Decreased susceptibility of penidllid-resistant pnenmococd to twentyfour pmactam antibiotics

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1 Journal of Antimicrobial Chemotherapy (99) 30, 79- Decreased susceptibility of penidllid-resistant pnenmococd to twentyfour pmactam antibiotics J. liriares**, T. Akmstf*, J. L. Perez', J. Ayats*, M A. Dominguez*,. Pallares* and. Martin* 'ervice of Microbiology; b ervice of Infectious Diseases, Hospital de Bellvitge, Universidad de Barcelona, Barcelona, pain The in-vitro activity of /Mactam antibiotics was compared using three groups of pneumococci and an agar dilution method comprising 00 penicillin-susceptible, 00 intermediately penicillin-resistant, and 00 highly penicillin-resistant pneumococcal strains. Our results show that intermediately penicillin-resistant and highly penicillin-resistant pneumococci had decreased sensitivity to other 0-lactam agents. According to their relative in-vitro activity, the antimicrobials were classified into three groups. The first group included drugs more active than penicillin (imipenem, meropenem, cefotaxime, ceftriaxone, and cefpirome), which could be useful for the treatment of infections due to penicillin-resistant strains. The second group showed slightly lesser activity than did penicillin, and included: ampicillin, cefdinir, cefuroxime, cefoperazone, azkxallin, mezlocillin, piperatilh'n, cephalothin, and cefamandole. The remaining antibiotics (oxacillin, cefixime, ceftizoxime, cefetamet, cefaclor, ceflazidime, cefoxitin, cefonicid, and latamoxef) showed poor activity against penicillin-resistant strains, precluding their use for empirical treatment in areas with a high prevalence of penicillin-resistant strains. Introduction treptococcus pneumoniae is an important bacterial pathogen causing pneumonia, meningitis and otitis media in adults and children. Although this bacterium was originally fully susceptible to penicillin, strains showing intermediate penicillin resistance (MICs 0-- mg/l) were first reported in 967 in Australia and New Guinea (Hansman & Bullen, 967). In 97, high-level penicillin resistance (MIC ^ mg/l) was observed in pneumococci isolated in outh Africa (Jacobs et al., 97). In the last two decades penicillin-resistant and multiresistant strains have emerged in many parts of the world (Appelbaum, 97; Klugman, 990; Allen, 99). Although the prevalence of such strains presents an irregular world-wide distribution, there is a trend towards an increasing number of countries in which antibiotic-resistant strains are being detected (Klugman, 990) as well as an increase in the frequency of isolation of resistant strains (Geslin, Fremaux & issia, 99; pika et al., 99; Linares et al., 99). The problem is significant in some countries such as outh Africa (Klugman, 990), pain (Casal, 9; Linares et al., 93; Latorre, Juncosa & anfeliu, 95), and Hungary (Marton et al., 99). In pain, the prevalence of penicillin-resistant pneumococci is among the Downloaded from at Pennsylvania tate University on March 5, 06 'Corresponding author ervice of Microbiology, Hospital de Bellvitge, Feixa Uarga i/n, 0907 Hospitatet de Uobregat, Barcelona, pain /9/ $0.00/0 99 The British ociety for Antimicrobial Chemotherapy

2 0 J. Iifiaits et al highest reported in the world (Fenoll et al., 99). These authors reported 9% of 5 clinical isolates of pneumococci to be of intermediate sensitivity to penicillin and 5-3% were highly penicillin-resistant. Data from our hospital showed that 7-% and -9% of 5 pneumococci isolated in 990 from normally sterile sources were intermediately resistant and highly resistant to penicillin, respectively (Linares et al., 99). The emergence of penicillin-resistant and multiresistant strains has posed serious problems in the treatment of pneumococcal diseases, mainly in the therapy of meningitis. The aim of this study was to determine the in-vitro activity of /Mactam antibiotics against 300 strains of. pneumoniae (00 penicillin susceptible, 00 intermediately resistant, and 00 highly resistant) in order to determine optimal therapy for pneumococcal infections caused by penicillin-resistant strains. Bacteria Materials and methods A total of 300 clinical isolates of. pneumoniae (00 penicillin susceptible, 00 intermediately resistant, and 00 highly resistant to penicillin) from blood, cerebrospinal fluid, lung (pleural fluid, transthoracic needle aspiration, protected bronchial catheter brush specimens) or sputum, were tested for antimicrobial susceptibility. All strains were isolated in Hospital de Bellvitge (Barcelona, pain). The majority of intermediately resistant and highly resistant strains were obtained between 9 and 990. Only single isolates from individual patients were examined and of 6 strains that were serotyped seven serotypes were identified: 3 (3-%), 6 (9-%), 9 (9-0%), 9 (50%), (7-%), (5-5%) and 5 (-7%). Antimicrobial agents Antimicrobial agents were supplied as laboratory standard powders of known potency, and stock solutions were made as recommended by the manufacturers. The following antimicrobials were studied: penicillin (C.E.P.A.,.A., Madrid, pain); ampicillin (mithkline Beecham, London, UK); cefdinir (Parke Davis & Co.); cefoperazone (Pfizer Inc.); azlocillin (Bayer, Germany); mezlocillin (Bayer, Germany); piperacillin (Lederle Laboratories, Pearl iver, NY, UA); cefuroxime (Glaxo Inc, UK); cephalothin (Eh' Lilly & Co., Indianapolis, UA); cefamandole (Eli Lilly & Co., Indianapolis, UA); oxacillin (mithkline Beecham, London, UK); cefixime (E. Merk-Darmstadt, Igoda.A. Barcelona, pain); ceftizoxime (mithkline Beecham, London, UK); cefetamet (Hoffman-Laoche Inc., Nutley, NJ, UA); cefaclor (Eli Lilly & Co., Indianapolis, UA); ceftazidime (Glaxo Inc., UK); cefoxitin (Merck harp & Dohme, West Point, PA, UA); cefonicid (mithkline Beecham, London, UK); latamoxef (Eli Lilly & Co. Indianapolis, UA); meropenem (ICI Pharmaceuticals, Cheshire, UK); cefotaxime (Hoechst, Germany); ceftriaxone (Hoffman-Laoche Inc., Nutley, NJ, UA); cefpirome (Hoechst, Germany); imipenem (Merk harp & Dohme, West Point, PA, UA). Downloaded from at Pennsylvania tate University on March 5, 06 usceptibility testing trains were tested using a standard plate agar dilution method. The inoculum was prepared by suspending several colonies from an overnight culture of. pneumoniae

3 usceptibility of pwrfrnhiyrp«i«nt pnemnococd from a 5% horse blood agar plate in Muelkr-Hinton broth, and then adjusting to a turbidity of McFarland standard. A further : 00 dilution was made to obtain a final inoculum of 0, which was delivered in nl by a teers replicator on to Mueller-Hinton agar plates supplemented with 5% defibrinated horse blood and containing doubling dilutions of antibiotic, and then incubated overnight at 3 C. The minimal inhibitory concentration (MIQ was defined as the lowest concentration of antimicrobial preventing visible growth. taphylococcus aureus ATCC 593 and. pneumoniae ATCC 6303 were used as control strains. The strains were classified for penicillin susceptibility according to the NCCL criteria (National Committee for Clinical Laboratory tandards, 990), as follows: susceptible (MIC < 0.06 mg/l), intermediately resistant (MIC 0-- mg/l), and highly resistant (MIC > mg/l). esults According to their relative in-vitro activity, the antimicrobials tested were classified into three groups shown in Tables I, II and III. Overall, a clear correlation was Table L In-vitro activity of /Mactam antibiotics more active than penicillin against penicillin-resistant pneumoticci, MICs are expressed in mg/l Antibiotic Penicillin * I» ' Iroipcncin s I Mcropcnciu s I Cefotaxime I Ccftriaxone I Cefpirome I MIC range «K>-OO <O0 - - <O0-O «0.0-0O3 - - <O0-O <O0-O03 O03-O5 - MIC,, <O0 <O0 0 <O0 <O0 <00 «*O0 MIC* <O0 <00 JOOI <O0 <O0, ujceptible to penicillin (MIC < 006 mg/l); I, intermediate resistance to penicillin (MIC 0-- mg/l); It rctistant rtraini (MIC > mg/l). Downloaded from at Pennsylvania tate University on March 5, 06

4 J. Linares et al Table IL In-vitro activity of /Mactam antibiotics less active than penicillin against penicillin-resistant pneumococct, MIC* are expressed in mg/l Antibiotic MIC range MIC, MIC*, Penicillin * I» < < <O0 Ampicillin I Cefdinir I Cefbperazone' I Azlocillin' I MezlocUin' I Piperacillin' I Cefuroxime I « O <O0-0O6 O < <O0 O06 <O0 <O0 <O0 I Downloaded from at Pennsylvania tate University on March 5, 06 Cephalothin I Cefamandole I ", usceptible to penicillin (MIC < 006 mg/l); I, intermediate resistance to penicillin (MIC 0-- mg/l); *, resistant strains (MIC > mg/l); 'only 0 strains were studied (30, 50 I, 30 ).

5 usceptibility of penkflhtt-resistant pnenmococd 3 Table EEL 0-Lactam antibiotics with poor in-vitro activity against penicillin-resistant pneumococci, MICs are expressed in mg/l Antibiotic MIC range MIC, MIC* Penicillin ' I* c <O0-O <00 Oxacillin I Cefixime I Ceftizoximc I Cefetamet I Cefador I Ccftazidime I Cefoxitin I Cefonicid I Latamoxef I *, usceptible to penicillin (MIC < 006 mg/l); M; intermediate resistance to penicillin (MIC 0- I mg/l); 'resistant strains (MIC > mg/l). Downloaded from at Pennsylvania tate University on March 5, 06

6 J. Iifiares et al observed between the degree of resistance to penicillin and the respective MICs for the other antibiotics as all /Mactams had higher MICs against penicillin-resistant pneumococci than against susceptible strains. The first group (Table I) was made up of five antibiotics more active than penicillin against penicillin-resistant pneumococci, and included the two carbapenems tested (imipenem and meropenem), and three third generation cephalosporins (cefotaxime, ceftriaxone and cefpirome). Imipenem was the most active drug tested. In the penicillin-resistant group of strains, the MIQp for these antibiotics was - times lower than those of penicillin. Table II shows the in-vitro activity of those /Mactams with similar or slightly lesser activity than penicillin. This group includes ampicillin, cefdinir, cefoperazone, azlocillin, mezlocillin, piperacillin, cefuroxime, cephalothin, and cefamandole. Finally, there was a group of /Mactam antibiotics (Table III) which showed poor < in-vitro activity, with MICs -6 times greater than those of penicillin; oxacillin, cefixime, ceftizoxime, cefetamet, cefaclor, ceftazidime, cefoxitin, cefonicid, and latamoxef were included in this group. Discussion The emergence of penicillin-resistant strains of. pneumoniae has changed the treatment of serious pneumococcaj infections. Clinical and microbiological failures have been observed when using penicillin in patients with meningitis caused by pneumococci with high or intermediate penicillin resistance (Viladrich et al., 9), precluding its empirical use in areas with a high prevalence of such strains. In addition, penicillinresistant pneumococci have been frequently associated with multiresistance to non- /Mactam antibiotics thereby limiting the usefulness of some classical alternative drugs (Liflares et al., 93; Klugman, 990; Fenoll et al., 99; Geslin et al, 99). In our experience, more than 70% of 9 strains with some degree of penicillin resistance are multiresistant to three or more non-/mactam antibiotics (Linares et al., 99). Penicillin-resistant strains are more resistant than penicillin-susceptible pneumococci to all /Mactam agents, and our results concur with those previously reported (Ward & Moellering, 9; Tweardy, Jacobs & peck, 93; Linares et al., 9; Latorre, Juncosa & anfeliu, 9; Klugman, 990; Fremaux et al., 99). The mechanism of penicillin resistance in. pneumoniae is mediated through alterations in at least four penicillin binding proteins (PBPs la, x, a, and b) (Zighelboim & Tomasz, 9; Tomasz, 97; Hackenbeck et al., 99). These changes in PBPs are responsible for the decreased affinity of all /Mactam antibiotics. The recent development of many /Mactam compounds with different microbiological and pharmacokinetic properties gives us the opportunity to study their in-vitro activity against these penicillin-resistant strains. The /Mactams we tested were classified into three groups according to their in-vitro activity against pneumococci. The first of them included imipenem, meropenem, cefotaxime, ceftriaxone and cefpirome. MICs for these compounds were four to eight times lower than those of penicillin, and they may be suitable for treating infections caused by penicillin-resistant strains. In addition, these drugs show favourable pharmacokinetics with good penetration into cerebrospinal fluid. Imipenem showed excellent in-vitro activity against highly penicillin-resistant pneumococci. However, it should not be employed in meningitis therapy since neurotoxic reactions such as seizures, confusion, and myoclonic activity have been reported in Downloaded from at Pennsylvania tate University on March 5, 06

7 usceptibility of penkflhn-resfatant pnemnococd 5 experimental animal studies (Calandra et al., 9; chliamser, Cars & Norrby, 99). Meropenem also had good activity against these strains, and has been shown not to cause a significant potentiation of metrazole-induced convulsions in mice (Patel & Giles, 99). However, further human clinical trials are necessary. As previously reported, cefpirome showed in-vitro activity similar to that of cefotaxime (Wise et al., 95) and had good cerobrospinal fluid penetration and bactericidal activity in experimental pneumococcal meningitis (Taubcr et al., 95), which deserves clinical evaluation. In our experience, good clinical and microbiological responses have been obtained with high doses of 300 mg/kg/day of cefotaxime or 50 mg/kg/day of ceftriaxone in patients with meningitis caused by pncumococci with MICs ^ mg/l (Viladrich et al., 9). However, two potential problems are that the activity of these third-generation cephalosporins might not be sufficient in cases of meningitis caused by strains with very high penicillin MICs (MIC > mg/l). trains with these characteristics have been isolated in outh Africa and Central Europe (Jacobs et al., 97; Appelbaum, 97; Marton et al., 99) but, fortunately, are not widespread at present. econdly, cefotaxime-resistant mutants have been obtained in the laboratory after several selection steps (Laible & Hakenbeck, 97). Unfortunately, four separate cases of serious pneumococcal infections caused by strains resistant to cefotaxime and ceftriaxone have been reported recently in the United tates (loas et al., 99; Figueiredo et al., 99). In both instances, non /Mactam antibiotics such as vancomycin may be an alternative drug for treating pneumococcal meningitis, although we have observed a high failure rate with intravenous vancomycin (Viladrich et al., 99). Intrathecal or intraventicular doses of vancomycin may be necessary for therapy in some unresponsive cases (Buzon et al., 9; Gump, 9). In patients with bacteraemic pneumococcal pneumonia caused by penicillin-resistant strains, including those with high-level penicillin resistance, ceftriaxone and cefotaxime would be suitable alternatives to penicillin (Pallares et al., 97). The second group of /Mactams (ampicillin, azlocillin, mezlocillin, piperacillin, cefdinir, cefuroxime, cephalothin, and cefamandole) showed in-vitro activity two- to four-times lower than penicillin. In general, results from the present study agree with those reported elsewhere (Ward & Moellering, 9; Tweardy et al., 93; Bosley et al., 97; Klugman, 990). Theoretically, this group of antibiotics may only be useful in the treatment of non-meningitic infections due to intermediately resistant pneumococcal strains, thus precluding their use as empirical therapy in areas with a high prevalence of highly penicillin-resistant pneumococci. Finally, a third group of antibiotics: oxacillin, cefixime, ceftizoxime, ceftazidime, cefetamet, cefaclor, cefoxitin, cefonicid, and latamoxef showed poor activity, with MICs to 6 times higher than penicillin. This makes them unsuitable for the treatment of pneumococcal strains showing some degree of resistance to penicillin. Oral /Mactam antibiotics, including some recently developed oral cephalosporins, showed moderate to poor activity against penicillin-resistant pneumococci. This is of special concern in the empirical treatment of less severe pneumococcal infections. For instance, cefaclor and cefixime have been recommended for the treatment of acute otitis media in children. According to previous reports (Bosley et al., 97) and our present results, these antibiotics should not be recommended for this purpose in areas in which penicillin-resistant pneumococci are prevalent. With respect to oral cephalosporins, only cefdinir and cefuroxime showed slightly less in-vitro activity to that of penicillin Downloaded from at Pennsylvania tate University on March 5, 06

8 6 J. Linares et al against these resistant strains. Although not studied by us, there are reports of cefpodoxime exhibiting activity similar to that of penicillin (Appelbaum et al., 99; Dabernat, Avril & Boussougant, 990; Fremaux et al., 99). In summary, /Mactam antibiotics show different spectrum of activity against penicillin resistant pneumococci. In our clinical experience, cefotaxime and ceftriaxone can be effective antibiotics for the treatment of serious infections caused by these strains. However, some other /Mactam antibiotics show moderate to poor activity that could limit their use in clinical practice. Acknowledgement Part of this work was presented at the 5th European Congress of Clinical Microbiology and Infectious Diseases, Oslo, 99. eferences Allen, K. D. (99). Penicillin-resistant pneumococci. Journal of Hospital Infection 7, 3-3. Appelbaum, P. C. (97). Worldwide development of antibiotic resistance in pneumococci. European Journal of Clinical Microbiology 6, Appelbaum, P. C, pangler,. K., Crotty, E. & Jacobs, M.. (99). usceptibility of penicillin-sensitive and -resistant strains of treptococcus pneumoniae to new antimicrobial agents, including daptomytin, teicoplanin, cefpodoxime and quinolones. Journal of Antimicrobial Chemotherapy 3, Bosley, G.., Elliott, J. A., Oxtoby, M. J. & Facldam,.. (97). usceptibility of relatively penicillin-resistant treptococcus pneumoniae to newer cephalosporin antibiotics. Diagnostic Microbiology and Infectious Disease 7, -7. Buzon, L. M., Guerrero, A., omero, J., antamaria, J. M. & Bouza, E. (9). Penicillin-resistant treptococcus pneumoniae meningitis successfully treated with vancomycin. European Journal of Clinical Microbiology 3, -3. Calandra, G., Lydick, E., Carrigan, J., Weiss, L. & Guess, H. (9). Factors predisposing seizures in seriously ill infected patients receiving antibiotics: experience with imipenem/ cilastatin. American Journal of Medicine, 9-. Casal, J. (9). Antimicrobial susceptibility of treptococcus pneumoniae: serotypc distribution of penicillin-resistant strains in pain. Antimicrobial Agents and Chemotherapy, -5. Dabernat, H., Avril, J. L. & Boussougant, Y. (990). In-vitro activity of cefpodoxime against pathogens responsible for community-acquired respiratory tract infections. Journal of Antimicrobial Chemotherapy 6, uppl. E. -6. FenoU, A., Martin-Bourgon, C, Mufioz,., Vicioso, D. & Casal, J. (99). erotypc distribution and antimicrobial resistance of treptococcus pneumoniae isolates causing systemic infections in pain, eviews of Infectious Diseases 3, Figueiredo, A. M.., Connor, J. D., everin, A., Vaz Pato, M. V. & Tomasz, A. (99). A pneumococcal clinical isolate with high-level resistance to cefotaxime and ceftriaxone. Antimicrobial Agents and Chemotherapy 36, 6-9. Fremaux, A., issia, G., Cohen,., Ichou, F. & Geslin, P. (99). usceptibility of pneumococci to oral and parenteral /Mactam agents: comparison of penicillin-resistant, intermediateresistant and susceptible pneumococci. Clinical impact in France in 99. In Program and Abstracts of the 3st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 99. Abstract 9. American ociety for Microbiology, Washington, DC. Geslin, P., Fremaux, A. & issia, G. (99). treptococcus pneumoniae: etat actuel de la sensibitilite aux b&ta-lactamines en France. Mise au point du Centre National de eference. Medicine et Maladies Infectieuses ( Ms), 3-. Gump, D. W. (9). Vancomycin for treatment of bacterial meningitis. eviews of Infectious Diseases 3, uppl.,.9-9. Hakenbeck,., Briese. T., Chalkley, L., Ellerbrok, H., Kalliokoski,., Latorrc, C. et al. (99). Downloaded from at Pennsylvania tate University on March 5, 06

9 usceptibility of penkflun-resistant paenmococd 7 Antigcnic variation of penicillin-binding proteins from penicillin-resistant clinical strains of treptococcus pneumoniae. Journal of Infectious Diseases 6, Hansman, D. & Bulkn, M. M. (967). A resistant pneumococcus. Lancet ii, 6-5. Jacobs, M.., Koomhof, H. J., obins-browne,. M., tevenson, C. M., Vennaak, Z. A., Freiman, I. et al. (97). Emergence of multiply resistant pneumococci. New England Journal of Medicine 99, KJugman, K. P. (990). Pneumococcal resistance to antibiotics. Clinical Microbiology eviews 3, Laible, G. & Hakenbeck,. (97). Penicillin-binding proteins in /Mactam-resistant laboratory mutants of treptococcus pneumoniae. Molecular Microbiology, Latorre, C, Juncosa, T. & anfeliu, I. (95). Antibiotic resistance and serotypes of 00 treptococcus pneumoniae strains isolated in a children's hospital in Barcelona, pain. Antimicrobial Agents and Chemotherapy, Latorre Otin, C, Juncosa Morros, T. & anfeliu ala, I. (9). Antibiotic susceptibility of treptococcus pneumoniae isolates from paediatric patients. Journal of Antimicrobial Chemotherapy, Linares, J., Garau, J., Dominguez, C. & Perez, J. L. (93). Antibiotic resistance and serotypes of treptococcus pneumoniae from patients with community acquired pneumococcal disease. Antimicrobial Agents and Chemotherapy 3, Linares, J., Pallares,., Alonso, T., Perez, J. L., Ayats, J., Gudiol, F. et al. (99). Trends in antimicrobial resistance of clinical isolates of treptococcus pneumoniae in Bellvitge Hospital, Barcelona, pain ( ). Clinical Infectious Diseases, in press. Linares, J., Perez, J. L., Garau, J., Murgui, L. & Martin,. (9). Comparative susceptibilities of penicillin-resistant pneumococci to co-trimoxazole, vancomycin, rifampicin and fourteen /J-lactam antibiotics. Journal of Antimicrobial Chemotherapy 3, Marton, A., Gulyas, M., Mufioz,. & Tomasz, A. (99). Extremely high incidence of antibiotic resistance in clinical isolates of treptococcus pneumoniae in Hungary. Journal of Infectious Diseases 63, 5-. National Committee for Clinical Laboratory tandards. (990). Methods for Dilution Antimicrobial usceptibility Tests for Bacteria that Grow Aerobically, nd edn; Approved tandard M7-A. NCCL, Villanova PA. Pallares,., Gudiol, F., Linares, J., Ariza, J., ufi, G., Murgui, L. et al. (97). isk factors and response to antibiotic therapy in adults with bacteremic pneumonia caused by penicillinresistant pneumococci. New England Journal of Medicine 37, -. Patel, J. B. & Giles,. E. (99). Meropenem: evidence of lack of proconvulsive tendency in mice. Journal of Antimicrobial Chemotherapy, uppl. A, chliamser,. E., Cars, O. & Norrby,.. (99). Neurotoxicity of /J-lactam antibiotics: predisposing factors and pathogenesis. Journal of Antimicrobial Chemotherapy 7, -5. loas, M., Barrett, F., Chesney, J., English, K., Hill, B. & Leggiadro,. (99). Cephalosporin failure in penicillin-resistant treptococcus pneumoniae meningitis. In Program and Abstracts of the 3st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 99. Abstract 07, p. 6. American ociety for Microbiology, Washington, DC. pika, J.., Facklam,.., Plikaytis, B. D., Oxtoby, M. J. & the Pneumococcal urveillance Working Group. (99). Antimicrobial resistance of treptococcus pneumoniae in the United tates, Journal of Infectious Diseases 63, 73-. Tauber, M. G., Hackbarth, C. J., cott, K. G., usnak, M. G. & ande, M. A. (95). New cephalosporins cefotaxime, cefpimizole, BMY, and H 0 in experimental pneumococcal meningitis in rabbits. Antimicrobial Agents and Chemotherapy 7, 30-. Tomasz, A. (97). Biochemistry and genetics of penicillin resistance in pneumococci. In treptococcal Genetics (Ferretti, J. J. & Curtis,., Eds), pp American ociety for Microbiology, Washington, DC. Tweardy, D. J., Jacobs, M.. & peck, W. T. (93). usceptibility of penicillin-resistant pneumococci to eighteen antimicrobials: implications for treatment of meningitis. Journal of Antimicrobial Chemotherapy, Viladrich, P. F., Gudiol, F., Linares, J., Pallares,., abate, I., ufi, G. et al. (99). Evaluation of vancomycin for therapy of adult pneumococcal meningitis. Antimicrobial Agents and Chemotherapy 35, Viladrich, P. F., Gudiol, F., Linares, J., ufi, G., Ariza, J. & Pallares,. (9). Characteristics Downloaded from at Pennsylvania tate University on March 5, 06

10 J. Lifiares et al and antibiotic therapy of adult meningitis due to penicillin-resistant pneumococci. American Journal of Medicine, Ward, J. I. & Moellering,. C. (9). usceptibility of pneumococci to beta-lactam agents: comparison of strains resistant, intermediate-resistant, and susceptible to penicillin. Antimicrobial Agents and Chemotherapy 0, 0-7. Wise,., Andrews, J. M., Cross, C. & Piddock, L. J. V. (95). The antimicrobial activity of cefpirome, a new cephalosporin. Journal of Antimicrobial Chemotherapy 5, Zighelboim,. & Tomasz, A. (9). Multiple antibiotic resistance in outh African strains of treptococcus pneumoniae. mechanism of resistance to /J-lactam antibiotics. eviews of Infectious Diseases 3, {eceived November 99; revised version accepted 5 May 99) Downloaded from at Pennsylvania tate University on March 5, 06