a Department of Medical Microbiology, Royal London Hospital, Whitechapel, London E1 1BB; b Copsewood, Clonmel Close, Harrow on the Hill, Middlesex HA2 0JZ; c Department of Medical Microbiology, Medway Maritime Hospital, Windmill Road, Gillingham, Kent ME4 5NY, UK
Although Salmonella strains only account for 1% or less of the confirmed cases of bacterial meningitis in neonates and infants,1,2 such infections are often associated with a high complication rate, a high mortality rate and a greater potential for relapse than occurs with meningitis caused by the more common Gram-negative pathogen, Escherichia coli.3 The possibility of Salmonella infection should be kept in mind whenever Gram-negative rods are seen in cerebrospinal fluid (CSF). If Salmonella spp. are grown from a site outside the central nervous system (CNS) in any unwell child, especially one under 6 months of age, consideration should be given to performance of a lumbar puncture. A pregnant woman who develops Salmonella infection or is an intestinal carrier of salmonellae may pose a risk to her baby of invasive meningitis. There is also an important association between keeping reptiles as pets and Salmonella CNS infections in children, and two fatal cases have recently been reported in the UK.4
Overall, antibiotic regimes for treatment of Salmonella meningitis in children have not been as successful as those used to treat E. coli meningitis.3 Antimicrobial agents used previously, either alone or in various combinations, have included chloramphenicol, ampicillin and co-trimoxazole. Some isolates are now resistant to one or more of these agents and reports suggest that treatment with ampicillin and/or chloramphenicol has been associated with a mortality rate of c. 30%.5,6 With regard to chloramphenicol, it is necessary to calculate the dose carefully because of its potential for toxicity, especially in neonates, but it is also essential that therapeutic levels are achieved and maintained. In 1987, treatment with cefotaxime or ceftriaxone, agents with few toxicity problems, was recommended for a minimum of 3 weeks (in the absence of cerebral abscess),5,7 but some reports have now indicated that the clinical results with such cephalosporins are not always as satisfactory as initially hoped.811 The American Academy of Pediatrics now recommends that treatment for Salmonella meningitis with cefotaxime or ceftriaxone should continue often for 4 weeks or more,12 although relapses following cefotaxime therapy have been reported even with 4 weeks of treatment.9,10,13 Meningitis caused by Salmonella spp. resistant to cephalosporins is uncommon, although it has occasionally been reported.14 The combination of a third-generation cephalosporin with gentamicin, widely used for initial treatment of meningitis caused by Gram-negative enteric bacilli, may not be appropriate when treating facultative intracellular organisms, such as salmonellae, because gentamicin has poor intracellular penetration. Furthermore, gentamicin does not efficiently penetrate the bloodbrain barrier and use of intraventricular gentamicin was associated with increased mortality in one study of Gram-negative bacilliary meningitis in infants that included patients with Salmonella infections (although not all of these were sensitive to gentamicin).15 So far, there is insufficient experience with imipenem and meropenem to judge whether they provide any therapeutic advantage, even though in experimental models, the rate of killing of salmonellae in CSF was more rapid with imipenem or ceftriaxone than with co-trimoxazole or chloramphenicol.16 In individual cases, imipenem has been used successfully,10,14 although meropenem, with its lower likelihood of CNS toxicity, may be preferable, especially if renal failure is present.
As an alternative, we suggest that consideration should be given to antibiotic therapy with a combination of ciprofloxacin and ceftriaxone (or ciprofloxacin and cefotaxime if jaundice or other factors preclude use of ceftriaxone, as discussed below). Data on the optimal duration of therapeutic regimes are lacking, but we would suggest that both agents should be administered for a minimum of 3 weeks and that this should be timed from the first sterile CSF. (The specimen should be taken no earlier than day 4 of therapy, as cultures from patients with Salmonella meningitis sometimes remain positive for prolonged periods.16) Although this antibiotic combination is not usually synergic, there is no evidence that it is antagonistic.17 Ciprofloxacin and third-generation cephalosporins have been used in combination with success for prolonged periods to treat cerebral abscesses caused by Salmonella spp.18,19 Ciprofloxacin use in paediatrics has been limited because of fears of arthropathy, although recent world-wide experience indicates that this is extremely uncommon.20,21 It is still not licensed for use in children, other than cystic fibrosis patients aged 517 years with Pseudomonas aeruginosa infections. However, although ciprofloxacin may be considered as appropriate in the treatment of serious paediatric infections where potential benefit outweighs risk. It penetrates CSF well22 and although concentrations are low, reflecting the relatively low concentrations obtained in plasma, they are likely to be many times greater than the MICs of susceptible Salmonella strains. There are reports of successful treatment using ciprofloxacin monotherapy,23,24 but on the basis of current experience and because of the possibility of ciprofloxacin resistance,14,25 (particularly following licensing of the related fluoroquinolone enrofloxacin for veterinary use in the UK26) we advocate the use of combined therapy.
In neonates, ceftriaxone is recommended for treatment of severe infections at a single daily dosage of 50 mg/kg27 (although a higher daily dosage was used in one reported case of Salmonella meningitis5). Use of ceftriaxone is not advised in jaundiced newborns or in those who are hypoalbuminaemic or acidotic, in whom bilirubin binding is likely to be impaired. Caution is also recommended in premature infants. The administration time should be 60 min to reduce the displacement of bilirubin from albumen and thus limit the risk of encephalopathy. Ceftriaxone may be associated with an increased risk of precipitation as its calcium salt in the bile, particularly if given in high doses in infants and small children. This is usually reversible. In older infants and children, the ceftriaxone dosage has been recommended as 80 mg/kg every 12 h for the first three doses, then 80 mg/kg (maximum 4 g single dose) once daily for treatment of the more common causes of meningitis.27 Where cefotaxime is used instead of ceftriaxone, a very high daily dosage of 200300 mg/kg has been recommended,7 although neonates were not specifically considered in this recommendation.
The iv dosage of ciprofloxacin recommended when benefits outweigh risks for treatment of general infections in children (other than those with cystic fibrosis) has recently been increased to 816 mg/kg/day in two divided doses. In case reports of successful treatment of Salmonella meningitis in two neonates, ciprofloxacin was given iv at 10 mg/ kg/day23 and 15 mg/kg/day24 in two divided doses. In another report, a considerably higher iv dosage of 30 mg/kg/day was used in infants aged 2 and 5 months with Salmonella meningitis.9 The oral dosage of ciprofloxacin now recommended for general infections in children (other than those with cystic fibrosis) is 1030 mg/kg/day in two divided doses. In a study of two neonates from Zaire with non-Salmonella Gram-negative bacillary meningitis, ciprofloxacin was given orally at c. 30 mg/kg/day, following 4 days of high dose iv therapy.29 However, in the UK, for treatment of such a serious infection as Salmonella meningitis, we recommend that, under normal circumstances, the whole ciprofloxacin course should be given iv rather than orally.
Subsequent modification of therapy may be indicated depending on sensitivity results and clinical response. Recommendations vary on the need to take further CSF specimens. In our opinion, routine follow-up lumbar punctures after the first negative CSF culture need only be performed if clinically indicated. Neuroimaging studies have been recommended for every patient with Salmonella meningitis in view of the high percentage of abnormalities detected.8 The information from these studies is also useful for review of treatment and prognosis. If present, a cerebral abscess will require treatment for a considerably longer period than would be given for meningitis alone.18,19
Finally, even after an apparently satisfactory clinical response to antibiotics, staff and parents should be made aware that there is still a need for vigilance because of the possibility of relapse.3,10,11 This may occur days or even weeks after apparently successful antibiotic treatment3 and although it is not always easy to detect in the early stages, progression may be rapid. As well as involving the CNS, relapse may be septicaemic. We are aware of several cases not reported in the literature where relapse occurred, including one where the infant died. Choice of antibiotics and dose for treatment of relapse should be based on the information given above, together with the sensitivity results from the new isolate. Not uncommonly, the new sensitivities will be the same as those originally detected and the relapse probably reflects the intracellular localization of the organism, together with inadequate antibiotic penetration into the CNS macrophages or other parts of the reticuloendothelial or biliaryintestinal systems. Length of antibiotic treatment following a relapse should considerably exceed the original treatment length and results of repeat neuroimaging studies, together with clinical response, should be taken into consideration.
Notes
* Corresponding author. Tel: +44-20-7377-7255; Fax: +44-20-7377-7330.
References
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