MINIREVIEW. Management of Meningitis Caused by Penicillin-Resistant Streptococcus pneumoniae

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1 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Oct. 1995, p Vol. 39, No /95/$ Copyright 1995, American Society for Microbiology MINIREVIEW Management of Meningitis Caused by Penicillin-Resistant Streptococcus pneumoniae MARÍA M. PARÍS, OCTAVIO RAMILO, AND GEORGE H. MCCRACKEN, JR.* Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas Since the isolation of the first penicillin-resistant Streptococcus pneumoniae strain in 1967 (23), there have been many reports of treatment failure in patients with pneumococcal infections caused by strains resistant to penicillin and other antimicrobial agents such as chloramphenicol, macrolides, trimethoprim-sulfamethoxazole, and the cephalosporins. As a result, the selection of antimicrobial agents for the treatment of infections caused by these organisms has become increasingly difficult. In particular, the emergence of pneumococci resistant to broad-spectrum cephalosporins has limited the choices of antibiotics for the treatment of pneumococcal meningitis. This minireview focuses on the specific problems encountered in managing patients with penicillin- and cephalosporin-resistant pneumococcal meningitis and discusses some therapeutic alternatives that have recently been explored. PREVALENCE OF RESISTANCE Strains of S. pneumoniae resistant to penicillin and/or other antibiotics have spread rapidly worldwide, but the patterns of resistance differ among countries. The highest level of resistance was reported in Hungary (41), where up to 59% of pneumococcal strains are resistant to penicillin and 45 and 26% are resistant to erythromycin and chloramphenicol, respectively. Although South Africa (16) also has a large percentage of penicillin-resistant isolates (45%), the incidence of resistance to other antibiotics is substantially lower (4 and 9% for erythromycin and chloramphenicol, respectively). In the United States (7), a recent survey involving 13 hospitals in 12 states found that 36 of 544 (6.6%) strains recovered from normally sterile sites were resistant to penicillin and that 16.4% of these isolates were also resistant to at least one other antibiotic (i.e., a cephalosporin, erythromycin, tetracycline, or trimethoprim-sulfamethoxazole). By contrast, a number of U.S. centers have reported rates of penicillin resistance that exceed 20%. At Children s Medical Center of Dallas, resistance to penicillin and cefotaxime increased from 8 and 0%, respectively, in 1981 to 1983 (26) to 19 and 12%, respectively in 1993 (50). In 1994, the incidence of resistant strains was 22 and 7%, respectively. The lower percentage for cefotaxime reflects the new breakpoint for resistance to the broad-spectrum cephalosporins ( 0.25 g/ml in 1992 and 1993 to 0.5 g/ml in 1994) (45). * Corresponding author. Mailing address: Department of Pediatrics, Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX Phone: (214) Fax: (214) IN VITRO SUSCEPTIBILITY TESTING Table 1 shows the new breakpoints for interpretation of S. pneumoniae susceptibilities to different antibiotics published by the National Committee for Clinical Laboratory Standards (45). The Fastidious Antimicrobial Susceptibility Panel (Microtech Medical Systems, Aurora, Colo.) and FOX Fastidious Panel (Micro Media Systems, Cleveland, Ohio) used in many hospital laboratories are not reliable for susceptibility testing of pneumococcal strains (35). Comparably accurate susceptibility testing results have been obtained by either the E test (AB Biodisk, North America, Inc., Culver City, Calif.) or the dilution method with Mueller-Hinton broth supplemented with 3 to 5% lysed horse blood (28, 35). Both of these methods can be used for testing S. pneumoniae isolates. Most of the in vitro studies of antibiotic combinations against S. pneumoniae were performed by the checkerboard titration method. More recently, time-kill curves have been used to assess whether different combinations of antibiotics have synergistic activity against penicillin-resistant strains. Two of those studies showed different results. Friedland et al. (18) observed a synergistic effect ( 2 log 10 decrease in CFU when compared with the CFU after treatment with the best antibiotic used alone) with the combination of ceftriaxone and vancomycin. By contrast, Doit et al. (12) showed that this combination was indifferent against penicillin-resistant pneumococci. Differences in the methodologies used in those studies can explain the discrepancy in the results. In the first study, the antibiotic concentrations used were equal or lower than the MICs for the organisms, whereas Doit et al. used the concentrations of antibiotics that were similar to those achieved in cerebrospinal fluid (CSF). It is unknown which of these results, if any, are clinically applicable, although combination therapy with ceftriaxone and vancomycin in experimental pneumococcal meningitis had a synergistic effect in reducing bacterial concentrations in CSF compared with either agent administered alone (17). THERAPY FOR MENINGITIS: CLINICAL EXPERIENCE AND ANIMAL STUDIES Numerous case reports of penicillin treatment failure in pneumococcal meningitis in children and adults have been published (1, 3, 8, 10, 11, 20, 21, 24, 25, 39, 44, 48, 53, 63). In some patients a larger dosage of penicillin or treatment with chloramphenicol was effective. Chloramphenicol was recommended as part of the initial therapy of bacterial meningitis on the basis of the easily achievable concentrations in CSF that exceeded the MICs for penicillin-resistant isolates (20). However, reports of chloramphenicol treatment failures were published starting in the late 1980s (14, 61, 62). In 1992, Friedland and Klugman (15) reported that patients with pneumococcal meningitis treated with chloramphenicol had worse neurolog- 2171

2 2172 MINIREVIEW ANTIMICROB. AGENTS CHEMOTHER. Antibiotic TABLE 1. New breakpoints for interpretation of MICs for S. pneumoniae a MIC ( g/ml) Susceptible Intermediate Resistant Penicillin Cefotaxime Ceftriaxone Chloramphenicol 4 8 Vancomycin 1 2 TMP-SMX b 0.5/9.5 1/19 2/38 4/76 Erythromycin Clindamycin Imipenem a Data are from reference 45. b TMP-SMX, trimethoprim-sulfamethoxazole. ical outcomes when the isolates were resistant to penicillin compared with the outcomes in patients infected with susceptible strains. This was explained by the high chloramphenicol MBCs ( 4 g/ml) for many of the penicillin-resistant strains, despite the low MICs for the strains. Thus, it would be prudent to determine the chloramphenicol MBC for penicillin-resistant pneumococcal isolates before starting therapy with this drug. Cephalosporins. The broad-spectrum cephalosporins (cefotaxime and ceftriaxone) have been used as standard therapy for bacterial meningitis in infants and children for many years (42). To date, 12 patients have been reported to have penicillin- and cephalosporin-resistant pneumococcal meningitis (11 children and 1 adult) that responded inadequately to ceftriaxone or cefotaxime therapy (Table 2) (2, 4 6, 9, 19, 27, 33, 38, 56). Cultures of CSF were positive for 3 to 14 days after the start of therapy. Many antibiotic regimens were given to these patients alone or in combinations that included vancomycin, chloramphenicol, rifampin, erythromycin, and imipenem. Four of these 12 patients had neurologic sequelae (27, 38, 56). In a retrospective review, Tan et al. (58) compared the outcomes of patients with meningitis caused by pneumococci for which MICs were 0.5 and 0.5 g/ml for cefotaxime and ceftriaxone, respectively; five patients were infected with strains for which MICs were 0.5 g/ml for these cephalosporins. The neurologic outcome in this latter group was similar to those in patients infected with organisms for which MICs were 0.5 g/ml. They suggested that patients with meningitis caused by strains for which the cefotaxime or ceftriaxone MIC was 1 g/ml may be adequately treated with either of these antimicrobial agents. More recently, two patients with meningitis caused by pneumococcal isolates for which ceftriaxone or cefotaxime MICs were 0.5 and 1 g/ml, respectively, were reported; both patients responded poorly to cephalosporin therapy (4, 9). The culture for one of these patients was positive for 5 days. Vancomycin. Vancomycin has been used as an alternative therapy for meningitis caused by cephalosporin-resistant strains of S. pneumoniae. Vancomycin failures have been reported in adults in Spain (60). Possible explanations for failed therapy include a low dosage (30 mg/kg of body weight per day in four divided doses) compared with that used in children (60 mg/kg/day in four doses) and concomitant dexamethasone therapy. Additionally, the concentrations of vancomycin in body fluid were highly variable, and it has been demonstrated that the penetration of vancomycin into the CSF is dependent on the degree of meningeal inflammation (43). The anti-inflammatory effect of dexamethasone (59) might have contributed to the reduced concentrations and bactericidal titers of vancomycin observed in some of these Spanish patients. Injection of vancomycin into the CSF space was used in two patients who failed initial therapy with intravenously administered vancomycin (9, 38). In the first patient, the CSF culture was sterile on the fourth day of therapy, but fever, meningeal signs, confusion, and stupor were still present. Within 24 h of the first intrathecal dose of vancomycin the clinical picture and CSF indices improved. The patient was healthy at the 1-year follow-up examination (9). The second patient had a positive CSF culture after 6 days of intravenous therapy with cefotaxime and penicillin. Subsequent therapy included vancomycin, cefotaxime, rifampin, and intraventricular vancomycin. A sterile CSF culture was documented 48 h after treatment with these drugs was initiated. Neurologic sequelae included hydrocephalus, seizures, and hypotonia (38). Because the safety and effectiveness of intrathecal and intracisternal vancomycin for therapy of pneumococcal meningitis are unknown, its use cannot be recommended. Rifampin. Rifampin has been administered with vancomycin to some patients who failed therapy with broad-spectrum cephalosporins (6, 27, 38). In time-kill experiments (18) and in animals with experimental meningitis (17), the combination of rifampin and vancomycin or rifampin and ceftriaxone was indifferent (neither a synergistic nor an antagonistic effect). Rifampin killed pneumococci in CSF at a slower rate than ceftriaxone or vancomycin in experimental meningitis (17, 46). Dexamethasone therapy did not reduce the penetration of rifampin into the CSF of rabbits (50). Because S. pneumoniae strains resistant to rifampin have been isolated in South Africa (16), surveillance of strains in communities should be conducted to determine the susceptibilities of isolates to rifampin before this drug is routinely used for initial empiric therapy for meningitis. Other antibiotics. Erythromycin (2) and imipenem (4, 5) have been used successfully in patients with penicillin- and cephalosporin-resistant pneumococcal meningitis. Two patients with meningitis caused by resistant strains were treated with imipenem, one of whom developed seizures on the ninth day of therapy (4). In a previous study, 7 of 21 (33%) pediatric patients treated with imipenem for bacterial meningitis developed seizures (64). Because of the potential risk of drug-related seizures, imipenem should be used with caution for therapy of meningitis and should be used only when other more suitable drugs are inappropriate. Other antibiotics such as meropenem (17), cefpirome (17), and clindamycin (52) have been tested as treatment against experimental pneumococcal meningitis. Meropenem was comparable to ceftriaxone and inferior to vancomycin in sterilizing the CSF cultures (17). Furthermore, the MICs of meropenem were higher than those of imipenem when they were tested against penicillin-resistant strains (57). In the same model cefpirome was as effective as vancomycin but was more effective than ceftriaxone in reducing bacterial counts in CSF (17). There are no available data regarding the clinical use of these drugs. Additionally, when clindamycin was used in a model of experimental meningitis (52) achieved good concentrations in CSF (approximately 10% of the concentrations in serum) and was effective in sterilizing CSF cultures after three doses. Moreover, clindamycin penetration into the CSF was not affected by dexamethasone therapy (52). Antibiotic combinations. Some patients with meningitis caused by drug-resistant pneumococci who failed therapy received combinations of antibiotics, such as vancomycin and chloramphenicol; vancomycin and rifampin; vancomycin, rifampin, and penicillin; and vancomycin, chloramphenicol, and rifampin with or without cefotaxime or ceftriaxone. Consider-

3 VOL. 39, 1995 MINIREVIEW 2173 TABLE 2. Clinical features of patients with penicillin- and cephalosporin-resistant pneumococcal meningitis who failed therapy Age History MIC ( g/ml) a Pen Reference CRO- CTX Initial therapy No. of days of positive CSF culture Day therapy changed Treatment Outcome 6 mo 4 wk prior admission, amoxicillin, cefaclor, TMP-SMX b 1 2 Cefotaxime, dexamethasone 6 6 Vancomycin rifampin Hydrocephalus ventriculo-peritoneal 9 Chloramphenicol shunt mo 1 wk before admission, amoxicillin-clavulanate 1 2 Cefotaxime 7 3 Chloramphenicol No sequelae 5 Penicillin 7 Imipenem 6 yr 18 months before this admission nasal fracture, nasal fistula 30 mo Temporal bone fracture at 10 mo of age, otorrhea and fistula repair at 20 mo of age, rhinorrhea on day of admission 28 mo 3 days of amoxicillin-clavulanate prior to this admission 2 2 Ampicillin Cefotaxime Chloramphenicol Erythromycin Two more episodes of pneumococcal meningitis treated with erythromycin Ceftriaxone, dexamethasone 4 2 Ceftriaxone, dexamethasone 13 mo 6 days of TMP-SMX /32 Cefotaxime, dexamethasone 13 mo Last 2 mo, cefaclor and amoxicillin; last 7 days, cefuroxime axetil ing the multiple combinations used and the limited number of patients treated, it is impossible to determine which of these regimens, if any, is most effective. By contrast, experiments conducted in animals to compare some of these regimens (17) demonstrated that the combination of vancomycin plus ceftriaxone was synergistic against pneumococci and was superior to either drug given alone in reducing the bacterial counts in CSF. This was not the case when rifampin was combined with either vancomycin or ceftriaxone (17). New antibiotics. Experimental agents such as the fluoroquinolones, CP-99,219 (13, 51) and clinafloxacin (29), and biapenem (57) have been shown to have excellent in vitro activities against penicillin-resistant strains. Clinafloxacin and CP-99, 219 were effective in reducing rapidly the bacterial concentrations in CSF in a model of experimental meningitis (17, 4 4 Vancomycin rifampin No sequelae, surgically repaired CSF 6 Penicillin leak 7 7 Chloramphenicol No sequelae 33 8 Vancomycin 6 5 Vancomycin Neurologically devastated 11 Chloramphenicol 4 8/8 Cefuroxime 3 c 3 Ceftriaxone dexamethasone 6 Vancomycin 6 Chloramphenicol 49). No clinical data are available to confirm these observations. Dexamethasone. Dexamethasone therapy has been shown to improve the neurologic outcomes of infants and children with bacterial meningitis, especially when it is caused by Haemophilus influenzae (36, 37, 47, 54). With respect to meningitis caused by S. pneumoniae, two earlier studies, a retrospective review of 97 pediatric patients (32) and a prospective trial of 106 patients (22), suggested a beneficial effect. More recently, a double-blind placebo-controlled study (31) of 56 children older than 2 years demonstrated a decrease in neurologic and/or audiologic sequelae at 1-year follow-up examinations (2 of 27 [7%] versus 7 of 26 [27%] [P 0.062] for dexamethasone- versus placebo-treated patients, respectively). Because steroids reduce antibiotic penetration into the CSF (30, 55), we conducted experiments in the rabbit meningitis No sequelae 56 4 mo One day of cefaclor 0.5 4/8 Cefotaxime 1 6 Vancomycin Moderate hearing 6 Chloramphenicol loss, unilateral 9 mo Amoxicillin 2 4 Ceftriaxone 6 c 7 Vancomycin No sequelae mo Unremarkable 2 8/16 Cefotaxime 6 6 Vancomycin, rifampin, chloramphenicol, intraventricular vancomycin Hydrocephalus, hypotonia 18 mo Unremarkable 1 0.5/0.5 Penicillin, cefotaxime 5 5 Imipenem No sequelae 4 29 yr Epilepsy 1 1 Cefotaxime 4 Vancomycin No sequelae 9 6 Intrathecal vancomycin a Pen, penicillin; CRO, ceftriaxone; CTX, cefotaxime. b TMP-SMX, trimethoprim-sulfamethoxazole. c Initial CSF culture was negative; second lumbar puncture had a positive CSF culture

4 2174 MINIREVIEW ANTIMICROB. AGENTS CHEMOTHER. model to evaluate the effect of dexamethasone therapy on the sterilization of CSF after intracisternal inoculation of two penicillin- and cephalosporin-resistant strains (50). Dexamethasone significantly decreased the penetration and concentrations of vancomycin in CSF and reduced the concentrations of ceftriaxone in CSF as well. In addition, when a highly resistant pneumococcal strain (MIC, 2 and 4 g/ml for penicillin and ceftriaxone, respectively) was used in the experiments, an increase in the mean number of CFU per milliliter and in the number of positive CSF cultures were observed at 24 h of therapy (14 h after the administration of the last dose of vancomycin) in the animals treated with dexamethasone (50). By contrast, the effectiveness of the combination of rifampin plus ceftriaxone was unaffected by concomitant dexamethasone therapy (50). It has also been shown that the combination of vancomycin and rifampin was effective in sterilizing CSF cultures, regardless of whether dexamethasone was administered (40). Klugman et al. (34) recently reported the CSF antibiotic concentrations in children with bacterial meningitis who were treated with dexamethasone and either ceftriaxone alone or in combination with vancomycin or rifampin. The dosage of vancomycin in these patients was 60 mg/kg daily in four divided doses. The mean CSF vancomycin concentrations and penetration into CSF (3.3 g/ml and 19%, respectively) were higher than those observed in our animal experiments (1.5 g/ml and 3%, respectively) (50). Additionally, the CSF of patients treated with ceftriaxone plus either vancomycin or rifampin had higher bactericidal activity against two cephalosporin-resistant pneumococcal strains than the CSF of patients treated with ceftriaxone alone (34). RECOMMENDATIONS On the basis of data from the pneumococcal meningitis models and limited clinical experience, it is impossible to make a single recommendation for initial empiric treatment that would be suitable for all patients with suspected or proven pneumococcal meningitis. We believe, however, that the following guidelines should be considered in managing such patients. (i) Physicians should be aware of the S. pneumoniae susceptibility patterns in their area and request their hospital laboratories to perform the E test (AB Biodisk, North America, Inc.) or dilution susceptibility tests on any pneumococcal isolates recovered from usually sterile body sites. (ii) Because penicillin-resistant pneumococci have been identified in many areas of the United States, initial empiric therapy for bacterial meningitis should be based on the possibility that it is the etiology of the patient s illness. We recommend therapy with ceftriaxone or cefotaxime and vancomycin (60 mg/kg/day divided in four doses), in addition to dexamethasone. (iii) Although dexamethasone therapy was shown to reduce the concentrations and activity of vancomycin in CSF in a model of experimental pneumococcal meningitis, data for children with meningitis who received dexamethasone and vancomycin therapy indicate that the concentrations in CSF exceed by at least fourfold the MIC for penicillin-resistant pneumococci. (iv) A repeat lumbar puncture in patients with pneumococcal meningitis to document eradication of the pathogen should be performed 24 to 36 h after the start of therapy, primarily in patients in whom the organism is cephalosporin resistant. (v) Alteration of the initial antimicrobial regimen should be based on the clinical response of the patient and on the results of the CSF culture and susceptibility studies from the second lumbar puncture. In the event that the patients clinical condition has worsened or that the follow-up gram-stained smear or culture of CSF indicates failure to reduce substantially or eradicate the organism, substitution of rifampin for vancomycin in the therapeutic regimen is recommended. (vi) Patients without complications should be treated for a minimum of 10 days. Additional studies in animal models and patients are required to define the role of new antimicrobial agents in the therapy of meningitis caused by multiple drug-resistant pneumococcal strains. Ongoing surveillance studies are important in identifying the changing patterns of resistance in different areas of the country. REFERENCES 1. Ahronheim, G. A., B. Reich, and M. I. Marks Penicillin-insensitive pneumococci. Am. J. Dis. Child. 133: Alonso, J., V. Madrigal, and M. García-Fuentes Recurrent meningitis from a multiply resistant Streptococcus pneumoniae strain treated with erythromycin. Pediatr. Infect. Dis. J. 10:256. (Letter.) 3. 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