
Bacterial meningitis acquired in the newborn period still carries a high mortality risk. The prognosis is especially grave if the causative organisms belong to certain Gram-negative species, namely Klebsiella, Pseudomonas, Proteus, and the 'water bugs' (McCracken, 1972; George, Cochrane, and Wheeler, 1961) . This latter group of bacteria includes Flavobacteria, Mimae, Xanthomonas, Achromobacter, Chromobacterium, Aerobacter, Serratia, and Erwinia. They have simple growth requirements, abound in water, and infect newborn infants through contamination of the environment (Macpherson, 1958; Sever, 1959) . Several epidemic outbreaks of meningitis in newborn nurseries caused by these organisms have been documented (Foley et al., 1961;  Plotkin and McKitrick, 1966 ; Rance et al., 1962) . Antimicrobial agents used in the treatment of this form of meningitis include erythromycin, chloramphenicol, vancomycin, and novobiocin (George et al., 1961; Hawley and Gump, 1973; Sindhu, 1971) . In the few infants who survive, the bacteriological response to these antibiotics has often been so delayed that host immune mechanisms probably play the major role in the eradication of these organisms (George et al., 1961 However, there are few reports of its use in the treatment of Gram-negative infection in the newborn (Naveh and Friedman, 1973) . We administered this antibiotic parenterally to our patients and directly into the cerebral ventricles through a Rickham ventriculostomy reservoir. Antibiotic levels in blood and cerebrospinal fluid (CSF) were measured. On the basis of our experience dosage recommendations are presented.
Materials and methods
The clinical profile and laboratory data of the 3 neonates are presented in Table I Rifamycin assay. Plastic plates containing 100 ml of nutrient agar seeded with 107 assay organisms were freshly prepared on day of use. Wells of 7-5 mm diameter were made and filled with standard antibiotic solutions and test samples in a sequential fashion with 3-5 replications of each sample. After ovemight incubation at room temperature (28°C), zone sizes were read with a caliper, to the nearest 0 1 mm. A standard curve was prepared for each plate on semilogarithmic paper and concentrations of test samples read off the linear scale (Bennett et al., 1966) .
Materials and methods
A strain of Staphylococcus pyogenes was used to assay low concentrations while a strain of Fl. meningosepticwn was used for high concentrations. Antibiotic standards were prepared in normal human serum for serum assay or in phosphate buffered saline for CSF assay.
Materials and methods
Results Serum rifamycin levels. Serum level-time curves for the 3 infants are shown in Fig. 1 . Peak serum rifamycin concentrations were observed 1 to 2 hours after the intramuscular dose, with a mean value of 14a 1 t±g/ml. The zero time levels represented values 12 hours after the previous dose. The mean rifamycin activity at this stage was 0 * 65 ptg/ml. below the minimal bactericidal concentrations for the infecting organisms. Serial CSF levels monitored 24 hours after daily intraventricular administration of 2 or 5 mg rifamycin ranged from 3 to 94 ,ug/ml (Fig. 3) . At the time of study the ventricular size was assessed by measurement of the head circumference and thickness of the frontal cerebral mantle. These dimensions are included in Table I . Though an identical dose of rifamycin (2 mg) was administered intrareservoir in 2 infants with greatly differing ventricular volume, daily CSF antibiotic concentrations were only marginally higher in the baby (Case 2) without significant ventricular dilatation. There was no evidence of drug accumulation within the CSF with the doses used. cin. Bilirubin was mainly conjugated with a maximal recorded level of 10-3 mg/100 ml (total). It persisted for 4-8 weeks and regressed spontaneously despite continuation of the drug. Full blood counts, blood urea, electrolytes, serum transaminases, and alkaline phosphatase levels were determined weekly. All levels were normal and they did not alter significantly during therapy.
Materials and methods
Response to therapy. All 3 infants developed hydrocephalus requiring shunts. Cases 2 and 3 are developing normally and only Case 1 was left with a significant neurological defect when last followed up at 9 months of age. Her developmental age was assessed as 6 months, and increased tone and reflexes were noted in all 4 limbs.
Discussion
Most paediatricians have experienced enormous difficulty in sterilizing the CSF of neonates with meningitis caused by 'water bugs' (George et al., 1961; Foley et al., 1961; Sindhu, 1971) . Factors contributing to the high fatality in this illness include delay in diagnosis, and delay in the accurate identification of the organism. Furthermore, these organisms have an unusual pattern of antibiotic sensitivity, being generally resistant to the conventional chemotherapeutic agents used in the treatment of neonatal meningitis, i.e. ampicillin, gentamicin, kanamycin, and chloramphenicol (Altmann and Bogokovsky, 1971) . Thus, by the time treatment with appropriate antibiotics is started, severe neurological damage has usually occurred. Even after the administration of suitable antibiotics the response is often unsatisfactory largely because of poor penetration into the CSF, together with the rapid development of resistance (George et al., 1961) .
Discussion
Studies in this hospital have shown that all 21 isolates of Flavobacteria cultured from neonates are sensitive to rifamycin-the MIC ranging from 0 *625-3 1 [±g/ml. Of the 20 antimicrobial agents tested in vitro against this organism by Altmann and Bogokovsky (1971), rifampicin was judged to be the most efficient. There are very few accounts of the use of this antibiotic in the treatment of neonatal bacterial infections, and we have not encountered any report of its use in meningitis. This prompted us to monitor blood and CSF levels of rifamycin in our patients. The wide variation in serum antibiotic levels in these infants is probably related to uncertain rates of absorption and excretion of drugs in the neonatal period. We found that, even in the presence of high serum levels and meningeal inflammation, rifamycin does not cross the blood-brain barrier in sufficient concentration for the effective treatment of neonatal meningitis. D'Oliveira (1972) similarly recorded CSF rifampin* levels between 0-041-1 37 ,ug/ml with the use of the drug in meningeal tuberculosis. Only in Case 2 in our series did the CSF antibiotic levels exceed the MIC for the organism when rifamycin was given intramuscularly. Lorber, Kalhan, and Mahgrefte (1970) , however, advised that since the most important factor in the prognosis of neonatal meningitis is the level of the antibiotic in the CSF, this level must exceed the MIC for the pathogen by 50-fold to be effective. This concentration can be adequately reached without causing systemic toxicity by direct intraventricular instillation of the drug. In our patients the high CSF rifamycin levels obtained by this method resulted in prompt sterilization of their ventricles. There was no evidence of cerebral irritability or convulsions during the course of intraventricular therapy.
Discussion
If during the course of treatment CSF leucocytosis persists despite adequate antibiotic concentration, and if repeated attempts to culture the organism fail, colonization within the reservoir should be suspected. This occurred in Case 2. The delay in removal of the ventriculostomy catheter after its colonization by the bacteria probably led to progressive hydrocephalus in this infant.
Discussion
In our experience, rifamycin is a safe and effective antibiotic in the treatment of certain variates of Gram-negative meningitis. The occurrence of jaundice alone during drug therapy is not a contraindication for its continued use. Because of the risk of potential hepatic toxicity, however, liver function tests should be monitored during treatment (Radner, 1973) . The cases selected for treatment should of course be determined by results of culture and sensitivity testing. Rifamycin discs are now used routinely in the University Hospital when testing organisms isolated from spinal fluid of neonates. We recommend treatment at first with rifamycin parenterally in a dosage of 40 mg/kg per day in two equal doses. In addition, daily intrathecal or preferably intraventricular instillation of the drug in a dosage of 2-5 mg/day is an essential complement to systemic therapy. Further study is required before we can confidently recommend the duration of intraventricular and parenteral therapy-we have probably erred on the side of caution in this respect.
Discussion
We are grateful to Dr. R. E. Weaver, Center for Disease Control, Atlanta, Georgia, U.S.A., for confirming the identity and serotyping the isolated organisms. flavobacteria meningitis. 
Rifamycin in neonatal


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