Seawater-Associated Highly Pathogenic Francisella hispaniensis Infections Causing Multiple Organ Failure

A rare case of Francisella hispaniensis infection associated with seawater exposure occurred in a deep-sea diving fisherman in Zhejiang, China. He had skin and soft tissue infection that progressed to bacteremia and multiple organ failure. Moxifloxacin treatment cleared the infections, but the patient suffered a sequela of heart damage.


DISPATCHES
F rancisella tularensis, the agent of tularemia, is an important human pathogen (1). Other Francisella species, such as F. philomiragia, mainly associated with saltwater exposure, rarely also cause human infections (2). F. hispaniensis, first isolated from the blood of a patient in Spain (3), is an emerging human pathogen, but its epidemiology and pathogenicity remain a mystery because only 2 cases have been reported (3,4). We report a case of F. hispaniensis infection in China.

Case Report
On September 6, 2018, a 64-year-old male fisherman sought care for a prominent cutaneous ulcer on the right lower chest, chest pain, and fever for 16 days and was admitted to The First Affiliated Hospital of Zhejiang University (Hangzhou, China). He was previously healthy without remarkable medical history. He worked as a deep-sea diving fisherman in Sanmen Bay, Taizhou, a coastal city in Zhejiang Province, adjoining the East China Sea. A superficial wound progressed to cellulitis in the right lower chest after a deep-sea dive without protective clothing. Low-grade fever and chest pain then developed. He received amoxicillin/clavulanic acid at a local clinic, and his fever resolved after 2 days. Because he felt better, he stopped taking the amoxicillin/clavulanic acid and resumed deep-sea diving. Two days later, his chest wound had worsened with purulent discharge, and his low-grade fever returned. Twelve days later he sought care at another hospital because of high fever and respiratory distress. He received 2 days of ceftizoxime followed by imipenem for 7 days, but his condition deteriorated, and irritability, chest tightness, nausea, vomiting, abdominal distension, chills, and high fever (39.4°C) developed. At admission to The First Affiliated Hospital of Zhejiang University School of Medicine, he had sepsis, hypotension, and leukocytosis and immediately received norepinephrine intravenous pumping, endotracheal intubation, sedation, mechanical ventilation, and continuous renal replacement therapy. His lower chest showed a large ulcer with bleeding, purulent discharge, and tissue necrosis (Figure 1, panel A). Laboratory test results showed highly elevated inflammatory markers, acidosis, coagulopathy, and elevated liver enzymes, bilirubin, creatinine, and troponin (Table 1). Chest computed tomography scan showed right lower lobe consolidation, pleural effusion in the right thoracic cavity, and multiple calcified lymph nodes in the mediastinum. Abdomen computed tomography    Drug susceptibility tests showed resistance to colistin, trimethoprim/sulfamethoxazole, third-generation cephalosporins, and carbapenems but susceptibility to piperacillin/tazobactam, cefepime, fluoroquinolones, aminoglycosides, and tetracyclines ( Table 2). Because a Bla-2/FTU-1 class-A β-lactamase is expressed among most Francisella species (6), the strain reported here also carries a homologue gene of 867 bp with 89.7% identity to the reference gene (GenBank accession no. NG_049110_FTU-1) (7). No plasmids were identified. Other resistance genes identified were aph(3′)-Ia, predicting resistance to kanamycin; mdf(A), predicting resistance to macrolide; and catA1, predicting resistance to phenicol. However, broth microdilution tests showed low MIC for kanamycin, erythromycin, azithromycin, and chloramphenicol ( Table 2). The reason for the inconsistency between the resistance genes detected and phenotypic susceptibility results is unclear and requires further investigation.
On the basis of the MIC results and the literature (4,8,9), we chose moxifloxacin (400 mg 1×/d injection) to treat the infection. After 14 days of treatment, the patient's symptoms markedly improved, and the chest wound started to heal. Most blood test results had returned to normal ranges (Table 1). However, his heart suffered long-term damage because of the myocarditis, and he required a pacemaker. He was discharged 28 days after admission.

Conclusions
In the 2 previously reported human F. hispaniensis infections, the bacteria were isolated from blood (3,4). The patient we report first suffered a trauma to unprotected skin of his chest that was exposed to seawater from which the bacteria entered the wound and caused the skin and soft tissue infections that progressed to bacteremia and sepsis. Like F. tularensis, F. hispaniensis appeared to be highly pathogenic and caused respiratory failure, septic shock, and multiple organ dysfunction syndrome. Unlike F. tularensis, F. hispaniensis grew well under regular culture condition. However, because of its rarity in the clinical setting, conventional biochemical methods misidentified the bacterium as S. paucimobilis. WGS is a powerful molecular method to provide the definitive identification.
Most interestingly, the bacteria appeared to have originated from seawater. Sanmen Bay has muddy beaches with shallow seawater and high microbial richness suitable for marine aquaculture (http://www.sanmen.gov.cn/art/2018/6/5/ art_1519452_20483713.html). F. hispaniensis also probably lives in seawater and under the right conditions could cause human infections. In 1 F. hispaniensis case, a woman in Australia had a fishhook injury, which was consistent with the seawater exposure hypothesis (4). Other Fransicella species, such as F. noatunensis, which inhabits the ocean, are major pathogens for fish and shellfish (10). The patient in our report acquired infection in August, the hottest month in Zhejiang Province. The high temperature could promote bacteria growth in the seawater and increase the likelihood of human exposure.
The F. hispaniensis isolate in our report exhibited a similar antimicrobial susceptibility pattern to F. tularensis. This finding is consistent with a study showing susceptibility of all 91 Francisella strains tested to aminoglycosides, tetracycline, and fluoroquinolones (11). Fluroquinolones, such as ciprofloxacin, are highly effective in treating infections caused by F. tularensis (12), F. philomiragia (2,13), F. novicida (14), and F. hispanensis (4). Third-generation cephalosporins and carbapenems are generally not active against Francisella spp. (9,11), as shown by failed treatment with ceftizoxime and imipenem in the case we describe. Studies based on mouse models showed moxifloxacin is more effective than ciprofloxacin in treating tularemia and is less affected by treatment delay (9,15). In this patient, moxifloxacin successfully treated F. hispaniensis infections without relapse.
In summary, clinicians need to be aware of the emerging and highly pathogenic F. hispaniensis, which is resistant to many β-lactams, including the cephalosporins and carbarpenems commonly used for empirical treatment. Our report also demonstrates that seawater exposure can be a risk factor for acquiring F. hispaniensis infection.