Pneumococcal susceptibility to meropenem in a Mid-South children's hospital.ABSTRACT Background. We investigated pneumococcal pneumococcal /pneu·mo·coc·cal/ (-kok´al) pertaining to or caused by pneumococci. susceptibility to meropenem in isolates from a tertiary children's hospital A children's hospital is a hospital which offers its services exclusively to children. The number of children's hospitals proliferated in the 20th century, as pediatric medical and surgical specialties separated from internal medicine and adult surgical specialties. where pneumococci are commonly resistant to penicillin and cefotaxime. Methods. From July 1998 to August 1999, meropenem susceptibilities were determined by E-test for all Streptococcus pneumoniae Streptococcus pneu·mo·ni·ae n. Pneumococcus. Streptococcus pneumoniae Microbiology A pathogenic streptococcus with 90 serotypes associated with pneumonia, bacteremia, meningitis Transmission Person to person Incidence isolates from blood or cerebrospinal fluid cerebrospinal fluid (CSF) Clear, colourless liquid that surrounds the brain and spinal cord and fills the spaces in them. It helps support the brain, acts as a lubricant, maintains pressure in the skull, and cushions shocks. and for penicillin-nonsusceptible pneumococcal isolates from other sites. Results. Isolates that were penicillin-susceptible or penicillin-intermediate were all susceptible to meropenem. Of 29 penicillin-resistant isolates, 27 were nonsusceptible to meropenem (13 intermediate, 14 resistant). Cefotaxime-susceptible isolates were all susceptible to meropenem. Of 11 cefotaxime-intermediate isolates, 10 were nonsusceptible to meropenem (9 intermediate, 1 resistant). Of 20 cefotaxime-resistant isolates, 17 were nonsusceptible to meropenem (4 intermediate, 13 resistant). Conclusions. Meropenem resistance is common among pneumococci with decreased susceptibility to penicillin or cefotaxime. The role of this agent in the treatment of invasive infections caused by pneumococci that are resistant to penicillin and cefotaxime may be limited. ********** STREPTOCOCCUS PNEUMONIAE is one of the principal bacterial pathogens of infants and children worldwide, and the rising prevalence of pneumococci with decreased susceptibility to penicillin and to cephalosporins Cephalosporins Definition Cephalosporins are medicines that kill bacteria or prevent their growth. Purpose Cephalosporins are used to treat infections in different parts of the body—the ears, nose, throat, lungs, sinuses, and has complicated the management of pneumococcal infections. Because delayed sterilization sterilization Any surgical procedure intended to end fertility permanently (see contraception). Such operations remove or interrupt the anatomical pathways through which the cells involved in fertilization travel (see reproductive system). of cerebrospinal fluid (CSF Cerebrospinal Fluid (CSF) Analysis Definition Cerebrospinal fluid (CSF) analysis is a laboratory test to examine a sample of the fluid surrounding the brain and spinal cord. ) and adverse clinical outcomes have been reported in patients with meningitis caused by cefo taxime-resistant pneumococci who are treated with third-generation cephalosporins alone, the American Academy of Pediatrics The American Academy of Pediatrics ("AAP") is an organization of pediatricians, physicians trained to deal with the medical care of infants, children, and adolescents. Its motto is: "Dedicated to the Health of All Children. recommends that combination therapy with vancomycin vancomycin (văn'kōmī`sĭn), antibiotic resembling penicillin in the way it acts. It is derived from the bacterium Streptomyces orientalis, which was isolated from soil of India and Indonesia. plus cefotaxime or ceftriaxone ceftriaxone /cef·tri·ax·one/ (cef?tri-ak´son) a semisynthetic, ß–resistant, third-generation cephalosporin effective against a wide range of gram-positive and gram-negative bacteria, used as the sodium salt. be administered to children with definite or probable bacterial meningitis bacterial meningitis Acute bacterial meningitis Neurology Meningeal inflammation caused by bacteria which, if untreated, is often fatal, or associated with significant sequelae Epidemiology 60% are community-acquired–CM, 40% nosocomial–NM Predisposing until culture and susceptibility results are available. (1,2) While cefotaxime or ceftriaxone alone is still generally considered adequate empiric therapy Empiric therapy is a medical term referring to the initiation of treatment prior to determination of a firm diagnosis. It is most often used when antibiotics are given to a person before the specific microorganism causing an infection is known. for nonmeningeal invasive pneumococcal infections, (1,2) this position has been challenged by recent studies (3,4) that suggest worse outcomes of pneumococcal pneumon ia among patients infected with penicillin-resistant isolates. Meropenem is a carbapenem antibiotic that is potentially attractive for treatment of invasive pneumococcal infections in children, including pneumonia and meningitis, because of its in vitro in vitro /in vi·tro/ (in ve´tro) [L.] within a glass; observable in a test tube; in an artificial environment. in vi·tro adj. In an artificial environment outside a living organism. activity against S. pneumoniae, penetration into the CSF and other body fluids, and favorable safety profile. Although in vitro pneumococcal resistance to meropenem has been observed, it is presently unclear to what extent this resistance will limit the clinical utility of this antibiotic. In our mid-South community, invasive pneumococcal isolates commonly demonstrate reduced susceptibility to penicillin and cefotaxime. (5-7) To investigate the susceptibility to meropenem among pneumococci with reduced susceptibility to penicillin or cefotaxime, we determined the in vitro susceptibility to meropenem of pneumococcal isolates in a mid-South tertiary children's hospital. METHODS Between July 1998 and August 1999, the minimum inhibitory concentration minimum inhibitory concentration Lab medicine The minimum antibiotic concentration needed to inhibit bacterial growth from a clinical isolate–eg, a bloodborne infection, which is a form of antimicrobial susceptibility testing. Cf Minimum bactericidal concentration. (MIC) to meropenem, cefotaxime, and penicillin was determined using a commercial E-test (AB Biodisk, Piscataway, NJ) for all S. pneumoniae isolates from blood or CSF submitted to the clinical microbiology Clinical microbiology The adaptation of microbiological techniques to the study of the etiological agents of infectious disease. Clinical microbiologists determine the nature of infectious disease and test the ability of various antibiotics to inhibit or kill laboratory. Meropenem MICs were also determined for pneumococcal isolates that were not susceptible to penicillin or cefotaxime from other body sites. Susceptibilities were assigned using the breakpoints currently recommended by the National Committee for Clinical Laboratory Standards (NCCLS NCCLS National Committee for Clinical Laboratory Standards ), (8) and E-test MICs were interpreted according to the manufacturer's instructions. Isolates with intermediate susceptibility or resistance were collectively classified as nonsusceptible. All information for this study was abstracted from the records of the clinical microbiology laboratory; no clinical information regarding patients was collected. RESULTS Fifty-three S. pneumoniae isolates from 53 patients were tested for meropenem susceptibility; none of the isolates were from multiple sites from the same patient. Sources included blood (n = 13), ear (n = 13), CSF (n = 7), eye (n = 6), urine (n = 2), pleural fluid pleural fluid n. The thin film of serous fluid between the visceral and parietal pleurae. (n = 2), mastoid mastoid /mas·toid/ (mas´toid) 1. breast-shaped. 2. mastoid process. 3. pertaining to the mastoid process. mas·toid n. The mastoid process. (n = 1), bone marrow (n = 1) and other respiratory sites (n = 8). In 1 patient with bacteremic bac·te·re·mi·a n. The presence of bacteria in the blood. bac  te·re pneumococcal meningitis pneumococcal meningitis Neurology Meningitis caused by S pneumoniae, the most common meningitis pathogen in adults, and 2nd most common in children > age 6, which typically has an abrupt onset Risk factors Recurrent meningitis, meningitis with , only the CSF isolate
was tested for meropenem susceptibility. Results of meropenem
susceptibility testing, stratified stratified /strat·i·fied/ (strat´i-fid) formed or arranged in layers. strat·i·fied adj. Arranged in the form of layers or strata. by susceptibility to penicillin and cefotaxime, are shown in the Table. Fourteen isolates were resistant to meropenem, 7 with MICs of 0.75 [mu]g/mL and 7 with MICs of 1.0 [mu]g/mL. Meropenem-resistant pneumococci were recovered from blood (n = 5), ear (n = 4), other respiratory sites (n = 3), eye (n = 1), and urine (n = 1). Isolates that were susceptible to penicillin or to cefotaxime were uniformly susceptible to meropenem. Most isolates with decreased susceptibility to penicillin or cefotaxime, ho wever, demonstrated decreased susceptibility to meropenem as well. Overall, 66% of penicillin-nonsusceptible pneumococci and 87% of cefotaxime-non-susceptible pneumococci were nonsusceptible to meropenem. Absolute MICs were lower for meropenem than for penicillin or cefotaxime. The maximum MICs observed in this series were 1.0 [mu]g/mL for meropenem, 6.0 [mu]g/mL for cefotaxime, and 12.0 [mu]g/mL for penicillin. Among 31 cefotaxime-nonsusceptible isolates, the [MIC.sub.90] for meropenem was 1.0 [mu]g/mL, compared with 4.0 [mu]g/mL for penicillin and 6.0 [mu]g/mL for cefotaxime. DISCUSSION The present study was conducted to evaluate the susceptibility to meropenem among pneumococci in a children's hospital serving a region with a high prevalence of pneumococcal resistance to penicillin and cefotaxime. Studies from the early 1990s (9-11) found virtually no pneumococcal resistance to meropenem, even among penicillin-resistant isolates. More recent reports indicated that 49% of penicillin-resistant pneumococci were resistant to meropenem, (12) and that 100% of penicillin-resistant isolates were resistant to meropenem. (13) Interpretation of these reports, however, is complicated by the fact that resistance rates were calculated using a meropenem susceptibility breakpoint The location in a program used to temporarily halt the program for testing and debugging. Lines of code in a source program are marked for breakpoints. When those instructions are about to be executed, the program stops, allowing the programmer to examine the status of the program of 0.125 [mu]g/mL (the breakpoint for imipenem), because NCCLS susceptibility criteria for meropenem had not been established when the studies were conducted. In recent studies that evaluated pneumococcal susceptibility to meropenem using current NCCLS criteria (ie, susceptibility breakpoint of 0.25 [micro]/mL), 63% of penicillin- resistant isolates from Taiwan were resistant to meropenem (14) and 52% of penicillin-resistant invasive isolates from 8 United States surveillance sites were nonsusceptible to meropenem. (15) Our results differ from those of the previous studies in that we found more frequent meropenem resistance among penicillin-resistant pneumococci than did the multistate US study, although our rate was still substantially lower than the extremely high meropenem-resistance prevalence in Taiwan. Our study from an exclusively pediatric pediatric /pe·di·at·ric/ (pe?de-at´rik) pertaining to the health of children. pe·di·at·ric adj. Of or relating to pediatrics. population in the mid-South, therefore, adds to a growing body of evidence that pneumococci with reduced susceptibility to penicillin or cefotaxime will frequently be resistant to meropenem as well. The clinical importance of pneumococcal resistance to meropenem remains to be defined. Nonetheless, our results have potential implications for the management of invasive pneumococcal infections, and particularly of meningitis, in children. Meropenem can successfully treat meningitis caused by many species of bacteria, including S. pneumoniae, in adults (16) and in children, (17,18) but clinical experience in using meropenem to treat meningitis caused by cefotaxime-resistant pneumococci is limited. (17-19) The efficacy of meropenem in treating cefotaxime-resistant pneumococcal meningitis may be limited by its penetration into the CSF when administered at currently recommended doses. Dagan et al (20) reported that, in patients with meningitis, CSF meropenem concentrations ranged from 0.1 to 2.8 [micro]g/mL within 4 hours after a 20 mg/kg dose given intravenously, and that concentrations ranged from 0.3 to 6.5 [micro]g/mL following a 40 mg/kg dose. Odio et al (18) reported that, in CSF samples from 48 children with meningitis who had received meropenem (40 mg/kg every 8 hours) for 24 to 36 hours, the mean meropenem concentration was 2.1 [micro]g/mL (range, undetectable to 18.8 [micro]g/mL). Considering that in our series cefotaxime-non-susceptible pneumococci demonstrated MICs as high as 1.0 [micro]g/mL to meropenem, it appears likely that concentrations of meropenem in CSF achieved with conventional dosing will not reliably exceed a level 8-fold greater than the minimum bactericidal concentration minimum bactericidal concentration Lab medicine The lowest concentration of an antibiotic that is bactericidal to ≥ 99.9% of an original inoculum. See Persistence phenomenon, Paradoxic effect, and Tolerance. , which is considered necessary for optimal management of bacterial meningitis. (2) Meropenem might be a potentially useful agent for the treatment of invasive pneumococcal infections in children. Our results and those of previous studies (13,14) indicate that penicillin-susceptible pneumococci are uniformly susceptible to meropenem. Meropenem is more active against pneumococci with high-level resistance to [beta]-lactams than are penicillin or cefotaxime, and it might be useful in the management of nonmeningeal infections caused by these organisms. Meropenem also is an alternative agent for treatment of pneumococcal infections in some patients with [beta]-lactam allergies. Further investigation is needed to determine the clinical relevance of pneumococcal resistance to meropenem, particularly in the management of patients with meningitis caused by pneumococci resistant to penicillin and cefotaxime. Our data, however, suggest that in the management of pneumococcal meningitis, empiric monotherapy with meropenem should only be used with trepidation, if at all. For now, prudence dictates the c ontinued inclusion of vancomycin in empiric therapy of suspected pneumococcal meningitis until the results of cultures and susceptibility testing are available.
TABLE
Meropenem Susceptibility of Streptococcus pneumoniae Isolates Stratified
by Susceptibility to Pencillin and Cefotaxime
No. of Susceptibility to Meropenem
*
Isolates Susceptible Intermediate
All isolates 53 26 13
Penicillin-susceptible 12 12 0
Penicillin-intermediate 12 12 0
Penicillin-resistant 29 2 13
Cefotaxime-susceptible 22 22 0
Cefotaxime-intermediate 11 1 9
Cefotaxime-resistant 20 3 4
Susceptibility Meropenem MICs ([mu]g/mL)
to Meropenem *
Resistant [MIC.sub.50] [MIC.sub.90]
All isolates 14 0.38 1.0
Penicillin-susceptible 0 0.012 0.026
Penicillin-intermediate 0 0.11 0.19
Penicillin-resistant 14 0.5 1.0
Cefotaxime-susceptible 0 0.023 0.125
Cefotaxime-intermediate 1 0.38 0.7
Cefotaxime-resistant 13 0.75 1.0
Meropenem
MICs
([mu]g/mL)
MIC Range
All isolates 0.004-1.0
Penicillin-susceptible 0.004-0.032
Penicillin-intermediate 0.023-0.190
Penicillin-resistant 0.047-1.0
Cefotaxime-susceptible 0.004-0.19
Cefotaxime-intermediate 0.125-1.0
Cefotaxime-resistant 0.125-1.0
* Susceptibility determined by E-test.
MIC = Minimum inhibitory concentration.
References (1.) American Academy of Pediatrics: Pneumococcal infections. 2000 Red Book: Report of the Committee on Infectious Diseases. Pickering LK (ed). Elk Grove Village Elk Grove Village, village (1990 pop. 33,429), Cook and Du Page counties, NE Ill., a suburb of Chicago; inc. 1956. With a population of c.100 at the time of its establishment on open farmland, the village has grown dramatically and steadily, largely because of its , Ill, American Academy of Pediatrics, 25th Ed, 2000, pp 452-460 (2.) American Academy of Pediatrics: Therapy of children with invasive pneumococcal infections. Pediatrics 1997; 99:289-299 (3.) Feikin DR, Schuchat A, Kolczak M, et al: Mortality from invasive pneumococcal pneumonia Pneumococcal Pneumonia Definition Pneumococcal pneumonia is a common but serious infection and inflammation of the lungs. It is caused by the bacterium Streptococcus pneumoniae. in the era of antibiotic resistance antibiotic resistance, n the ability of certain strains of microorganisms to develop resistance to antibiotics. antibiotic resistance , 1995-97. Am J Public Health 2000; 90:223-229 (4.) Metlay JP, Hofmann J. Cetron MS, et al: Impact of penicillin susceptibility on medical outcomes for adult patients with bacteremic pneumococcal pneumonia. Clin Infect Dis 2000; 30:520-528 (5.) Leggiadro RJ, Barrett FF, Chesney PJ, et al: Invasive pneumococci with high-level penicillin and cephalosporin cephalosporin (sĕf'əlōspôr`ĭn), any of a group of more than 20 antibiotics derived from species of fungi of the genus Cephalosporium and closely related chemically to penicillin. Cephalosporins, e.g. resistance at a mid-South children's hospital. Pediatr Infect Dis J 1994; 13:320-322 (6.) Leggiadro RJ, Davis Y, Tenover FC: Outpatient drug-resistant pneumococcal bacteremia bacteremia: see septicemia. bacteremia Presence of bacteria in the blood. Short-term bacteremia follows dental or surgical procedures, especially if local infection or very high-risk surgery releases bacteria from isolated sites. . Pediatr Infect Dis J 1994; 13:1144-1146 (7.) Arnold KE, Leggiadro RJ, Breiman RF, et al: Risk factors for carriage of drug-resistant Streptococcus pneumoniae among children in Memphis, Tennessee. J Pediatr 1996; 128:757-764 (8.) National Committee for Clinical Laboratory Standards: Performance Standard for Antimicrobial Susceptibility Testing, 10th Informational Supplement, M100-S10. Wayne, PA, National Committee for Clinical Laboratory Standards, 2000 (9.) van de Beek D, Hensen EF, Spanjaard L, et al: Meropenem susceptibility of Neisseria meningitidis Neisseria men·in·git·i·dis n. The bacteria that is the causative agent of cerebrospinal meningitis; meningococcus. Neisseria meningitidis and Streptococcus pneumoniae from meningitis patients in The Netherlands. J Antimicrob Chemother 1997; 40:895-897 (10.) Marchese mar·che·se n. pl. mar·che·si 1. An Italian nobleman ranking above a count and below a prince. 2. Used as the title for such a nobleman. A, Debbia EA, Arvigo A, et al: Susceptibility of Streptococcus pneumoniae strains isolated in Italy to penicillin and ten other antibiotics. J Antimicrob Chemother 1995; 36:833-837 (11.) Spangler SK, Jacobs MR, Appelbaum PC: Susceptibilities of 177 penicillin-susceptible and -resistant pneumococci to FK 037, cefpirome, cefepime, ceftriaxone, cefotaxime, ceftazidime, imipenem, biapenem, meropenem, and vancomycin. Antimicrob Agents Chemother 1994; 38:898-900 (12.) Pikis A, Donkersloot JA, Akram S, et al: Decreased susceptibility to imipenem among penicillin-resistant Streptococcus pneumoniae. J Antimicrob Chemother 1997; 40:105-108 (13.) Fuchs PC, Barry AL, Brown SD: Pneumococcal susceptibility to meropenem [letter]. J Antimicrob Chemother 1996; 37:1036-1037 (14.) Hsueh PR, Teng LJ, Lee LN, et al: Extremely high incidence of macrolide and trimethoprim-sulfamethoxazole resistance among clinical isolates of Streptococcus pneumoniae in Taiwan. J Clin Microbial microbial pertaining to or emanating from a microbe. microbial digestion the breakdown of organic material, especially feedstuffs, by microbial organisms. 1999; 37:897-901 (15.) Whitney CG, Farley MM, Hadler J, et al: Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United States. N Engl J Med 2000; 343:1917-1924 (16.) Schmutzhard E, Williams KJ, Vukmirovits G, et al: A randomised Adj. 1. randomised - set up or distributed in a deliberately random way randomized irregular - contrary to rule or accepted order or general practice; "irregular hiring practices" comparison of meropenem with cefotaxime or ceftriaxone for the treatment of bacterial meningitis in adults. J Antimicrob Chemother 1995; 36(suppl A):85-97 (17.) Klugman KP, Dagan R, Meropenem Meningitis Study Group: Randomized ran·dom·ize tr.v. ran·dom·ized, ran·dom·iz·ing, ran·dom·iz·es To make random in arrangement, especially in order to control the variables in an experiment. comparison of meropenem with cefotaxime for treatment of bacterial meningitis. Antimicrob Agents Chemother 1995; 39:1140-1146 (18.) Odio CM, Puig JR, Feris JM, et al: Prospective, randomized investigator-blinded study of the efficacy and safety of meropenem vs cefotaxime therapy in bacterial meningitis in children. Pediatr Infect Dis J 1999; 18:581-590 (19.) John CC, Aouad G, Berman B, et al: Successful meropenem treatment of multiply resistant pneumococcal meningitis. Pediatr Infect Dis J 1997; 16:1009-1011 (20.) Dagan R, Velghe L, Rodda JL, et al: Penetration of meropenem into the cerebrospinal fluid of patients with inflamed meninges meninges (mĭnĭn`jēz), three membranous layers of connective tissue that envelop the brain and spinal cord (see nervous system). The outermost layer, or dura mater, is extremely tough and is fused with the membranous lining of the skull. . J Antimicrob Chemother 1994; 34:175-179 RELATED ARTICLE: KEY POINTS * Pneumococci with full susceptibility to penicillin or cefotaxime are uniformly susceptible to meropenem. * Pneumococci with decreased susceptibility to penicillin and cefotaxime are also frequently resistant to meropenem. * Among penicillin-resistant pneumococci, the meropenem resistance rate is higher in our mid-South children's hospital than that reported in a recent multistate study, but not as high as that reported in Taiwan. * The efficacy of meropenem in treating cefotaxime-resistant pneumococcal meningitis may be limited by its penetration into the cerebrospinal fluid when administered at currently recommended doses. From the Department of Pediatrics, Division of Infectious Disease Infectious disease A pathological condition spread among biological species. Infectious diseases, although varied in their effects, are always associated with viruses, bacteria, fungi, protozoa, multicellular parasites and aberrant proteins known as prions. , University of Tennessee Health Science center The University of Tennessee Health Science Center (UTHSC) in Memphis includes the Colleges of Allied Health Sciences, Dentistry, Graduate Health Sciences, Medicine, Nursing and Pharmacy. Its pediatric residency program is affiliated with Le Bonheur Children's Medical Center. and Le Bonheur Children's Hospital, and the Infectious Disease Laboratory Le Bonheur Children's Hospital, Memphis, Tenn. Presented at the Southern Regional Meeting of the Southern Society for Pediatric Research, New Orleans, La, February 17-19, 2000. Reprint requests to Steven C. Buckingham, MD, Le Bonheur Children's Medical Center Le Bonheur Children's Medical Center is a 225-bed children's hospital Located in Memphis, Tennessee. It has more than 500 medical staff representing 45 pediatric specialties. Its pediatric residency program is affiliated with the University of Tennessee Health Science Center. , Room 301, West Tower, 50 N Dunlap St, Memphis, TN 38103. |
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