766 Notes Vol. 12. No. 10
Ceftriaxone versus Penicillin G in the Short-Term Treatment of
Meningococcal Meningitis in Adults
K. M a r h o u m El Filali, M. N o u n , A. Chakib, M. Zahraoui, H. H i m m i c h *
Short-term treatment with ceflriaxone 2 g once daily for two days (group 1) was compared to treatment with a standard regimen of penicillin G (group 2) for six days in adults with meningococ- cai meningitis. Thirty-six patients were allocated in a randomized fashion to a treatment group: 16 to group 1 and 20 to group 2. The clinical and microbiological results were comparable in the two treatment groups. In both groups cultures of cerebrospinal fluid were sterile after 24 hours.
One patient in each group died. In group 1 one case o f fulminant meningococcemia and one case of brain abscess required further antibiotic treat- ment. It is concluded that short-term treatment with ceftriaxone is feasible but patients with severe forms of meningitis would not be eligible for treatment with this regimen, and careful fol- low-up of the patients receiving ceftriaxone is necessary.
Meningococcal meningitis is a life-threatening disease which may assume epidemic proportions in many parts of Africa. One of the classical regimens for treatment of meningococcal menin- gitis is penicillin G given parenterally every four hours for six days. During an epidemic ad- ministration of such a regimen may be very dif- ficult for the hospital to carry out. Therapy of shorter duration which requires fewer daily injec- tions could thus have a major advantage over the use of penicillin G. Of the drugs showing efficacy in the treatment of meningococcal meningitis, cefotaxime and ceftriaxone seem to be the drugs of choice due to their potential activity in the central nervous system and their good safety (1).
While cefotaxime has a short half-life requiring four injections daily in severe cases, the con- centration of ceftriaxone in the cerebrospinal fluid (CSF) persists above the MIC for suscep- Infectious Diseases Unit, Medical School of Casablanca, 19 Rue Tarik Ibn Zyad, Casablanca, Marocco.
tible bacteria for over 24 hours after a single daily injection. This property renders ceftriaxone par- ticularly suitable for treatment of meningococcal meningitis in an epidemic situation. Martin et al.
(2) and Kavaliotis et al. (3) showed in randomized clinical trials that four-day treatment of menin- gococcal meningitis with ceftriaxone is as effica- cious as the standard eight-day penicillin G regimen. In Senegal, Cadoz et al. (4) treated 31 patients with meningococcal meningitis using ceftriaxone for a mean of three days or standard- length treatment with amoxicillin.
The present study was designed to determine whether a two-day course of ceftriaxone is as ef- ficacious in the treatment of meningococcal meningitis as a six-day course of penicillin G.
Patients and Methods. Between March 1989 and December 1990 all patients over 16 years of age hospitalized with suspected meningitis in the In- fectious Diseases Unit of Casablanca were in- cluded in the study. The diagnosis of meningococ- cal meningitis was based on a positive CSF cul- ture or detection of meningococcal polysac- charide antigen in the CSE In addition, a diag- nosis of meningococcal meningitis was also ac- cepted if the patient presented with the charac- teristic clinical features of meningitis and purulent CSF during an epidemic. Patients were excluded from the study if they were known to be allergic to penicillin. A lumbar puncture was per- formed on admission (day 0) and repeated on days 1 and 5. Investigations, including a complete range of blood and CSF tests, and determination of levels of alanine aminotransferase, aspartate anainotransferase, urea and creatinine, were per- formed on days 0 and 5.
Patients were randomly assigned to one of the two therapeutic groups: patients in group 1 received ceftriaxone 2 g i.v. once daily for two days; patients in group 2 received penicillin G 300,000 IU/kg/day i.v. every four hours for six days. A response to therapy was assessed on the basis of the time needed to achieve deferves- cence, disappearance of meningeal symptoms and full recovery of consciousness. Cure was defined as disappearance of all clinical signs of meningitis and normalization of microbiological findings. Failure was defined as death or persist- ence of meningitis requiring further antibiotic treatment. Patients continued to be evaluated on an outpatient basis for at least two months.
Results and Discussion. Thirty-six patients ful- filled the inclusion criteria and were randomly as- signed to receive one of the two regimens: 16
Vol. 12, 1993 767
Table 1: Characteristics of patients in the two treatment groups.
Ceftriaxone Penicillin G P value
(n = 16) (n = 20)
Age* (years) 30.4 ± 16.6 27.7 + 12.1 NS
Sex
Male 8 17 p <0.05
Female 8 3
Duration of symptoms 2.4 - 1.9 2.3 ± 1.7 NS
prior to admission* (days)
Temperature* (*C) 38.8 ± 0.5 38.7 ± 0.7 NS
Number with impaired 3 4 NS
consciousness CSF appearance
Turbid 9 12 NS
Purulent 6 8 NS
Cell count
< 1500/ml 5 6 NS
> 1500/ml 11 14 NS
Albumin level* (g/l) 2.9 ± 3.8 2.7 ± 1.7 NS
Glucose level* (g/I) 0.24 ± 0.18 0.17 -+ 0.12 NS
Diagnosis of
meningococcal meningitis
CSF culture 4 9 NS
CSF Gram stain alone 3 2 NS
Antigen in CSF alone 2 6 NS
Clinical findings 7 3 NS
*Mean value plus one standard deviation.
received ceftriaxone and 20 penicillin G. T h e ini- tial characteristics of the two groups were com- Parable e x c e p t for gender, t h e r e being m o r e males in g r o u p 2. T h e n u m b e r o f confirmed cases of meningococcal meningitis was 26, 9 in group 1 and 17 in group 2. T h e serogroups o f the menin- gococci were group A (8 cases in group 1 and 14 in group 2), g r o u p B (1 case in group 1 and 2 cases in group 2) and group Y (1 case in group 2).
Table 1 shows the characteristics of the patients With meningococcal meningitis in the two groups.
The response to t h e r a p y was c o m p a r a b l e in the two groups (Table 2). T h e r e were no differences in CSF findings in patients treated with ceftriaxone or penicillin G. In both groups CSF cultures p e r f o r m e d 24 hours after starting t h e r a p y was sterile. O n day 5 the cell c o u n t in CSF Was below 100 cells/ml in 13 patients in group 1.
The protein and glucose levels in CSF reached normal values in the two groups after five days.
T h i r t e e n of the 16 patients (81.3 %) treated with ceftriaxone and 19 of the 20 patients (95 %) treated with penicillin were cured.
One patient in each t h e r a p y group died. T h e patient t r e a t e d with penicillin died after falling into a d e e p c o m a 48 hours after starting therapy.
T h e death of the patient receiving ceftriaxone Was d u e to acute renal failure and hemostasis
which did n o t improve on thiamphenicol therapy.
T h e patient died on day 7 after d e v e l o p m e n t o f shock. A brain scan p e r f o r m e d on day 6 was nor- mal. In group 1, two patients were given treat- ment for m o r e than two days and thus were con- sidered as cases of failure. O n e patient had ful- minant meningococcemia, and in view of the severity of the disease ceftriaxone was given for seven days. T h e second patient had persistent neurological signs and symptoms although ceftriaxone was given for two days. A com- puterized t o m o g r a p h y scan revealed a brain abscess. T h e t r e a t m e n t was changed to thiam- phenicol and surgical drainage was p e r f o r m e d . In b o t h groups tolerance of the t r e a t m e n t was good. Two m o n t h s a f t e r discharge no patients had neurologic sequelae.
Neisseria meningitidis is a very susceptible microorganism, several antibiotics having low MICs for the organism (5, 6), and this has en- couraged attempts at short-term t h e r a p y of meningococcal meningitis. R e y et al, (7) and Wali et al. (8) successfully treated meningococcal meningitis with a single injection of long-acting chloramphenicol. Mac Farlane et al. (9) used with the same success a single injection o f long-acting penicillin. Viladrich et al. (10) t r e a t e d patients with meningococcal meningitis with a four-day
768 Eur. J. Clin, Micr0biol. Infect. Dis.
Table 2: Clinical response to therapy in the two groups.
Ceftriaxone Penicillin G P value
(n = 16) (n = 20)
Mean time ± SD to apyrexia 3.1 -+ 1.4 3.8 ± 1.8 NS
Mean time ± SD to disappearance of 4.4 -+ 1.5 3.9 ± 1.9 NS
meningeal signs (days)
Mean time ± SD to 3.7 ± 2.1 3.3 -+ 1.1 NS
recovery of consciousness (days)
r e g i m e n of penicillin G. In addition to having a long half-life and a low M I C for Neisseria menin- gitidis, ceftriaxone exhibits g o o d p e n e t r a t i o n into the CSF (11). T h e r e f o r e s h o r t - t e r m t r e a t m e n t of m e n i n g o c o c c a l meningitis with this agent could be an interesting t h e r a p e u t i c alternative. C a d o z et al. ( 4 ) u s e d ceftriaxone f o r t r e a t m e n t of menin- gococcal meningitis given in two i.m. injections daily in nine patients and in a single dose in six o t h e r patients. T h r e e patients died within the first three hours; all patients t r e a t e d with a single dose r e c o v e r e d .
In o u r study f e v e r persisted after two days of c e f t r i a x o n e t h e r a p y but C S F cultures w e r e nega- tive. T h e p e r s i s t e n c e of f e v e r m a y h a v e b e e n due to r e l e a s e o f p y r o g e n i c cytokines f r o m necrotic tissue and m a r c o p h a g e s . T h e study shows that 2 g of c e f t r i a x o n e given once daily for two days in adults with m e n i n g o c o c c a l meningitis is as effec- tive as a six-day course of penicillin G. H o w e v e r , we do not consider that patients with severe meningitis would be eligible for s h o r t - t e r m treat- m e n t with ceftriaxone. M o r e o v e r , careful surveil- lance of patients on c e f t r i a x o n e t h e r a p y is neces- sary b e c a u s e of potential complications. T h e r e was no increase in the mortality rate of menin- gococcal meningitis using the s h o r t - t e r m ceftriaxone r e g i m e n for t r e a t m e n t in c o m p a r i s o n with the s t a n d a r d t h e r a p y regimens (3, 12).
In conclusion, s h o r t - t e r m t r e a t m e n t of menin- gococcal meningitis is possible with ceftriaxone if the disease is of m o d e r a t e severity. T h e r e g i m e n has several a d v a n t a g e s in that it reduces the w o r k load o f the nursing staff and shortens the hospital stay. This in turn m a y r e d u c e the risk of nosocomial infections and the overall cost of p a t i e n t m a n a g e m e n t (13,14).
R e f e r e n c e s
1. Kaplan SL: New aspects of prevention and therapy of meningitis. Infectious Disease Clinics of North America 1992, 6: 197-214.
2. Martin E, Hohi P, Guggi T, Kayser FH, Fernes M:
Short course single daily ceftriaxone monotherapy for acute bacterial meningitis in children. Results of a Swiss multicenter study. Infection 1990, 20: 70-82.
3. Kavaliolis J, Manios SSG, Kansouzidou A, Danielidis V: Treatment of childhood bacterial meningitis with ceftriaxone once daily: open, prospective, randomizes, comparative study of short course versus standard length therapy. Chemotherapy 1989, 35: 296--303.
4. Cadoz M, Denis F, Guerma T, Prince-David M, Diop Mar I: Comparaison bact6riologique, pharmacologi- queet clinique de l'amoxicilline et du ceftriaxone dans 300 m6ningites purulentes. Pathologic Biologie 1089, 30: 522-525.
5. Prado V, Cohen J, Banff A, Cordero J, Ledermann V, Cofr~ J, Reyes L: Ceftriaxone in the treatment of bacterial meningitis in children. Chemotherapy 1986, 32: 383-390.
6. Marlin E, Konp J, Paravieinl U, Stoeckel K: Phar- macokinetics of ccflriaxone in neonates and infants with meningitis. Journal of Pediatrics 1984, 105: 475- 481.
7. Rey M, Qnedraogo L, Salion P, Perinn L: Traitement minute de la m6ningite c6r6bro-spinale 6pid6mique par injection intramusculaire unique de chloram- ph6nicol. Med6cine et Maladie Infectieuses 1976, 6:
120-124.
8. Wall SS, MacFarlane JT, Weir WRC: Single injection treatment of meningococcal meningitis: II: Long acting chloramphenico| Transactions of the Royal Society of Tropical Medicine 1979, 73: 693-689.
9. MacFarlane JT, Anjorin FI, Cleland PG, Hasan-King M, Tor-Agbldye, Wall SS, Weir WRC; Willie ltC, Yahaya HN, Greenwood BM: Single Injection treat- ment of meningococcal meningitis: I: Long acting penicillin. Transactions of the Royal Society of Tropi- cal Medicine 1979, 73: 693-679.
10. Viladrich PF, Pailares R, Ariza J, Ruff G, Gudiol F:
For days of penicillin therapy for meningococcal meningitis. Archives of Internal Medecine 1986, 146:
2380-23382.
11. Dankner WM, Connor JD, Sawyer M, Straube R, Spector SA: Treatment of bacterial meningitis with once daily ceftriaxone therapy. Journal of Anti- microbial Chemotherapy 1988, 21: 637--645.
12. Zavala I, Barrera E, Nava A: Ceftriaxone in the treat- ment of bacterial meningitis in adults. Chemotherapy 1989, 34 Supplement 1: 47-52.
13. Auvergnat JC, Le Tallec JY, Marehou II, Massi P, Carriere JP, Armengaud M: Antibiotherapie recourcic de m6ningites h m~ningocoque: cinq jours de ceftriaxone. Pathologie Biologic 1988, 36: 735-737.
14. McCracken GH: Novel approaches to therapy of meningitis. Bulletin of the New York Academy of Medicine 1987, 63: 500-506.
