Treatment of Listeria monocytogenes bacteremia with oral levofloxacin in an immunocompromised patient

A 72-year-old woman presented with fever, malaise, and diarrhea. The patient was conscious, and was negative for meningeal signs on physical exam. Blood tests revealed elevated C-reactive protein (CRP) and white blood cell count with neutrophil dominance. Suspecting a bacterial infection, empirical antimicrobial treatment with oral levofloxacin was initiated after collecting two sets of blood culture. On the 3rd day, the patient's fever resolved. On the 7th day, Listeria monocytogenes bacteremia was diagnosed with both blood cultures turning positive. On the 15th day, the patient’s symptoms had improved. We ceased treatment when the CRP level decreased. Listeria monocytogenes is a gram-positive bacterium that causes serious infections in elderly and immunocompromised hosts. Penicillin, ampicillin, amoxicillin, and gentamicin are recommended for the treatment of Listeria infections. It has been reported that new fluoroquinolones may be effective in vitro and in animal models. Although further evidence is required, new fluoroquinolones, especially levofloxacin, may provide an option for the treatment of Listeria infection.


Introduction
Listeria monocytogenes is a bacterium that invades the cytosol of cells and causes gastroenteritis, often resulting in debilitating effects in healthy adults. It can cause life-threatening invasive infections especially in pregnant women, newborns, the elderly, transplant recipients, and immunocompromised patients. L. monocytogenes are naturally present in moist environments, soil, water, and decaying vegetation and animals. Moreover, they survive and grow when subjected to refrigeration and other food preservation measures. It is often transmitted to humans through unpasteurized milk, sausages, and raw meat [1]. The most common type of Listeria infection is the infection of the central nervous system (CNS), followed by bacteremia or sepsis, with a mortality rate of up to 70 % [2]. Listeria sepsis or bacteremia accounts for one-third of adult cases of invasive listeriosis, with symptoms typically manifesting as fever and chills [3]. Beta-lactam antibiotics, such as penicillin, ampicillin, amoxicillin, and gentamicin have bactericidal effects and are recommended for the treatment of listeriosis [4]. Recently, fluoroquinolones have also been reported to be effective against L. monocytogenes in vitro and in animal models [5][6][7]; however, there are few clinical case reports. Here, we describe a case of successful treatment of Listeria bacteremia with oral levofloxacin in an immunosuppressed patient.

Case
A 72-year-old woman arrived at the emergency department complaining of a fever (39 • C), malaise (since 4 days), and watery diarrhea (since 5 days). She had eaten sausages prior to the fever; however, detailed information regarding the date or type of sausage was unclear. She had a history of rheumatoid arthritis, controlled with prednisolone (5 mg/day) and methotrexate (16 mg/week).

Clinical course
On initial evaluation, the patient was conscious, had a fever of 38.3 • C, and had tachycardia with a heart rate of 120 beats per minute. Physical examination revealed that nuchal rigidity, jolt accentuation, and Kernig sign were negative. The patient informed not being in contact with any sick individuals but recollected having eaten sausages a few days before the fever. Blood tests revealed an elevated C-reactive protein (CRP) level of 12.72 mg/dL and increased white blood cell count of 8,600/µL with neutrophil dominance (Table 1). Liver enzymes, kidney function, and coagulation factors were within normal limits. The * Correspondence to: Shonan Kamakura General Hospital, 1370-1, Okamoto, Kamakura, Kanagawa 247-8533, Japan.
E-mail address: sushi.sova.udon@gmail.com (Y. Ishihara). urinary culture was negative for bacteria. Because the patient did not show meningeal signs, we did not perform a lumbar puncture. Nonenhanced computed tomography of the chest and abdomen showed no abnormalities. Considering that the patient was immunocompromised, we collected two sets of blood culture. Suspecting bacterial infection, empirical antimicrobial treatment with oral levofloxacin (500 mg/day) was initiated. The patient's fever resolved on the 3rd day of treatment. L. monocytogenes bacteremia was diagnosed on the 7th day with a positive blood culture, which was susceptible to levofloxacin, ampicillin, erythromycin, minocycline, and vancomycin. On the 15th day, as the CRP level had decreased to 1.46 mg/dL, we ceased treatment (Fig. 1). Because the patient's symptoms had improved, blood cultures were not collected again. In addition, as the patient appeared to be healthy after the end of treatment, the follow-up was terminated.

Discussion
Here, we describe a case of L. monocytogenes bacteremia in an immunocompromised patient who was successfully treated with oral levofloxacin. In this case, levofloxacin, which had been prescribed as an empiric therapy for suspected bacterial infections, was suitable for treatment.
Listeria bacteremia causes flu-like symptoms, such as febrile illness and diarrhea, without local symptoms. Cases of bacteremia complications in CNS listeriosis are relatively high, at about 40 %, and are highrisk cases with a high mortality rate. Patients with Listeria infection in the CNS exhibit altered mental status, fever, seizure, focal neurological symptoms, and nuchal rigidity approximately 60 % of the time [1,8]. In this case, the patient showed no signs of altered mental status and rigidity; thus, CNS listeriosis was thought to be negative. It was assumed that ingestion of contaminated sausages caused infection via the intestinal tract; however, stool cultures were not performed as her diarrhea had resolved.
L. monocytogenes is a facultative cellular, intracellular parasitic bacterium; therefore, the ideal antimicrobial agent should penetrate host cells and bind to intracellular targets. Penicillin, ampicillin, and amoxicillin are frequently used for treating Listeria infections. Combination therapies, such as adding gentamicin to ampicillin, have been reported to be most effective against this bacterium in vitro; however, gentamicin is not active against intracellular bacteria [1]. Rifampin, vancomycin, linezolid, and carbapenems are used as alternatives, and trimethoprim is used in case of intolerance of beta-lactams [9]. Gentamicin in combination with ampicillin remains the primary treatment; however, over 30 % of patients fail antibiotic therapy, therefore further secondary treatments are being considered [10]. New fluoroquinolones, such as levofloxacin, clinafloxacin, sparfloxacin, and moxifloxacin, have been reported to penetrate intracellularly, be concentrated in the cytoplasm of host cells, and show bactericidal effect against L. monocytogenes in multiple studies in vitro [11][12][13]. Among the new fluoroquinolones, levofloxacin was the most active against L. monocytogenes in vitro [5]. In animal models, the efficacy of levofloxacin against L. monocytogenes has been demonstrated in mice [6]. A clinical case report of levofloxacin being effective against monocytogenes meningitis also exists [14]. However, no large-scale clinical studies have been conducted. Additional clinical studies are necessary to provide further evidence of the effectiveness of levofloxacin against L. monocytogenes bacteremia as exemplified in the present case.
In conclusion, L. monocytogenes bacteremia was treated with oral levofloxacin. This treatment method might be an option for patients with Listeria infections; however, it is being currently used only in selected cases, such as when existing therapies are contraindicated for the patient. Although pharmacologically effective, there is little evidence of its use as a standard of care; therefore, further clinical studies are needed to establish evidence for the same.

Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Funding
This research received no specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

Authors' contributions
YI was responsible for the coordination and writing of the manuscript. All authors participated in the discussion during manuscript  preparation. All the authors have agreed to publish this manuscript. All authors meet the ICMJE authorship criteria.

Conflict of Interest
The authors declare that they have no conflicts of interest.