*Department of Pediatrics, Yokohama Minato Red-Cross Hospital, Yokohama and †Department of Child Neurology, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
Address correspondence and reprint requests to Hiroshi Sakuma, MD, Department of Child Neurology, National Center Hospital for Mental, Nervous and Muscular Disorders, National Center of Neurology and Psychiatry, 4-1-1, Ogawa-Higashicho, Kodaira, Tokyo, Japan. E-mail: email@example.com.
A 5-day-old female infant developed meningitis due to Chryseobacterium meningosepticum. Although the isolate was resistant to empirical antibiotics such as penicillins, cephalosporins, and aminoglycosides, she was successfully treated with intravenous ciprofloxacin and trimethoprim-sulfamethoxazole without adverse reactions including arthropathy and jaundice. This result justifies the use of ciprofloxacin and trimethoprim-sulfamethoxazole for neonatal meningitis caused by C. meningosepticum.
Chryseobacterium meningosepticum, formerly known as Flavobacterium meningosepticum, is a gram-negative bacillus, which has been known to cause meningitis in newborns. Neonatal meningitis caused by C. meningosepticum, which is uniformly resistant to commonly used antibiotics, is associated with high mortality rate and severe neurological sequelae. Although a previous report had focused on the efficacy of vancomycin and rifampin,1 the standard regimen for antimicrobial chemotherapy against C. meningosepticum is still in controversy. Thus, we describe a case of C. meningosepticum meningitis successfully treated with ciprofloxacin and trimethoprim-sulfamethoxazole.
A full-term 5-day-old female infant weighing 2934 g was admitted to the hospital because of fever. She was born after an uncomplicated pregnancy and delivery. Neither preterm rupture of membrane nor maternal infections were noted. The Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. On the third day of her life, she had a fever of 38°C that declined temporarily on the next day when she was discharged from the maternity hospital. Upon admission, the patient had a temperature of 39.1°C. She was active, well nourished, and conscious. She was slightly icteric, but her anterior fontanel was not bulged, and neck stiffness was absent. Neurological examination was unremarkable. The complete blood cell count showed a white blood cell (WBC) count of 16,900/μL, a hemoglobin level of 10.6 g/dL, and a platelet count of 334,000/μL. The C-reactive protein was 1.2 mg/dL, and the serum basic chemistry was normal. We immediately conducted a sepsis workup because severe bacterial infection was suspected. Lumbar puncture yielded cloudy cerebrospinal fluid (CSF) with a protein concentration of 286 mg/dL, a glucose concentration of 4 mg/dL, and a WBC count of 10,800/μL, of which, 72% were neutrophils, 6% were lymphocytes, and 22% were monocytes. Many gram-negative bacilli were observed on the CSF smear. The patient was diagnosed with bacterial meningitis and was hospitalized in the neonatal intensive care unit. Empirical intravenous antimicrobial chemotherapy of ampicillin (400 mg/kg per day) and cefotaxime (300 mg/kg per day) was initiated. Intravenous dexamethazone (0.6 mg/kg per day) and immunoglobulin (200 mg/kg per day) were also administered for 2 days. On the third day of hospitalization, the patient still had fever associated with vomiting and decreased oral intake. She displayed irritability and hypertonicity and developed a generalized tonic seizure. The CSF examination revealed a cell count of 5000/μL, a glucose of 4 mg/dL, and numerous bacilli on Gram stain. Ampicillin and cefotaxime were replaced by ceftazidime (200 mg/kg per day), tazobactam/piperacillin (300 mg/kg per day), and panipenem/betamipron (120 mg/kg per day). On the fourth day, C. meningosepticum was first isolated from blood and CSF cultures. Serotype of the bacteria was not tested. Antimicrobial susceptibility testing using disk diffusion method (Kirby-Bauer technique) showed that the isolate was susceptible to tazobactam/piperacillin, minocycline, ciprofloxacin, and trimethoprim-sulfamethoxazole but resistant to ampicillin, cefotaxime, ceftazidime, and panipenem/betamipron. She remained critically ill, and her CSF still contained a large number of cells (15,100 WBCs/μL) and bacilli on day 5; hence, ceftazidime and panipenem/betamipron were withdrawn, whereas ciprofloxacin (20 mg/kg per day) and trimethoprim-sulfamethoxazole (10 mg/kg per day of trimethoprim) were initiated. Because these antimicrobial agents had not been approved for neonatal use in our country, informed consent was obtained from the patient's parents. Consequently, her temperature returned to normal, followed by gradual normalization of cell count and protein levels in CSF. Cultures of blood and CSF were sterile after the seventh day. The patient completed a 21-day course of combined antimicrobial chemotherapy and was discharged on the 28th day of hospitalization. No adverse reactions such as hyperbilirubinemia, myelosuppression, rickets, and liver dysfunction were observed during treatment. Upon discharge, the patient underwent magnetic resonance imaging, electroencephalogram, and auditory brain stem response; results did not show any abnormality. Follow-up of the patient at age 1 revealed normal motor and intellectual development without neurological sequelae.
Chryseobacterium meningosepticum is an immotile, oxidative, and gram-negative bacillus ubiquitously distributed in nature, especially in soil and water. It was first classified by King2 in 1959 and has been recognized as an opportunistic pathogen in newborns and in immunocompromised adults. Nosocomial infections in neonatal intensive care units have been documented. Medical devices including water taps, stock solutions, and respiratory equipment can be reservoirs of C. meningosepticum. The source of acquisition for this organism was not confirmed, despite extensive environmental surveillance. There was no additional case of infection from the hospital where she was born.
Neonatal meningitis caused by C. meningosepticum is uncommon but is of clinical concern because of its poor prognosis and high mortality rate. Dooley et al3 summarized previously reported cases of C. meningosepticum meningitis-of whom, 65% had died. Approximately two thirds of survivors were reported to have developed hydrocephalus due to ventriculitis. Chryseobacterium meningosepticum is highly resistant to empirical antibiotics including penicillins, cephalosporins, and aminoglycosides. Although appropriate choice of antibiotics is crucial in the early stage of meningitis, this is a difficult task because of the multidrug-resistant nature of this organism.
Di Pentima et al1 reported 3 cases of C. meningosepticum meningitis, which were successfully treated with intravenous vancomycin and rifampin. They concluded that the combination of vancomycin and rifampin is an appropriate regimen for neonatal meningitis caused by this organism because the combination of these antibiotics showed in vitro synergy. However, a recent report from the SENTRY Antimicrobial Surveillance Program (1997-2001) suggested that vancomycin should not represent satisfactory therapeutic option for Chryseobacterium infections.4 Other antimicrobial agents including erythromycin, chloramphenicol, and carbapenems are also not promising. Although minocycline shows a high rate of sensitivity,5 it is contraindicated for neonates because of the risk of permanent teeth discoloration. Rifampin, one of the most active agents against this pathogen in vitro, is unavailable for intravenous use in Japan.
Ciprofloxacin is a broad-spectrum fluoroquinolone that is efficacious in treating infections caused by gram-negative bacilli. However, its use in children has been strictly restricted to special conditions because of potential cartilage toxicity shown by experimental animal study. Nevertheless, it has been widely used in infants and even in neonates because of its efficacy to cure otherwise incurable systemic bacterial infection. Clinical studies in neonates have found no short-term hematologic, renal, or hepatic adverse effects and no association with clinical arthropathy and linear growth impairment at 1-year follow-up.6 The patient has had a normal growth parameter for her age without any joint problems. Twelve cases of neonatal and infantile nosocomial meningitis treated with intravenous ciprofloxacin in dosages of 10 to 60 mg/kg per day resulted in a favorable outcome.7 Gogos et al8 demonstrated that ciprofloxacin is sufficiently diffused into the CSF of patients with inflamed and noninflamed meninges. Considering the increasing resistance of C meningosepticum to ciprofloxacin, other quinolones, including gatifloxacin or levofloxacin, may be an alternative.5
Chryseobacterium meningosepticum is also sensitive to trimethoprim-sulfamethoxazole. Linder et al9 treated 9 septic infants with trimethoprim-sulfamethoxazole, and bacteriologic cure was achieved in 8 cases. The CSF-to-serum concentration ratio ranged from 0.13 to 0.53 for trimethoprim and 0.19 to 0.63 for sulfamethoxazole. Although a wide range of dosages was used orally and intravenously, Dudley et al10 recommended a loading dosage of trimethoprim of 10 to 12 mg/kg and a maintenance dosage of 6 mg/kg every 8 hours or 8 mg/kg every 12 hours for adult meningitis. The use of trimethoprim-sulfamethoxazole during the neonatal period has provoked a great deal of controversy because of its potential cause of hyperbilirubinemia. This drug binds to albumin and competes with bilirubin. However, sulfamethoxazole did not displace bilirubin from albumin-binding sites even in concentrations far above the therapeutic range.11 Moreover, the bilirubin concentration was normal during trimethoprim-sulfamethoxazole treatment in the patient. In vitro synergy testing of ciprofloxacin and trimethoprim-sulfamethoxazole is necessary to support the validity of this combination.
In conclusion, we successfully treated a case of neonatal C. meningosepticum meningitis with ciprofloxacin and trimethoprim-sulfamethoxazole. Thus, this combination should be considered a therapeutic option for neonatal meningitis caused by C. meningosepticum.
The authors thank Dr Kikuko Oku for the helpful suggestions in the diagnosis and treatment of the patient.
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