THE CLINICAL IMPACT OF RESISTANCE IN THE MANAGEMENT OF PNEUMOCOCCAL DISEASE

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THE CLINICAL IMPACT OF RESISTANCE IN THE MANAGEMENT OF PNEUMOCOCCAL DISEASE Robert J. Leggiadro, MD

Drug-resistant Streptococcus pneumoniae (DRSP) isolates have become increasingly prevalent worldwide, including many areas of the United States.'j Although unfavorable outcomes with penicillin treatment of meningitis caused by these strains have been well-described, the impact of DRSP on other manifestations of pneumococcal disease treated with penicillin and other agents continues to warrant further ~larification.~, 32 This article reviews current concepts of epidemiology, diagnosis, management, and prevention of DRSP infection. DEFINITIONS AND MECHANISMS

Pneumococcal susceptibility to penicillin is defined by the National Committee for Clinical Laboratory Standards (NCCLS) as a minimal inhibitory concentration (MIC) less than 0.1 &mL.26 Penicillin-nonsusceptible pneumococci (PNSP) include those strains with MIC breakpoints 0.1-1.0 pg/mL (intermediate) and those with MICs greater than or equal to 2.0 Fg/mL (resistant). Pneumococcal cephalosporin susceptibility interpretive standards are limited to cefuroxime axetil, cefotaxime, ceftriaxone, and cefipime.26Strains with MICs less than or equal to 0.5 kg/mL are defined as susceptible, those with MICs equal ~~

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From the Department of Pediatrics, St. Vincent's Medical Center of Richmond, Staten Island, New York; and New York University School of Medicine, New York, New York ~~

INFECTIOUS DISEASE CLINICS OF NORTH AMERICA

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VOLUME 11 * NUMBER 4 DECEMBER 1997

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to 1.0 pg/mL intermediate, and MICs greater than or equal to 2.0 pg/ mL are resistant. Pneumococcal resistance to beta-lactam antibiotics is a function of altered penicillin-binding proteins (PBPs), usually transpeptidases, involved in cell wall synthesis.12The level of resistance demonstrated is directly related to the number of PBPs involved, and the affinities of different beta-lactam antibiotics for each of the pneumococcal PBPs (la, lb, 2a, 2b, and 2x) vary. For example, resistance to thirdgeneration cephalosporins occurs with altered forms of PBPs l a and 2x, whereas penicillin resistance requires alteration of PBP 2b in addition.13 Pneumococcal resistance to the carbapenem imipenem is a result of alterations in PBP 2b and 2x. EPIDEMIOLOGY

The pneumococcal serotypes most commonly associated with drug resistance are those most often responsible for infection and carriage in children, namely, 6, 14, 19, and 23.2 Of concern, however, is a recent report suggesting capsular transformation of a drug-resistant serotype 23 F organism to serotype 14 in vivo.4 This observation has major implications for the development and implementation of pneumococcal conjugate vaccines, which currently include only a limited number of serotypes. For example, a drug resistant organism of a serotype included in the vaccine may transform to a serotype not included in the vaccine, but remain drug resistant. Risk factors for acquisition of DRSP include previous antimicrobial therapy, day care center attendance, hospitalization, and white race.2,3, 19*31 The latter may be a reflection of socioeconomic factors that result in greater access to health care, including antibiotic^.^, l9

IDENTIFICATION

Detection of DRSP in the laboratory is crucial to surveillance and management of this microbial threat. At a minimum, penicillin and cefotaxime/ceftriaxone susceptibility must be determined for all S. pneurnoniae isolates from usually sterile ~ i t e s The . ~ oxacillin disk diffusion test continues to be a reliable screening method for identifying penicillinsusceptible pneumococci. Those isolates with zone diameters of greater than or equal to 20 mm around a 1 pg oxacillin disk can be considered susceptible to all beta-lactam agents. However, isolates with zone diameters less than or equal to 19 mm should have MICs to penicillin and other clinically important drugs, including cefotaxime or ceftriaxone, determined by an agar or broth dilution method. MICs also may be determined using antimicrobial gradient strips (E test method). As of this writing, 15 states and New York City have implemented DRSP surveillance to characterize the public health impact of this pathogen, and 12 were planning such surveillance?

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MANAGEMENT

Although there have been numerous reports documenting microbiologic and clinical failure with extended-spectrum cephalosporin therapy in patients with meningitis caused by DRSP, the clinical impact of these strains on other manifestations of pneumococcal infection remains to be determined.22,28 A large, prospective study of pneumococcal pneumonia in adults from Barcelona suggested that the levels of resistance to penicillin and cephalosporins reported did not seem to increase mortality in this patient p ~ p u l a t i o nFor . ~ ~patients treated with penicillin G or ampicillin, the mortality was 25% in the 24 with penicillin resistant strains and 19% in the 126 with penicillin susceptible isolates. Results were similar for those patients treated with ceftriaxone or cefotaxime, with a mortality rate of 22% in 59 with penicillin resistant strains and 25% in 127 with penicillin susceptible isolates. There also seemed to be little correlation among specific antimicrobial therapy, susceptibility test results, and clinical outcome in 12 infants and children with outpatient DRSP bacteremia who had follow-up in a study from Memphis.23Initial treatment regimens for these patients included oral amoxicillin (3 patients), loracarbef (2 patients) or amoxicillin-clavulanic acid (1 patient), and one dose of intramuscular cephalosporin followed by an oral betalactam agent (4patients) or erythromycin-sulfisoxazole (1 patient). Two patients were not treated initially. Another report from Memphis suggested that children with DRSP skeletal infections likely will fail to respond to standard empiric antibiotic regimens, e.g. nafcillin and cefotaxime, employed in the management of pediatric bone and joint infections.' MENINGITIS

Although optimal therapy for infections caused by DRSP is not known at present, several options are available to the clinician facing this challenge? Currently, it seems prudent to treat all pediatric and adult patients with purulent meningitis empirically with vancomycin combined with either cefotaxime or ceftriaxone while awaiting cerebrospinal fluid (CSF) culture and antimicrobial susceptibility test results. This approach seems appropriate even if the prevalence of penicillinand cephalosporin-resistant pneumococcal isolates is low (< lo%), or unknown in a specific geographic area, for several reasons. Rates and prevalence of DRSP continue to increase and become more widespread, respectively, making it difficult to predict when the first case of DRSP meningitis will be identified in a given region. The first such patient seen in an area may have an unfavorable outcome if not managed aggressively from the start. In addition, pneumococcal meningitis now is relatively more common given the dramatic decrease in Huemophilus influenzue type b (Hib) disease since the advent of the Hib protein conjugate vaccine? This makes the possibility of unnecessary treatment

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for pathogens other than S. pneumoniue much less likely. Empiric therapy may be tailored accordingly when results of susceptibility testing become available. High-dose penicillin alone remains the drug of choice for meningitis caused by penicillin-susceptible pneumococcal strains. The extendedspectrum cephalosporins, cefotaxime or ceftriaxone are preferred if the isolate is penicillin resistant, but cephalosporin susceptible (MIC 10.5 pg/mL), because of the favorable reported experience with these agents in the therapy of meningitis. The suggested dose of cefotaxime for penicillin resistant pneumococcal meningitis is 250 to 300 mg/ k g / d a ~ . ~ ~ Vancomycin in combination with either cefotaxime or ceftriaxone generally is recommended for the treatment of meningitis caused by pneumococci that are confirmed to be penicillin- and cephalosporinresistant.16,24, 28 The recommended dose of vancomycin for penicillin resistant pneumococcal meningitis is 60 m g / k g / d a ~ .Combination ~ vancomycin and ceftriaxone therapy in a rabbit pneumococcal meningitis model had a synergistic effect in reducing CSF bacterial concentrations compared with either drug a10ne.l~ Alternative combination regimens for penicillin- and cephalosporinresistant pneumococcal meningitis include rifampin with extended-spectrum cephalosporins, rifampin with vancomycin, and vancomycin with 28, 32 The regimen selected should be guided by suschloramphenicol.161 ceptibility testing results. Before chloramphenicol is used in this setting it may be helpful to determine the organism’s minimal bactericidal concentration (MBC). Poor clinical response has been reported in patients with strains demonstrating relatively high chloramphenicol MBCs greater than or equal to 4 pg/mL.I8 Although imipenem and the newly licensed meropenem have been suggested as therapeutic options for penicillin- and cephalosporin-resistant pneumococcal meningitis, the use of imipenem is limited by its propensity to cause seizures, especially in children with meningitis.16, Furthermore, rates of pneumococcal resistance to imipenem up to 20% recently have been reported?, Although some authors do not recommend the use of dexamethasone in children likely to have pneumococcal meningitis because of a lack of evidence for decreased neurologic sequelae in pediatric patients with confirmed disease concurrently treated with dexamethasone, others support it.5,28 However, a repeat lumbar puncture 24 to 48 hours into appropriate therapy for penicillin resistant pneumococcal meningitis generally is recommended to document microbiologic cure?, 28 PNEUMONIA High-dose, intravenous penicillin alone may be effective in pneumococcal pneumonia caused by strains with penicillin MICs less than or equal to 2.0 pg/mL.Sr 27 However, many investigators would use cefuroxime, cefotaxime, or ceftriaxone in these patients if the organism’s cephalosporin MIC is 8 pg/mL or less.16Cephalosporin therapy also has been

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reported to be successful in treating cases of bacteremic cellulitis and sinusitis due to such strains.22Empiric therapy combining vancomycin and an extended-spectrum cephalosporin seems appropriate for any patient with life-threatening pneumonia believed to be bacterial in eti~logy.~, 22 INVASIVE DISEASE Combination therapy with vancomycin and either cefotaxime or ceftriaxone also is indicated in the management of suspected sepsis in patients predisposed to invasive pneumococcal d i ~ e a s e As . ~ a result of their experience with penicillin- and cephalosporin-resistant pneumococcal sepsis and meningitis in children with sickle cell disease, investigators from the southeastern United States suggest six criteria for the addition of vancomycin to cefotaxime or ceftriaxone in the initial management of fever in this patient population.ll These include the following: (1)meningitis; (2) another potentially serious focus of infection such as pneumonia; (3) septic shock or a "toxic" appearance; (4) a history of bacterial sepsis; (5) white blood cell count less than 5000/mm3 or greater than 30,000/mm3; or (6) absolute neutrophil count less than 200/mm3." Combination therapy with vancomycin and either cefotaxime or ceftriaxone also should be considered in the initial management of sepsis or peritonitis in children with nephrotic syndrome,2O and in life-threatening pneumococcal disease in patients infected with human immunodeficiency virus (HIV).15A recent study found that HIV-infected children with invasive pneumococcal disease were more likely to have penicillin resistant isolates than controls.25 OTITIS MEDIA

Some information is available on the clinical impact of DRSP on the outcome of therapy for otitis media. One epidemiologic study suggested an association between nasopharyngeal carriage of multiply resistant pneumococci and the occurrence of refractory otitis media among children at a day care center in Ohio.3l A more recent report described impaired bacteriologic and clinical responses for otitis media caused by pneumococci with intermediate MICs to penicillin when treated with cefaclor or cefuroxime a~eti1.l~ Because an etiologic agent uncommonly is identified in otitis media, sinusitis, or outpatient pneumonia, it is difficult to assess the efficacy of empiric oral therapy, and thus determine optimal therapy in these less serious forms of pneumococcal infection. In addition to DRSP, beta-lactamase-producing Haernophilus influenme and Moruxella catarrhalis also must be considered in selecting alternative therapy for unresponsive otitis media when the etiologic agent is unknown. Increasing the dose of amoxicillin from 40 mg/kg/day to 80 mg/

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kg/day is one way to achieve a higher middle-ear fluid concentration of antibiotic to overcome penicillin re~istance.~ Adding amoxicillin to the combination drug amoxicillin-clavulanic acid without increasing the standard dose of clavulanic acid, a beta-lactamase inhibitor potentially important for H. influenzae or M . catarrhalis, is another option. These two pathogens also may respond to cehroxime axetil, cefprozil, and cefpodoxime-oral cephalosporins with the most in vitro activity against pneumococcal strains with decreased susceptibility to peni~illin.~ Although these drugs may be effective in otitis media caused by pneumococcal strains demonstrating intermediate levels of resistance to penicillin, they may not be successful in treating outpatient infections caused by pneumococci with high-level penicillin resistance or any level of cephalosporin resistance. Cefixime, cefaclor, and loracarbef have the least activity of the oral cephalosporins against PNSP. The combination drug erythromycin-sulfisoxazole and the new macrolides clarithromycin or azithromycin also represent appropriate alternative therapy for otitis media, sinusitis, and mild pneumonia suspected to be caused by penicillin resistant pneumococci when beta-lactamaseproducing H. influenzae, or M . cafarrhaliscannot be ruled Depending on regional pneumococcal susceptibility profiles, trimethroprim-sulfamethoxazole may be considered for these indications, as well. However, high (26%-54%) rates of trimethoprim-sulfamethoxazoleresistance have been reported in some areas of the United States?, l9 Chloramphenicol also may be considered on occasion if supported by local susceptibility data?, 24 Erythromycin and clindamycin represent appropriate therapy in ambulatory pneumococcal infections if the isolate is available and determined to be susceptible. Neither drug is appropriate if H. influenzae or M . catarrhalis is a possibility. Rifampin in combination with either of these drugs also may be considered. Myringotomy and sinus surgery may be therapeutic and diagnostic interventions in recalcitrant cases of otitis media and sinusitis, respectively. Parenteral vancomycin may be indicated when oral antimicrobial alternatives have been exhausted. PREVENTION

Strategies for preventing DRSP infection include the promotion of judicious antimicrobial use, adherence to current guidelines for use of the presently available 23-valent pneumococcal vaccine, and development of an effective pneumococcal protein-conjugate vaccine.6Inappropriate antibiotic use is common in clinical practice, and preliminary data from Iceland suggest that a reported decrease in prevalence of PNSP was directly related to decreased penicillin use.21Suggested modifications in the management of otitis media have recently been published.29These include adherence to strict diagnostic criteria, individualized treatment courses, limited indications for treating secretory otitis media, and restricted prophylaxis for recurrent otitis media.29

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Although it is approximately 60% effective in preventing invasive disease, the currently available pneumococcal vaccine is underused. Among those at risk it is recommended for are persons 65 years of age and older.’O However, less than 30% of this population has received it. Conjugate pneumococcal vaccines effective for children less than 2 years of age still are being developed and evaluated. Nosocomial transmission of DRSP has been documented, including recent nursing home outbreaks. Hospitalized patients with DRSP should be cared for with standard precautions. Vaccinating patients at risk should be considered in outbreak situations, including nursing homes and day care centers. Effective prophylaxis in such settings remains to be determined.30,31 References 1. Abbasi S, Orlicek SL, Almohsen I et al: Septic arthritis and osteomyelitis caused by penicillin and cephalosporin-resistant Streptococcus pneumoniue in a children’s hospital. Pediatr Infect Dis J 15:78, 1996 2. Appelbaum PC: Antimicrobial resistance in Streptococcus pneumoniae: An overview. Clii Infect Dis 1577, 1992 3. Arnold KE, Leggiadro RJ, Breiman RF et a 1 Risk factors for carriage of drug-resistant Streptococcus pneumoniae among children in Memphis, Tennessee. J Pediatr 128:757, 1996 4. Barnes DM, Whittier S, Gilligan PH et al: Transmission of multidrug-resistant serotype 23F Streptococcus pneumoniue in group day care: evidence suggesting capsular transformation of the resistant strain in vivo. J Infect Dis 171:890, 1995 5. Bradley JS, Kaplan SL, Klugman KP et al: Consensus: management of infections in children. Pediatr Infect Dis J 141037, 1995 6. Butler JC, Hofmann J, Cetron MS et al: The continued emergence of drug-resistant Streptococcus pneumoniue in the United States: An update from the Centers for Disease Control and Prevention’s Pneumococcal Sentinel Surveillance System. J Infect Dis 174:986, 1996 7. Centers for Disease Control and Prevention: Defining the public health impact of drugresistant Streptococcus pneumoniue: report of a working group. MMWR 45 (No. RRl), 1996 8. Centers for Disease Control and Prevention: Assessment of National Reporting of Drug-Resistant Streptococcus pneumoniue-United States, 199551996, MMWR 45947, 1996 9. Centers for Disease Control and Prevention: Progress toward elimination of Huemophilus infuenzae type b disease among infants and children-United States, 1987-1995. MMWR 45901, 1996 10. Centers for Disease Control and Prevention: Pneumococcal polysaccharide vaccine. MMWR 38:64,1989 11. Chesney PJ, Wilimas JA, Presbury G et al: Penicillin- and cephalosporin-resistant strains of Streptococcus pneumoniue causing sepsis and meningitis in children with sickle cell disease. J Pediatr 127.526, 1995 12. Coffey TJ, Dowson CG, Daniels M et al: Genetics and molecular biology of betalactam-resistant pneumococci. Microb Drug Resist 1:29, 1995 13. Coffey TJ, Daniels M, McDougal LK et al: Genetic analysis of clinical isolates of Streptococcus pneumoniae with high-level resistance to expanded-spectrum cephalosporins. Antimicrob Agents Chemother 39:1306, 1995 14. Dagan R, Abramson 0, Leibovitz E et al: Impaired bacteriologic response to oral cephalosporins in acute otitis media caused by pneumococci with intermediate resistance to penicillin. Pediatr Infect Dis J 15980, 1996

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15. Frankel RE, Virata M, Hardalo C et al: Invasive pneumococcal disease: clinical features, serotypes, and antimicrobial resistance patterns in cases involving patients with and without human immunodeficiency virus infection. Clin Infect Dis 23:577, 1996 16. Friedland IR, McCracken GH: Management of infections caused by antibiotic-resistant Streptococcus pneumoniae. N Engl J Med 331:377, 1994 17. Friedland IR, Paris M, Ehrett S et al: Evaluation of antimicrobial regimens for treatment of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis. Antimicrob Agents Chemother 371630, 1993 18. Friedland IR, Klugman KP: Failure of chloramphenicol therapy in penicillin-resistant pneumococcal meningitis. Lancet 339:405, 1992 19. Hofmann J, Cetron MS, Farley MM et a1 The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta. N Engl J Med 333:481, 1995 20. Ilyas M, Roy S, Abbasi S et al: Serious infections due to penicillin-resistant Streptococcus pneumoniae in two children with nephrotic syndrome. Pediatr Nephrol 10:639, 1996 21. Kristinsson KG, Hjalmarsdottir MA, Gndnason TH. Epidemiology of penicillin resistant pneumococci in Iceland-hope for the future? (Abstract C9). In Programs and Abstracts of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, 1995 22. Leggiadro RJ, Barrett FF, Chesney PJ et al: Invasive pneumococci with high level penicillin and cephalosporin resistance at a mid-south children’s hospital. Pediatr Infect Dis J 13:320, 1994 23. Leggiadro RJ, Davis Y, Tenover FC: Outpatient drug-resistant pneumococcal bacteremia. Pediatr Infect Dis J 13:1144, 1994 24. Leggiadro RJ: Penicillin- and cephalosporin-resistant Streptococcus pneurnoniae: an emerging microbial threat. Pediatrics 93:500, 1994 25. Mao C, Harper M, McIntosh K et al: Invasive pneumococcal infections in human immunodeficiency virus-infected children. J Infect Dis 1735370, 1996 26. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial susceptibility testing. Villanova, P A National Committee for Clinical Laboratory Standards 14(16), 1994 27. Pallares R, Linares J, Vadillo M et al: Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain. N Engl J Med 333474, 1995 28. Paris MM, Ramilo 0, McCracken G H Management of meningitis caused by penicillinresistant Streptococcus pneurnoniae. Antimicrob Agents Chemother 39:2171, 1995 29. Paradise J: Managing otitis media-a time for a change. Pediatrics 96712,1995 30. Rauch AM, ORyan M, Van R et al: Invasive disease due to multiply resistant Streptococcus pneumoniae in a Houston, Texas, day-care center. AJDC 144:923, 1990 31. Reichler MR, Allphin AA, Breiman RF et al: The spread of multiply resistant Streptococcus pneumoniae at a day care center in Ohio. J Infect Dis 166:1346, 1992 32. Sloas Mh4, Barrett FF, Chesney PJ et a1 Cephalosporin treatment failure in penicillinand cephalosporin-resistant Streptococcus pneumoniae meningitis. Pediatr Infect Dis J 11:662, 1992 33. Viladrich PF, Gudiol F, Linares J et al: Characteristics and antibiotic therapy of adult meningitis due to penicillin-resistant pneumococci. Am J Med 845339,1988 34. Wong VK, Wright HT, Ross LA et al: Imipenem/cilastatin treatment of bacterial meningitis in children. Pediatr Infect Dis J 10:122, 1991

Address reprint requests to Robert J. Leggiadro, MD Department of Pediatrics St. Vincent’s Medical Center of Richmond 355 Bard Avenue Staten Island, NY 10310