Equivalence of ceftriaxone and rifampicin in eliminating nasopharyngeal carriage of serogroup B Neisseria meningitidis

Greg Simmons*, Nicholas Jones and Lester Calder

Auckland Healthcare Public Health Protection, Auckland, New Zealand


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The efficacy of ceftriaxone in eliminating nasopharyngeal carriage of Neisseria meningitidis was compared with that of rifampicin during an epidemic of serogroup B meningococcal disease in Auckland, New Zealand. Household contacts of cases had a throat swab taken and were randomized to treatment. Carriers had a repeat swab taken 6 days later to determine efficacy of treatment. Ceftriaxone (98.2%) was equivalent to rifampicin (97.6%) in eliminating serogroup B N. meningitidis. It is cheaper than rifampicin and has the advantage of full compliance and fewer contraindications, but its acceptability by patients may limit its use as a first-line prophylactic agent.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The New Zealand epidemic of meningococcal disease dates from 1991 and is predominantly due to serogroup B Neisseria meningitidis. The current drug of choice for chemoprophylaxis is rifampicin,1 which has several disadvantages.2 The purpose of this study was to determine whether ceftriaxone is equivalent to rifampicin in eliminating the carriage of serogroup B N. meningitidis and to compare adverse events associated with these two antimicrobial agents.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Participants were household contacts of people with notified meningococcal disease occurring from July 1996 to November 1998 in Auckland. Exclusion criteria included: a history of adverse reaction to rifampicin, cephalosporins or lignocaine anaesthetic; impaired liver function; pregnancy; or current antibiotic treatment. After informed consent (approved by the local ethics committee), participants completed a standardized questionnaire administered by a public health nurse.

A per-oral pharyngeal specimen was obtained with a dry straight cotton-tipped swab. Each tonsillar bed and the posterior nasopharynx were swabbed, and the swab was plated directly on to modified Thayer–Martin medium (Fort Richard Laboratories, Auckland, New Zealand) and placed into a candle jar for transport to the laboratory. Plates were incubated at 36°C in 5% CO2 and examined at 24, 36, 48 and 60 h. Colonies resembling Neisseria spp.underwent oxidase testing and, if oxidase-positive, Gram's stain. Three colonies of Gram-negative diplococci were subcultured on to individual sheep blood agar plates for identification and typing. Subculture plates were incubated for 18–24 h at 36°C in 5% CO2. Neisseria spp. were further identified using a rapid carbohydrate degradation test (Neisseria Kwik; Microbiologics, St Cloud, MN, USA). Serogrouping was performed using N. meningitidis antisera A, B and C (Murex Diagnostics, Dartford, UK).

The sensitivity of isolates to ceftriaxone and rifampicin was determined using the Etest (AB Biodisk, Solna, Sweden). The medium used was Mueller–Hinton agar (Difco Laboratories, Detroit, MI, USA) supplemented with 5% sheep blood; incubation was for 18 h at 37°C with 5% CO2.

Participants were randomized to receive ceftriaxone or rifampicin. For those receiving rifampicin the first dose was observed. Rifampicin treatment consisted of four oral doses at 12 h intervals. Dosages were 5 mg/kg for children under 1 month old and 10 mg/kg for children of >=1 month. Adults and children weighing >60 kg were given 600 mg per dose. Ceftriaxone dosages were 125 mg im (vastus lateralis muscle) for children <12 years and 250 mg for adults and children >=12 years, with 2 mL of 1% lignocaine as diluent. For identified meningococcal carriers, a second swab was taken 6 days after the first to determine the efficacy of treatment. ‘Efficacy’ was defined, for the purposes of this study, as the proportion of meningococcal carriers who were culture-negative at 6 days.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Of the 1041 household contacts invited to participate, 864 (83.0%) agreed. Eight (0.9%) participants were lost to follow-up. One of these was a meningococcal carrier. The two treatment groups were similar in terms of age, gender and ethnic distribution.

The efficacy of the two medications in eliminating all serogroups of N. meningitidis was similar (Table IGo): 95.1% (95% confidence interval (CI) 88.0–98.7%) for rifampicin and 97.0% (95% CI 91.5–99.4%) for ceftriaxone. Efficacy for serogroup B N. meningitidis was very similar: 97.6% (95% CI 87.4–99.9%) and 98.2% (95% CI 90.1–100.0%), respectively. All seven isolates from therapeutic failures were sensitive to rifampicin and ceftriaxone with MICs of 0.004–2 and <0.002 mg/L, respectively.


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Table I. Carriage prevalence of N. meningitidis, duration of follow-up and efficacy of clearance by chemoprophylactic agents
 
The incidence of adverse events is shown in Table IIGo. Overall, the frequency of adverse events was slightly higher among those taking rifampicin. No serious reactions, such as anaphylactic shock or acute hypersensitivity to either medication, were documented. Twenty-four per cent of those receiving ceftriaxone reported pain in the injected leg the day after administration and the majority complained of pain at the site of injection for up to 30 min.


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Table II. Incidence (95% confidence interval) of adverse events for 2 day treatment with rifampicin or single-dose im ceftriaxone
 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
There have been a number of studies of the efficacy of rifampicin in eliminating carriage of N. meningitidis35 using the same dosage and treatment duration as this study. Apart from that performed by Schwartz et al.6 reporting an efficacy of 75%, all other studies have estimated rifampicin efficacy at 91–92%, which is very close to that found in this study (95%). The sensitivity of a single throat swab for determining nasopharyngeal carriage of meningococci has been estimated at 70%7 and may be as low as 50% depending on techniques used in identification,8 although one study reported a sensitivity of 93%.9 One possible explanation for the high efficacy for both medications is that there was poor sensitivity of the method for detecting carriage at day 6. As a consequence, the follow-up swab may have over-estimated drug efficacy by >=30%. However, this should not have had a differential effect leading to bias in the estimates of efficacy for the two treatments. A further non-differential bias is the natural attrition of carriage between the first and second throat swabs in meningococcal carriers. In the absence of an untreated group this effect was impossible to quantify but would have falsely elevated the point estimates of efficacy. The short interval between treatment and throat swab aimed to reduce this bias.

While this study did not specifically investigate the efficacy of ceftriaxone and rifampicin for serogroup C N. meningitidis, of 13 participants carrying this serogroup (eight given ceftriaxone and five rifampicin) there was one treatment failure in the rifampicin group. Based on this finding, and the fact that the ceftriaxone MIC range was the same (0.004–0.008 mg/L) for serogroups B and C in New Zealand between 1996 and 1998, there would seem little point in further investigating efficacy for serogroup C N. meningitidis.

There were no secondary cases of meningococcal disease among participants in this study. It was, therefore, not possible to measure the effectiveness of ceftriaxone in terms of secondary case prevention.

The frequency of adverse events for rifampicin was higher than that found in other studies of 2 day courses.4,10 Both medications were used in children in their first month of life, without complication. While pain at the injection site is likely to be a barrier to its acceptability, ceftriaxone has a number of clear advantages over rifampicin, including full compliance and fewer contraindications because of potential drug interactions or pregnancy. In addition, the cost per course of ceftriaxone ($NZ11 including needle and syringe) was much lower than that of rifampicin ($NZ18). There was little difference in the time required to administer the two treatments. The time taken to enquire about contraindications and to counsel patients on the dosage regimen and adverse events for rifampicin was similar to that required for the administration of ceftriaxone.

There will be a range of issues to consider in deciding whether to give prophylactic ceftriaxone to close contacts of meningococcal disease cases. However, doubt concerning ceftriaxone's efficacy in eliminating nasopharyngeal carriage of serogroup B N. meningitidis should no longer be one of them.


    Acknowledgments
 
We thank Anne McCarthy, Michael Brokenshire and Ruth Pirie for laboratory and analytical assistance. We are indebted to the public health nurses of Auckland Healthcare Public Health Protection. This study was supported by a grant from Roche Pharmaceuticals (NZ) Ltd.


    Notes
 
* Correspondence address. Auckland Healthcare Services Ltd, Private Bag 92605, Symonds Street, Auckland 1, New Zealand. Tel: +64-9-623-4613; Fax: +64-9-630-7431; E-mail: gregs{at}ahsl.co.nz Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . American Academy of Paediatrics. (1997). Meningococcal infections. In Red Book: Report of the Committee on Infectious Diseases, 24th edn, (Peter, G., Ed.), pp. 357–62. American Academy of Paediatrics, Elk Grove Village, IL.

2 . Skolnick, J. L., Stoler, B. S., Katz, D. B. & Anderson, W. H. (1976). Rifampin, oral contraceptives, and pregnancy. Journal of the American Medical Association 236, 1382.[Abstract]

3 . Devine, L. F., Johnson, D. P., Rhode, S. L., Hagerman, C. R., Pierce, W. E. & Peckinpaugh, R. O. (1971). Rifampin: effect of two-day treatment on the meningococcal carrier state and the relationship to the levels of drug in sera and saliva. American Journal of the Medical Sciences 261, 79–83.[ISI][Medline]

4 . Munford, R. S., Vasconcelos, Z. J., Phillips, C. J., Gelli, D. S., Gorman, G. W., Risi, J. B. et al. (1974). Eradication of carriage of Neisseria meningitidis in families: a study in Brazil. Journal of Infectious Diseases 129, 644–9.[ISI][Medline]

5 . Stuart, J. M., Cartwright, K. A. V., Robinson, P. M. & Noah, N. D. (1989). Does eradication of meningococcal carriage in household contacts prevent secondary cases of meningococcal disease? British Medical Journal 298, 569–70.[ISI][Medline]

6 . Schwartz, B., Al-Tobaiqi, A., Al-Ruwais, A., Fontaine, R. E., A’ashi, J., Hightower, A. W. et al. (1988). Comparative efficacy of ceftriaxone and rifampicin in eradicating pharyngeal carriage of group A Neisseria meningitidis. Lancet i, 1239–42.

7 . Norton, J. F. & Baisley, I. E. (1931). Meningococcus meningitis in Detroit in 1928–1929. IV. Meningococcal carriers. Journal of Preventative Medicine 5, 357–67.

8 . Schoenbach, E. B & Phair, J. J. (1948). Appraisal of techniques employed for the detection of subclinical (inapparent) meningococcal infections. American Journal of Hygiene 47, 271–81.[ISI]

9 . Cartwright, K. A. V., Stuart, J. M., Jones, D. M. & Noah, N. D. (1987). The Stonehouse survey: nasopharyngeal carriage of meningococci and Neisseria lactamica. Epidemiology and Infection 99, 591–601.[ISI][Medline]

10 . Band, J. D. & Fraser, D. W. (1984). Adverse effects of two rifampicin dosage regimens for the prevention of meningococcal infection. Lancet i, 101–2.

Received 30 March 1999; returned 7 September 1999; revised 15 October 1999; accepted 20 January 2000