for glycopeptides and polymyxins against F. tularensis, it is likely that this bacterium is resistant to both antibiotic classes since its isolation from environmental samples was obtained using a selective medium containing 4 mg/L of vancomycin and 8 x 10 4 U/L of polymyxin B (Petersen et al., 2009).

Bactericidal activity
A few studies have evaluated the bactericidal activity of antibiotics against F. tularensis by determining the MBCs (minimum antibiotic concentration allowing 3-log or greater reduction of a bacterial inoculum).For fluoroquinolones (ofloxacin and ciprofloxacin) MBCs were close to MICs demonstrating the high bactericidal activity of these antibiotics against F. tularensis (Maurin et al., 2000;Aloni-Grinstein et al., 2015).The MBC/MIC ratios ranged from 2 to 8 for gentamicin and streptomycin compatible with a bactericidal activity of these aminoglycosides, at least for the most susceptible strains (Maurin et al., 2000;Caspar et al., 2014;Aloni-Grinstein et al., 2015).Less favorable MBC/MIC ratios were found for doxycycline (i.e., from 4 up to 512) suggesting lack of bactericidal activity (Maurin et al., 2000;Aloni-Grinstein et al., 2015).One study found no bactericidal activity of doxycycline at concentrations up to 8 mg/L (Caspar et al., 2014).Therefore, tetracyclines should be considered mainly bacteriostatic against F. tularensis.Thiamphenicol, erythromycin, and trimethoprim-sulfamethoxazole displayed MBC/MIC ratios of 2, 4 and 16, respectively (Maurin et al., 2000;Aloni-Grinstein et al., 2015).However, due to their high MICs, these antibiotics can be considered weakly or nonbactericidal on F. tularensis.Rifampicin was more effective (MBC, 1 mg/L; MBC/MIC ratio of 2) (Maurin et al., 2000), but as previously mentioned this antibiotic must not be used as monotherapy.

Methods
The activity of antibiotics against intracellular F. tularensis was determined in variable eukaryotic cell systems, including murine macrophage-like cells (P388D1 and J774.1),Vero cells, A549 cells, and MRC5 cells (Maurin et al., 2000;Ahmad et al., 2010;Madrid et al., 2013;Sutera et al., 2014a;Aloni-Grinstein et al., 2015).The cell systems may also vary according to the bacterial inoculum used to infect cell monolayers and the multiplicity of infection (MOI, i.e., the ratio of bacteria to cells), the time antibiotics are added after cell infection, and the length antibiotic exposure of infected cells.The bacterial inoculum used to infect cells varied from 1.2 × 10 5 CFU (Maurin et al., 2000) to 10 7 CFU (Sutera et al., 2014a).MOIs varied from 1 to 3,000 (Ahmad et al., 2010;Madrid et al., 2013;Aloni-Grinstein et al., 2015).Antibiotics were usually added to culture supernatant after cell infection and removal of non-phagocytized bacteria (i.e., 1-3 h post-infection).Antibiotic activity was then evaluated after a short (15-24 h) (Ahmad et al., 2010;Madrid et al., 2013;Aloni-Grinstein et al., 2015) or long (3-5d) (Maurin et al., 2000;Sutera et al., 2014a) incubation period of antibiotic exposure of infected cells.The antimicrobial activity was deduced from: (1) changes in the intracellular bacterial load, using the CFU counting (Maurin et al., 2000) or a qPCR method (Aloni-Grinstein et al., 2015); or (2) changes in cell lysis rate caused by bacterial multiplication, after staining cell monolayers with a vital dye (Sutera et al., 2014a) or by measuring the release of lactate dehydrogenase (LDH) (Madrid et al., 2013).The minimum inhibitory extracellular concentration (MIEC) is the antibiotic concentration in the cell culture supernatant allowing complete inhibition of bacterial growth or cell lysis.
Overall, data obtained in cell models are difficult to interpret because of methodological heterogeneity between studies.However, the fluoroquinolones had the strongest bactericidal activity against intracellular F. tularensis, gentamicin had a delayed bactericidal activity, and doxycycline was only bacteriostatic.Among other antibiotic classes, rifampicin displayed the lowest MIECs. 10.3389/fmicb.2023.1348323 4 Antibiotic resistance in F. tularensis

Natural resistance
Francisella tularensis is naturally resistant to most beta-lactams, polymyxins, glycopeptides, sulfonamides, and trimethoprim (Caspar and Maurin, 2017;Kassinger and van Hoek, 2021).Two genes code for beta-lactamases, including Bla1 considered as a non-functional beta-lactamase (Antunes et al., 2012) and Bla2 (or FTU-1), a weak Ambler Class A carbapenemase inducing high-level resistance to penicillins but low-level resistance to cephalosporins and carbapenems (Bina et al., 2006).An AcrAB RND efflux system confers resistance to ampicillin, carbenicillin, and cefoperazone in the LVS strain (Bina et al., 2008).Natural high-level resistance to the macrolides in type B bv II (clade B12) strains is due to A2059C mutation (compared to other clades) in the three copies of the rrl gene encoding the 23S rRNA (Karlsson et al., 2016).

Acquired resistance to antibiotics
No acquired resistance to antibiotics has been reported so far in natural humans or animal strains of F. tularensis (Caspar and Maurin, 2017;Kassinger and van Hoek, 2021).In vitro, antibioticresistant mutants have been selected in the virulence attenuated LVS strain.Resistance to fluoroquinolones was mainly associated with mutations in the genes coding DNA gyrase (gyrA and gyrB) or topoisomerase IV (parC and parE) (La Scola et al., 2008;Sutera et al., 2014bSutera et al., , 2020;;Jaing et al., 2016;Caspar et al., 2017;Biot et al., 2020), and in genes coding for efflux pump of the MexH family RND transporter or AcrAB-TolC (Biot et al., 2020).Deletion of fupA/B gene, coding an iron-binding membrane protein, was also involved (Siebert et al., 2019).High-level erythromycin resistance was selected in type B bv I isolates due to mutations in the 23S rRNA gene (Gestin et al., 2010).Tetracycline resistance was obtained by introducing a plasmid containing the Tet repressor gene (TetR) (Pavlov et al., 1996;LoVullo et al., 2012;Sheshko et al., 2021).Streptomycin resistance was associated with mutations involving several genes, including rpsL gene coding the 30S ribosomal protein S12 (Biot et al., 2020).Rifampicin-resistance was related to mutations in rpoB gene, coding the subunit B of the RNA polymerase (Bhatnagar et al., 1994).Combined resistances to ciprofloxacin, doxycycline, and chloramphenicol were also selected in the LVS strain (Sutera et al., 2014b;Biot et al., 2020;Mehta et al., 2022).

Antibiotic activity in animal models
Tularemia animal models have included mice, rats, guinea pigs, rabbits, and non-human primates (NHP) (Stundick et al., 2013).The disease severity depends on the animal species, bacterial strain, and dose and route of infection.Mice usually develop a fatal infection when challenged with a low dose of type A (1-10 cfu) or type B (10-100 CFU) strain, including the LVS strain.Fischer 344 rats are more susceptible to type A infection than Sprague-Dawley rats, but both are resistant to LVS infection.Among NHP, African green monkey and Cynomolgus macaques are more susceptible to type A infection than Rhesus macaques (Glynn et al., 2015).
6 Tularemia treatment in humans

General comments
The following paragraphs summarize literature data on treatment efficacy in tularemia patients according to different clinical situations.Although some patients are likely redundant across different publications, this review includes 2,482 tularemia cases, corresponding to 1,174 (47.3%) men, 1,173 (47.3%) women, while for 135 (5.8%) patients the sex was not specified.The pediatric population represents 10.6% of these cases.All tularemia cases were reported as proven or probable.Treatment data were not consistently reported between studies.Treatment durations were around 7-10 days for aminoglycosides and 2-3 weeks for Frontiers in Microbiology 11 frontiersin.orgtetracyclines and fluoroquinolones.However, the total duration of antibiotic treatment was often not specified, particularly for patients receiving several antibiotics either alternately or concomitantly.We considered the treatment failure and relapse rates reported by the authors without modification.Treatment failures and relapses usually corresponded to the absence of clinical improvement during or after appropriate antibiotic treatment and reappearance of clinical symptoms after a marked improvement or even an apparent cure, respectively.In both cases, a new antibiotic treatment was administered often combined with a surgical procedure.

Acute, life-threatening diseases
Tularemia can manifest as acute diseases with spontaneous mortality rates up to 30% for type A strains, in North America (Dennis et al., 2001).These infections usually correspond to the typhoidal and pneumonic forms (Dennis et al., 2001;Feldman et al., 2001;Matyas et al., 2007).A World Health Organization group of consultants reported in 1970 that aerosol delivery of a virulent strain of F. tularensis (people inhaling at least 25 bacteria) would infect half of the exposed population, with a death rates of about 25% in untreated people and 1% in people receiving appropriate antibiotic prophylaxis within 48 h postexposure (World Health Organization, 1970).Current treatment and prophylactic recommendations are well adapted to manage these acute infections (Dennis et al., 2001;Bossi et al., 2004).Gentamicin can be used in adults, including pregnant women, and children.Fatal infections, however, can occur despite appropriate treatment (Feldman et al., 2001).

Classical forms of tularemia in adults 6.3.1 Ulceroglandular and glandular tularemia
Table 6 summarizes data from tularemia case series with a predominance of the UG or GL forms.Many other sporadic UG or GL tularemia cases have been reported in several countries but with similar findings than those reported in case series (Pérez-Castrillón et al., 2001;Jackson et al., 2012;Sobolewska-Pilarczyk et al., 2014;Boone et al., 2015;Formińska et al., 2015;Calin et al., 2017;Pekova et al., 2017;Whitten et al., 2017;Haulrig et al., 2020;Kubiliute et al., 2021).The UG and GL forms are predominant worldwide, except in some countries such as Turkey (see below).
Beta-lactams (penicillin, amoxicillin, amoxicillin-clavulanate, cefuroxime, cefotaxime, ceftriaxone), macrolides (clarithromycin, clindamycin), and antituberculosis drugs often given as empirical treatments in UG and GL tularemia patients were ineffective (Maurin et al., 2011;Jackson et al., 2012;Sobolewska-Pilarczyk et al., 2014;Boone et al., 2015;Formińska et al., 2015;Pekova et al., 2017;Whitten et al., 2017;Haulrig et al., 2020;Kubiliute et al., 2021).Overall, gentamicin, ciprofloxacin (as well as levofloxacin and moxifloxacin) and doxycycline were the most successful treatments.However, several courses of antibiotic therapy were often prescribed because of poor clinical response and chronic evolution especially in the approximately 30% of UG or GL tularemia patients suffering from lymph node suppuration.The antibiotic therapy was adapted empirically according to the clinical and radiological findings.Treatment failure and relapse rates were usually high but variable between studies [e.g., 21.3% in Evans et al. (1985) and 38.6% in Maurin et al. (2011)].Relapses were more frequent in patients with a significant treatment delay.For example, in the case series from Missouri (USA) (Weber et al., 2012), the mean treatment delay was 13 days (range, 0-82 days), but 21 days for patients evolving to lymph node suppuration.In a French series (Darmon-Curti et al., 2020), treatment delay was significantly longer (p = 0.006) for patients requiring surgery (mean, 52.1 days; range, 7-175 days) compared to those cured without surgery (mean, 32.1 days; range 1-87 days).In some studies, failure rates were higher for doxycycline versus ciprofloxacin (i.e., 4.5 versus 42.8%) (Pérez-Castrillón et al., 2001).Drainage or removal of suppurated lymph nodes were needed for cure in 12.4% up to 57.9% of patients (Maurin et al., 2011;Kızıl et al., 2012;Weber et al., 2012;Boone et al., 2015;Formińska et al., 2015).Many patients (29.7-58%) required hospitalization because of disease severity or more frequently the need for surgical intervention (Maurin et al., 2011;Weber et al., 2012;Darmon-Curti et al., 2020).However, severe cases requiring hospitalization are more likely to be reported than milder cases and thus might be overestimated in the literature.In some patients, complications occurred while under appropriate antibiotic therapy, including continued enlargement of the infected lymph nodes, involvement of new lymph nodes, regional and systemic complications (Jackson et al., 2012;Kızıl et al., 2012;Weber et al., 2012;Formińska et al., 2015;Calin et al., 2017;Haulrig et al., 2020;Kubiliute et al., 2021).A few patients with UG or GL forms died (2/418, 0.48% for the above sporadic cases and case series).Death usually occurred in patients with underlying health condition, e.g., a cardiovascular disease (Weber et al., 2012).Altogether, the above data emphasizes the need for specific medical and surgical treatment recommendations for patients suffering from UG or GL forms of tularemia, especially when experiencing lymph node suppuration.
The same treatment options were used for treatment of keratitis and dacryocystitis (Steinemann et al., 1999;Celik et al., 2013;Köse and Hoşal, 2019).Three-weeks treatment with doxycycline was effective to treat posterior uveitis in a 52-year-old man, but with loss of vision of the involved eye (Terrada et al., 2016).Although treatment of F. tularensis intraocular infection is not standardized, it should be emphasized that ciprofloxacin intravenously has more favorable intraocular pharmacokinetics properties than doxycycline and gentamicin (Kulshrestha et al., 1981;Mounier et al., 1988;Fiscella et al., 1998;Morlet et al., 2000).

Pneumonic tularemia
Pneumonic tularemia is most often of mild to moderate severity (see above for severe type A pneumonia) (Table 8).Type B pneumonia typically have a prolonged course, with intermittent fever, mild respiratory symptoms, progressive weight loss, and development of mediastinal or hilar lymphadenopathy.Diagnosis is difficult and often delayed because of poor specificity of clinical and radiological findings.It should be suspected when pulmonary hypermetabolic lymph nodes are found on FDG-PET/CT scan in a clinical and epidemiological context compatible with tularemia (Martinet et al., 2021).
Pneumonic tularemia has been reported in case series (Centers for Disease Control and Prevention (CDC), 2009;Väyrynen et al., 2017;Darmon-Curti et al., 2020) or as sporadic cases (Matyas et al., 2007;Fritzsch and Splettstoesser, 2010;Mahy et al., 2011;Rimawi et al., 2014;Fachinger et al., 2015).For the above three case series, representing 116 PN cases, no death was reported.Most patients had respiratory symptoms and 50% up to 90% had abnormal lung radiological findings, including frequent hilar or mediastinal lymphadenopathy.Väyrynen et al. (2017) reported a delay in hospital admission of 1-45 days (mean 9.9 days) and a hospital stay of 0-24 days (mean, 8.6 days).Among 84 patients from two series, five patients (5.9%) required admission to an intensive care unit due to respiratory distress [ Centers for Disease Control and Prevention (CDC), 2009;Väyrynen et al., 2017].In these series from the USA and Finland, respectively, a fluoroquinolone was administered in 41 and 77.6% of patients, a tetracycline in 49 and 15.5%, an aminoglycoside in 47 and 6.9%, and these antibiotics were combined in most patients.Complications included sepsis, pleural effusion and empyema, endocarditis, pericarditis, and splenic hematoma [ Centers for Disease Control and Prevention (CDC), 2009;Väyrynen et al., 2017;Darmon-Curti et al., 2020].

Typhoidal tularemia
Typhoidal tularemia is often a severe life-threatening disease (see above) but can also correspond to less severe clinical manifestations, in particular for type B infections (Han et al., 2004;Maurin et al., 2011;Nakamura et al., 2018).This form has been often reported in patients with underlying medical conditions, especially immunosuppression (Han et al., 2004;Maurin et al., 2011;Nakamura et al., 2018).Although tularemia is rarely fatal, a large proportion of deaths occur in patients with a TY form (Han et al., 2004;Maurin et al., 2011;Nakamura et al., 2018).Treatment data are scarce because TY forms are often mixed with other forms in case series (Hofinger et al., 2009;Maurin et al., 2011;Weber et al., 2012;Darmon-Curti et al., 2020).Whatever the severity of the disease, most patients have F. tularensis bacteremia and should receive an aminoglycoside (gentamicin or streptomycin, for 10-14 days) as a first-line antibiotic (Dennis et al., 2001;Bossi et al., 2004).We previously suggested combining an aminoglycoside with a fluoroquinolone in patients with severe tularemia for rapid extracellular and intracellular efficacy because the intracellular penetration of aminoglycosides is slow (Caspar and Maurin, 2017), but the superiority of combined antibiotic therapy compared to monotherapy is not established.Fortunately, empirical treatment in patients with TY tularemia often combined a beta-lactam (amoxicillin clavulanate, cefoperazone, or imipenem) with an antibiotic active against F. tularensis such as an aminoglycoside or a fluoroquinolone (Han et al., 2004;Maurin et al., 2011;Nakamura et al., 2018).When an aminoglycoside was used, an oral relay with a fluoroquinolone or a tetracycline for 2 weeks was often considered.It is notable that relapses usually do not occur in patients with TY tularemia receiving appropriate antibiotic therapy.

Soft tissue infections
Soft tissue infections in tularemia patients are rare and mainly include cellulitis and subcutaneous abscesses (Junkins and Snyder, 2011;Şenel et al., 2015;Arslan et al., 2016;Whitsell and Becker, 2020;Kreutzmann et al., 2021).They may occur through direct inoculation or hematogenous spread of F. tularensis to the skin or extension of a lymph node suppuration to the adjacent tissue.
A 49-year-old woman with facial cellulitis after a scalp tick bite was treated with amoxicillin-clavulanate plus gentamicin, then doxycycline plus ceftriaxone due to suspicion of Lyme disease (Arslan et al., 2016).After treatment failure, streptomycin was given for about 1 week for suspected tularemia with full recovery.A hand abscess with axillary and epitrochlear lymphadenopathy developed after a cat bite in a 66-year-old woman despite pasteurellosis prophylaxis with amoxicillin-clavulanate (Whitsell and Becker, 2020).She was cured after surgical drainage of the abscess and doxycycline treatment for 1 month.A 15-year-old boy developed OG tularemia with submandibular lymph node infection extending to the parotid gland and masseter muscle (Kosker et al., 2013).He was cured after suppurated lymph node excision and treatment with streptomycin (10 days) and tetracycline (8 weeks).A 60-year-old man with OG tularemia and orbital cellulitis did not improve under sulbactam-ampicillin treatment (Kreutzmann et al., 2021).He was cured after excision of suppurated cervical lymph nodes and treatment with ciprofloxacin relayed by doxycycline because of side effects.

Endocarditis and aortic infections
Francisella tularensis endocarditis is a rare complication of tularemia and mostly occurred in men older than 55 years (Tancik and Dillaha, 2000;Salit et al., 2013;Yeom et al., 2015;Gaci et al., 2017;Olivo et al., 2019;Darmon-Curti et al., 2020;Kaeppler et al., 2020).F. tularensis infection involved native cardiac valves (Tancik and Dillaha, 2000;Salit et al., 2013;Gaci et al., 2017), a prosthetic valve (Kaeppler et al., 2020), or a pacemaker (Gaci et al., 2017).Beta-lactams (amoxicillin-clavulanate, piperacillin-tazobactam, cefotetan, cefazolin, ceftriaxone), erythromycin, and vancomycin were ineffective, including in some patients receiving gentamicin concomitantly (Tancik and Dillaha, 2000;Salit et al., 2013;Gaci et al., 2017;Kaeppler et al., 2020).Thus, the first-line treatments for endocarditis caused by Staphylococcus or Streptococcus species are not suitable for tularemia endocarditis.Most patients with tularemia endocarditis received gentamicin intravenously for at least 2 weeks.Ciprofloxacin or another fluoroquinolone was often combined to gentamicin or administered orally as a relay.The total duration of the specific treatment varied from 6 weeks to up to 12 weeks (Olivo et al., 2019).In some patients complications occurred while on appropriate antibiotic therapy, including a pulmonary embolism despite 14 days of intravenous gentamicin and ciprofloxacin (Olivo et al., 2019).Interestingly, in many patients, cardiac valve vegetations were still detected by echocardiography up to 6 months after the end of treatment (Salit et al., 2013;Olivo et al., 2019;Kaeppler et al., 2020).In one patient with severe complications (e.g., pulmonary embolism) and poor compliance to the antibiotic therapy, mitral valve replacement was performed.In other patients, persistence of cardiac vegetations was not associated with relapse and patients recovered without complications (Salit et al., 2013;Kaeppler et al., 2020).Although no definite recommendation can be raised from these anecdotal tularemia endocarditis cases, a 2-week course of intravenous gentamicin alone or combined with intravenous fluoroquinolone followed by 4 weeks oral administration of a fluoroquinolone seems a good alternative in the absence of severe complications.Cardiac surgery was rarely performed and mainly justified by a high risk of hemodynamic failure.Most patients were infected with F. tularensis type B and no death was reported.
Two cases of F. tularensis aortitis have been reported (Briere et al., 2016;Darmon-Curti et al., 2020;Kuzmova et al., 2023).A 85-year-old man developed fever and a systolic murmur due to minimal aortic insufficiency (Briere et al., 2016).Enhanced CT and FDG-PET/CT scans revealed an inflammatory infrarenal aortic aneurysm.After 5 days of vancomycin plus gentamicin, doxycycline was administered due to F. tularensis positive blood cultures.Nineteen days later, part of the aorta was replaced by an aorto-aortic allograft.F. tularensis was PCR detected in the removed aortic tissues.The patient further received 3 months of doxycycline plus levofloxacin and was considered cured.An aortic endograft infection was reported in a 79-year-old man (Kuzmova et al., 2023).F. tularensis was isolated from the aortic and periaortic tissues.He was cured after replacing the aortic graft and gentamicin plus ciprofloxacin treatment for 2 weeks then ciprofloxacin for 10 weeks 6.4.5 Prosthetic joint infections Clary et al. (2022) reported a finger interphalangeal joint arthritis caused by Francisella tularensis inoculated through a cat bite.The patient was cured after receiving gentamicin for 4 weeks.Most reported osteoarticular infections involved knee or hip prostheses, in persons aged 49-84 years, and more frequently men than women.These infections occurred from 1 month up to 25 years after surgical placement of the prosthesis (Cooper et al., 1999;Rawal et al., 2017;Chrdle et al., 2019;Azua and Voss, 2020;Darmon-Curti et al., 2020;Ponderand et al., 2023).Suspected modes of infection included cleaning a rabbit barn (Chrdle et al., 2019), oral contamination (abdominal symptoms), gardening (Chrdle et al., 2019), respiratory infection (Ponderand et al., 2023), skin abrasion after falling (Darmon-Curti et al., 2020), and tick bite (Cooper et al., 1999).Symptoms mainly included fever, joint pain, and difficulty in moving the infected joint.Diagnosis was often delayed of several weeks to months (Cooper et al., 1999) and usually established by F. tularensis isolation from osteoarticular or blood samples.Local complications were occasionally observed [e.g., hip hematoma (Darmon-Curti et al., 2020)], but no systemic complication which might be related to the fact that only F. tularensis type B strains were involved.Cure was usually obtained by combining an antibiotic treatment with surgical replacement of the infected joint prosthesis.Four patients were reported to be cured after doxycycline treatment (Rawal et al., 2017;Chrdle et al., 2019;Azua and Voss, 2020;Escovar et al., 2023).One patient was cured after receiving doxycycline for 6 weeks plus knee prosthesis replacement (Chrdle et al., 2019).Another patient denied surgery and was considered cured only after receiving doxycycline for 1 year (Rawal et al., 2017).The last patient also received a long term treatment with doxycycline (Azua and Voss, 2020).A patient with infected knee prosthesis was administered a lifelong doxycycline treatment because the prosthesis could not be totally removed (Ponderand et al., 2023).A patient with knee prosthesis infection who denied surgical treatment relapsed after receiving 10 days of gentamicin and 21 days of doxycycline, but then was cured with ciprofloxacin for 20 days (Chrdle et al., 2019).Some patients received an antibiotic therapy (e.g., doxycycline for 3 months, gentamicin, or ofloxacin for 6 weeks), then the infected prosthesis was replaced and antibiotics were further administered after surgery (e.g., ciprofloxacin for 3 months, ciprofloxacin plus doxycycline for 9 weeks, or amikacin for 5 days plus ciprofloxacin for 6 weeks) (Darmon-Curti et al., 2020;Ponderand et al., 2023).A complex case was reported in a 68-year-old man with a knee arthroplasty because of rheumatic arthritis (Cooper et al., 1999).The patient first experienced a postoperative prosthesis infection caused by Enterococcus faecalis.One year later, knee inflammation led to prosthesis removal with insertion of a joint spacer with erythromycin-containing cement.After several antibiotic courses with poor clinical response his symptoms improved under ciprofloxacin plus rifampicin combination.A new total knee arthroplasty was placed 3 months later.Diagnosis of tularemia was available at that time likely after several months of evolution of the disease.The patient further received 6 months of ciprofloxacin plus rifampicin and was considered cured.Overall, the therapeutic management of F. tularensis prosthetic joint infections was highly variable between patients, reflecting diagnostic difficulties and the need for treatment adaptation to the context and clinical evolution of each patient.However, all patients were considered cured from their F. tularensis infection.

Tularemia in children
Tularemia occurs less frequently in children than in adults, mainly due to a lower risk of exposure to infection sources (e.g., animal contacts and tick bites).Children are more likely to be infected when the predominant mode of infection is mosquito bite or consumption of contaminated water (Eliasson and Bäck, 2007;Kaya et al., 2011;Gozel et al., 2014;Tezer et al., 2015;Karlı et al., 2018;Dryselius et al., 2019).Data on tularemia treatment in children are summarized in Table 9.
OP tularemia dramatically improved after 10 days of intravenous gentamicin (6 mg/kg/day) (Nemmour et al., 2019).However, he relapsed 2 weeks later with fever, dysphagia and worsening of neck swelling.An MRI exam revealed a left parapharyngeal abscess and necrotic cervical lymph nodes.He was cured after drainage of the parapharyngeal abscess and resection of suppurated lymph nodes and an antibiotic therapy with intravenous gentamicin (6 mg/kg/day, 2 weeks) followed by oral doxycycline for 2 weeks.A 15-year-old boy developed OG tularemia with submandibular and preauricular lymphadenopathy, and subsequent infection of the parotid gland and masseter muscle (Kosker et al., 2013).Lymph node swelling persisted despite 14 days of gentamicin.He then received streptomycin plus ciprofloxacin rapidly replaced by tetracycline due to fluoroquinolone allergy.Cure was obtained by combining lymph node excision, and streptomycin for 10 days plus tetracycline for 8 weeks.A 5-year-old boy developed UG tularemia with abdominal pain 2 weeks after tick bites (Garver et al., 1994).He received gentamicin (7.5 mg/kg/day) and oxacillin (200 mg/kg/day).However, radiological exams revealed bilateral peri-hilar infiltrates, cervical lymphadenopathy, spleen nodules, and mild hepatomegaly.He recovered after excision of suppurated lymph nodes and gentamicin for 7 days.Interestingly, splenic nodules persisted for several months.A 11-year-old Polish boy with UG and PN tularemia received empirical treatment with cefotaxime, clarithromycin, and clindamycin for 11 days without improvement (Sobolewska-Pilarczyk et al., 2014).He was cured after receiving gentamicin (10 mg/kg/day) plus amoxicillin/clavulanate (3.6 g/day, IV, 7 days), followed by ceftriaxone (2 g/d, 6 days) plus cotrimoxazole (1,920 mg/d, 10 days).

Tularemia in pregnant women
Tularemia cases occurring in pregnant women remain scarce (Table 10).Two UG tularemia cases occurring in pregnant women after contact with rabbits during their 16th week of gestation were reported in the USA before the antibiotic era (Bricker, 1931;Bowe and Wakeman, 1936).One experienced spontaneous abortion and the second premature birth.More recently, Ata et al. ( 2013) reported an OP tularemia case in a 36-year-old women at 6 weeks of gestation.Empirical treatment with amoxicillinclavulanate for 10 days was ineffective.She denied any specific antibiotic therapy and pregnancy evolved to intrauterine fetal death.These cases highlight the potential obstetrical complications of untreated tularemia in pregnant women.
One patient with a GL form received 7 days of gentamicin (Saranovic et al., 2023).
Although gentamicin can induce congenital deafness, and ciprofloxacin and other fluoroquinolones have been associated with teratogenic effects in animal models (Johnsrud et al., 2019), none of the five mothers receiving these antibiotics nor their infants had side effects (Yeşilyurt et al., 2013;Saranovic et al., 2023).Gentamicin remains the first-line treatment in pregnant women with severe tularemia (Dennis et al., 2001;Bossi et al., 2004).Azithromycin was administered during pregnancy in two patients with OP or UG forms, respectively (Dentan et al., 2013;Johnsrud et al., 2019) and josamycin in one patient with an UG form (Charles et al., 2008).These macrolides are considered moderately active against F. tularensis, but they likely represent a safe alternative in pregnant women with mild forms of tularemia in areas where F. tularensis type B bv II strains are absent.

Discussion
The aim of this review was to summarize current literature on treatment of human tularemia and highlight the inadequacy of current recommendations, the primary objective of which is the management of multiple and often serious infections in a context of biological threat (Dennis et al., 2001;Bossi et al., 2004).Human infections with F. tularensis greatly vary in their sources and modes of infection, clinical presentation, diagnosis and treatment delays, evolution, and outcome, and according to the patients' underlying health and immune status before infection.
The aminoglycosides remain the first line antibiotics advocated to treat severe tularemia cases, including severe pneumonic and typhoidal forms, especially when caused by the most virulent type A strains (Dennis et al., 2001;Bossi et al., 2004).Streptomycin and gentamicin have likely equivalent effectiveness in patients with systemic diseases.Streptomycin is no longer available in many countries, and usually not administered to young children and pregnant women because of higher nephrotoxicity and ototoxicity compared to gentamicin.Some other aminoglycosides [e.g., tobramycin (Heine et al., 2017;Caspar et al., 2018)] have similar in vitro activity against F. tularensis, but experience in treating tularemia with these molecules is too scarce to consider them as alternatives.Since end of the 1990's aminoglycoside are administered once daily rather than in multiple dosing regimen.Single dose administration evidenced similar efficacy along with reduced probability of nephrotoxicity (Eliopoulos et al., 2007;Avent et al., 2011).The WHO guidelines still recommend administration of gentamicin in two doses while one daily dose in recommended in the consensus statement from Dennis et al. (2001).
Fluoroquinolones or tetracyclines are considered first line antibiotics in patients with mild to moderate severity diseases (Tärnvik and Chu, 2007;Hepburn and Simpson, 2008;Maurin, 2020;Wawszczak et al., 2022).Most of these patients suffer from local or regional infection with lymphadenopathy.The outstanding question is whether one of these two classes of antibiotics is more effective and should be considered as a priority in the treatment of these glandular forms of tularemia.Ciprofloxacin is by far the most prescribed fluoroquinolone, while levofloxacin and moxifloxacin are also considered effective.In recent years, doxycycline was almost the only tetracycline administered to tularemia patients.Arguments that may be in favor of prescribing a fluoroquinolone rather than doxycycline are: (1) fluoroquinolones are bactericidal against F. tularensis in vitro while doxycycline is only bacteriostatic (Maurin et al., 2000;Caspar and Maurin, 2017); (2) fluoroquinolones are more effective in animal models than doxycycline, especially for severe infections caused by type A strains (Russell et al., 1998;Rotem et al., 2012); and (3) lower relapse and failure rates are usually reported in humans treated with fluoroquinolones compared to tetracyclines (Pérez-Castrillón et al., 2001;Meric et al., 2008;Erdem et al., 2014).However, some studies have reported fewer relapses with doxycycline compared to fluoroquinolones (Darmon-Curti et al., 2020).In many patients, treatment failures and relapses are related to the site of infection (e.g., prosthetic infection), treatment delay higher than 2-3 weeks, and the occurrence of complications such as lymph node suppuration (Meric et al., 2008;Komitova et al., 2010), rather than the antibiotic treatment administered.In many reports, success rates were higher in patients treated within the first 3 weeks following disease onset (Helvaci et al., 2000;Celebi et al., 2006;Komitova et al., 2010;Gönen, 2013;Tezer et al., 2013;Ulu-Kilic et al., 2013;Oz et al., 2014).In a study in Bursa (Turkey), success rate whatever the antibiotic regimen chosen was 22/31 (66%) before 3 weeks and but only 21/67 (31%) after 3 weeks.Similarly, Meric et al. (2008) showed by logic regression analyses of 145 cases, that instauration of treatment after the 2nd week doubled therapeutic failure rate.Indeed, complications such as persistence of lymphadenopathies, abscess formation, suppuration or necrosis are fewer if treatment is started during the first 3 weeks (Helvaci et al., 2000;Eliasson and Bäck, 2007;Chitadze et al., 2009;Oz et al., 2014).In particular, Oz et al. (2014) observed 38% abscess formation in 55 children when treatment began early, increasing to 62% after a 3-week delay.In Konya (Turkey), treatment of 16 oropharyngeal tularemia was achieved by antibiotic therapy alone in 9 cases diagnosed within 3 weeks whereas the 7 remaining cases for which delay was superior to 3 weeks, all required lymph node excision (Tezer et al., 2013).Hence, treatment failures and relapse rates are often high in case series, but highly depends on the included patients (Evans et al., 1985;Meric et al., 2008;Maurin et al., 2011;Weber et al., 2012;Ulu-Kilic et al., 2013;Erdem et al., 2014;Darmon-Curti et al., 2020).Many other criteria may determine the choice of a fluoroquinolone or a tetracycline, in particular the history of allergy or intolerance to these drugs, possible side effects, the patient's medical status, age, etc.
It should be emphasized that in many patients with lymph node suppuration or other complications, several antibiotic courses were administered using different antibiotic classes, in combination or alternatively.This practice was either systematic or dictated by an unfavorable and prolonged evolution of the infection.In this case, it is likely that the effectiveness of the treatment corresponded to the cumulative effect of the different antibiotic courses, and ultimately to the total duration of antibiotic therapy.In any case, it is difficult to compare the effectiveness of successive antibiotic therapies in this context, especially since a surgical treatment (e.g., for resection of suppurated lymph nodes) was often added to the medical care.It should be stressed that acquired resistance to antibiotics has never been demonstrated in F. tularensis which currently allows several courses with the same antibiotic in each patient.Specific situations include tularemia occurring in children, pregnant women, and immunocompromised patients.Gentamicin is still advocated as first line treatment for severe systemic infections.In children, a fluoroquinolone or doxycycline can be administered.Although side effects are rare, strict medical surveillance is mandatory.Fluoroquinolones and tetracyclines are classically contraindicated in pregnant women, although fluoroquinolones have been used successfully and without severe side effects in a few pregnant women with tularemia (Yeşilyurt et al., 2013).Azithromycin or josamycin, occasionally combined with drainage or resection of suppurated lymph nodes has been reported as successful in a few pregnant women in areas where type B biovar II strains are absent (Charles et al., 2008;Dentan et al., 2013;Johnsrud et al., 2019).Further evaluation of such antibiotic treatment is needed.Tularemia in immunocompromised patients is often a systemic lifethreatening disease, which needs to be systematically discussed in endemic areas.Treatment in immunocompromised hosts is like that in immunocompetent patients, but a longer duration of antibiotic administration depending on treatment delay should likely be considered.
Almost every organ can be involved in patients experiencing F. tularensis bacteremia.The antibiotic treatment is still based on the aminoglycosides (streptomycin or gentamicin), the fluoroquinolones, and doxycycline.However, because these complications are rare, only anecdotal reports are available.For each complication, the optimum antibiotic treatment remains to be established, especially the antibiotic or antibiotic combination to be used, and the treatment duration.Other antibiotic classes have been considered for treatment of these complications.Chloramphenicol has been used with success in patients with tularemia meningitis (Hofinger et al., 2009).Because of the risk of fatal aplastic anemia, the prescription of this antibiotic must be limited, and its usefulness well assessed.The use of rifampicin in combination with another first-line antibiotic has been reported, especially for osteoarticular infections (Ponderand et al., 2023).None of the other available antibiotic classes have been reported as useful for treating tularemia.
Due to lack of information and insufficient comparable data, no meta-analyses can be performed to date to draw strong conclusions on therapeutic failure rate by clinical form, antibiotic treatment administered, or treatment delay.To reach this goal, studies should at least give the following data for each reported case independently to be able to aggregate all the data: age, sex, clinical form of tularemia, antibiotic treatment (molecules, doses, duration of administration), appropriate treatment delay after disease onset, lymph node suppuration with spontaneous or induced drainage, surgical procedures, and disease evolution (therapeutic failure or relapse, death).Therefore, therapeutic failure and relapse should be clearly defined.Although this review does not make it possible to construct solid therapeutic recommendations, we have tried to establish proposals considering current literature data (Table 12).These proposals must be discussed by a group of experts to develop new recommendations adapted to the diversity of clinical situations encountered during tularemia.
Overall, this review emphasizes the diversity and complexity of human infections with F. tularensis.Although antibiotic treatment is based on only three antibiotic classes, tularemia is often a chronic disease requiring several antibiotic courses combined with surgical treatment for cure.Severe forms and deep infections, although rare, may justify specific therapeutic approaches.Recommendations should be established for treatment of human tularemia cases considering the diversity of clinical symptoms, complications, and patient's health status.It should also be stressed that tularemia diagnosis remains difficult and treatment delay of more than 2 weeks has a significant impact on antibiotic treatment efficacy and

TABLE 2
MICs of aminoglycosides against Francisella tularensis.

TABLE 3
MICs of fluoroquinolones against Francisella tularensis.

TABLE 5
Survival rates in F. tularensis-infected mice treated with antibiotics compared to untreated animals (100% death rate).
Antibiotic administration route, po: per os, in: intranasal, ip: intraperitoneal, iv: intravenous, pi: post-infection.*Percentage of animals that survived at the end of treatment (d21); **Percentage of animals among the survivors that survived the following 16 days (d37).

TABLE 6
Antibiotic efficacy in tularemia patients with predominant UG or GL forms.

TABLE 7
Antibiotic efficacy in tularemia patients with predominant OP forms.

TABLE 8
Antibiotic efficacy in tularemia patients with PN forms.
. Overall, tularemia diagnosis was established by the isolation of F. tularensis from blood samples, lymph nodes, a lung nodule, or an elbow joint 10.3389/fmicb.2023.1348323TABLE11Antibiotic efficacy in immunocompromised patients with tularemia.
10.3389/fmicb.2023.1348323TABLE12Antibiotictreatment suggestions for treating tularemia (doses are for adults) according to clinical form based on current literature.Clinical forms: ulceroglandular (UG), glandular (GL), oculoglandular (OG), oropharyngeal (OP), pneumonic (PN), typhoidal (TY).($) Streptomycin can be used instead of gentamicin in countries where this antibiotic is still available although it's usually considered more toxic.*Antibiotic dosages are for adults.Treatment duration should be adapted to the patient status (e.g., longer in immunocompromised patients) and disease evolution.Treatment of tularemia in children should likely be similar to those for adults with appropriate dosage.