Activity of faropenem against resistant isolates of Streptococcus pneumoniae

Diagnostic Microbiology and Infectious Disease 41 (2001) 89 –92

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Note

Activity of faropenem against resistant isolates of Streptococcus pneumoniae Jennifer A. Blacka,*, Ellen Smith Molanda, Stephen A. Chartrandb, Kenneth S. Thomsona a

Center for Research in Anti-infectives and Biotechnology, Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Department of Medical Microbiology and Immunology, 2500 California Plaza, Omaha, NE 68178, USA b Department of Pediatric Infectious Disease, Creighton University School of Medicine, Department of Medical Microbiology and Immunology, 2500 California Plaza, Omaha, NE 68178, USA Received 28 May 2001; accepted 8 August 2001 Presented at the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada in September of 2000.

Abstract An in vitro study of the activity of 9 agents against 181 US pediatric isolates of Streptococcus pneumoniae identified imipenem and faropenem as the most active agents. Overall, faropenem was the most potent oral agent inhibiting 98% of isolates at 1 ␮g/mL. © 2001 Elsevier Science Inc. All rights reserved.

More active, oral agents are needed for treatment of all infections caused by multiply antibiotic resistant strains of Streptococcus pneumoniae (Friedland & McCracken, 1994; Klugman & Wasas, 1995; Amyes & Thomson, 1998) especially in pediatric infections. These strains are increasing in prevalence and have spread worldwide with major geographical areas of concern being South Africa, Spain, Central and Eastern Europe, and parts of Asia (Davies et al., 2000). Faropenem is an oral ␤-lactam antimicrobial with a penem structure. This oral ␤-lactam has a broad spectrum of activity against both aerobic and anaerobic Gram-positive and Gram-negative bacteria (Inoue & Mitsuhashi, 1994). It is reported to be active against S. pneumoniae isolates with decreased susceptibility to penicillin (Cormican & Jones, 1995; Reinert et al., 1999; Okuda et al., 2000). In contrast to the fluoroquinolones, which are not indicated for pediatric infections due to safety concerns (Schaad et al., 1995), faropenem offers the potential safety of ␤-lactam therapy. With this in mind, a study was designed to compare the activities of faropenem, imipenem, penicillin, amoxicillin/ clavulanate, cefprozil, cefuroxime axetil, azithromycin, clarithromycin, and trimethoprim/sulfamethoxazole against a panel of 181 US pediatric isolates of S. pneumoniae. Imi* Corresponding author. Tel.: ⫹1-402-280-1881; fax: ⫹1-402-2801225. E-mail address: [email protected] (J.A. Black).

penem was used as a reference agent. The isolates were recently collected from 12 day care centers in urban and rural Nebraska including the communities of Hastings, Fremont, Lincoln, and Omaha or from a pediatric clinic in Bardstown, Kentucky. The Nebraska isolates were nasopharyngeal colonizing strains and were collected from children 2 to 24 months old. A variety of S. pneumoniae serotypes and pulse field gel electrophoresis subtypes were found in the penicillin-nonsusceptible isolates from Nebraska (Boken et al., 1996). Most of the Bardstown isolates were from the middle ear of patients either enrolled in clinical drug trials or who had failed therapy with amoxicillin. The isolates were chosen to provide varying levels of penicillin resistance (25% susceptible, 48% intermediate, and 27% resistant). They were not random isolates. MICs were determined by the microbroth dilution method according to the National Committee for Clinical Laboratory Standards (NCCLS) using Mueller-Hinton broth supplemented with 2–5% lysed horse blood, and incubated at 37°C in ambient air (National Committee for Clinical Laboratory Standards, 2000a). NCCLS susceptibility breakpoints were applied where applicable, i.e., for all agents except faropenem (National Committee for Clinical Laboratory Standards, 2000b). The following drug powders were purchased from Sigma Chemical Co., St. Louis, MO (penicillin, amoxicillin, cefuroxime, trimethoprim, and sulfamethoxazole) or were supplied by the following companies:

0732-8893/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved. PII: S 0 7 3 2 - 8 8 9 3 ( 0 1 ) 0 0 2 8 3 - 8

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J.A. Black et al. / Diagnostic Microbiology and Infectious Disease 41 (2001) 89 –92

Table 1 In vitro activities of 9 antimicrobial agents against 181 isolates of S. pneumoniaea Agent

Range Faropenem Imipenem Penicillin Amoxicillin/ clavulanate Cefprozil Cefuroxime axetil Azithromycin Clarithromycin Trimethoprim sulfamethoxazolee

Penicillin-susceptibleb (n ⫽ 45)

All strains (n ⫽ 181)

ⱕ0.002–2 ⱕ0.002–1 ⱕ0.015–16 ⱕ0.015–16

MIC50 MIC90 Range 0.12 0.06 0.5 0.5

0.5 0.25 2 2

ⱕ0.06–32 2 8 ⱕ0.007–⬎8 2 8 ⱕ0.06–⬎16 0.12 8 ⱕ0.015–⬎16 ⱕ0.015 2 ⱕ0.06–⬎4 ⬎4 ⬎4

MIC50

ⱕ0.002–0.03 0.007 ⱕ0.002–0.015 0.004 ⱕ0.015–0.06 ⱕ0.015 ⱕ0.015–0.12 ⱕ0.015 ⱕ0.06–0.5 ⱕ0.007–1 ⱕ0.06–4 ⱕ0.015–1 ⱕ0.06–⬎4

Penicillin-intermediatec (n ⫽ 87) MIC90 0.015 0.007 0.06 0.06

Range 0.015–0.5 0.007–0.12 0.12–1 0.03–2

MIC50 0.12 0.06 0.5 0.5

Penicillin-resistantd (n ⫽ 49) MIC90 Range 0.25 0.12 1 1

0.12 0.25 0.12–8 2 4 0.03 0.25 0.12–8 2 4 ⱕ0.06 0.12 ⱕ0.06–⬎16 0.12 8 ⱕ0.015 ⱕ0.015 ⱕ0.015–⬎16 ⱕ0.015 2 0.25 ⬎4 0.12–⬎4 ⬎4 ⬎4

0.25–2 0.06–1 2–16 1–16

MIC50 MIC90 0.5 0.25 2 2

2–32 8 2–⬎8 4 ⱕ0.06–⬎16 4 ⱕ0.015–⬎16 1 0.25–⬎4 ⬎4

1 0.5 8 4 16 8 ⬎16 ⬎16 ⬎4

In vitro activities measured in MICs (in ␮g/mL). MIC50 and MIC90, MICs at which 50 and 90% of the isolates were inhibited; respectively. Strains were classified by susceptibility to penicillin (see footnotes b, c, d). b Penicillin MIC ⱕ0.06 ␮g/mL c Penicillin MIC 0.12–1 ␮g/mL d Penicillin MIC ⱖ2 ␮g/mL e The concentrations listed refer to trimethoprim a

Bayer Inc., West Haven, CT (faropenem), Merck, Rahway, NJ (imipenem), Pfizer, Inc., Groton, CT (azithromycin), Abbott Laboratories, Abbott Park, IL (clarithromycin), SmithKline Beecham Pharmaceuticals, Collegeville, PA (lithium clavulanate), and Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ (cefprozil). Against these pediatric isolates, imipenem and faropenem were the most potent agents inhibiting 90% of isolates at 0.25 ␮g/mL and 0.5 ␮g/mL and all isolates at 1 ␮g/mL and 2 ␮g/mL respectively and were four- to eightfold more potent than penicillin and amoxicillin/clavulanate (Tables 1 and 2). Eighty-six percent of all isolates were susceptible to imipenem. Susceptibility could not be evaluated for faropenem because breakpoints have not been established. Among the other oral agents 92% of all isolates were susceptible to amoxicillin/clavulanate, 65% to clarithromycin, 63% to azithromycin, 52% to cefprozil, and less than 50% were susceptible to cefuroxime axetil, trimethoprim/sulfamethoxazole, and penicillin. Among the penicillin-susceptible isolates, imipenem inhibited all isolates at 0.015 ␮g/mL and faropenem at 0.03 ␮g/mL (Table 2). All penicillin-susceptible isolates were susceptible to the other ␤-lactam agents, 93% to the macrolides, and 71% to trimethoprim/sulfamethoxazole. As penicillin MICs increased, the potency of all agents decreased including non-␤-lactam agents. The penicillin-intermediate isolates were inhibited by 0.12 ␮g/mL of imipenem and 0.5 ␮g/mL of faropenem. According to the current NCCLS susceptibility criteria (National Committee for Clinical Laboratory Standards, 2000b), amoxicillin/clavulanate would be considered to be the more clinically active agent even though penicillin and amoxicillin/clavulanate were similar in potency against these strains. For example, imipenem and amoxicillin/clavulanate were the

only evaluable (excluding faropenem) ␤-lactam agents to which 100% of the penicillin-intermediate isolates were susceptible. Fifty-six percent of the penicillin-intermediate isolates were susceptible to cefprozil, 46% to cefuroxime axetil, 61% to clarithromycin, 59% to azithromycin, and 20% to trimethoprim/sulfamethoxazole. All penicillin-resistant isolates were inhibited by 1 ␮g/mL of imipenem and by 2 ␮g/mL of faropenem (Table 2). Sixty-nine percent of the penicillin-resistant isolates were susceptible to amoxicillin/clavulanate, 49% to imipenem, 47% to clarithromycin, 45% to azithromycin, and less than 5% to trimethoprim/sulfamethoxazole and cefprozil. None were susceptible to cefuroxime axetil or penicillin. Overall, faropenem was the most potent oral agent inhibiting 98% of isolates at 1 ␮g/mL (Table 2). As penicillin MICs increased, the activity of all ␤-lactam agents were similarly reduced with MICs increasing up to 64- to 128fold (Table 2). The macrolides and trimethoprim/sulfamethoxazole were also less active against penicillin-intermediate and -resistant strains. These data suggest that if serum and tissue levels greater than 1 ␮g/mL can be safely achieved and maintained, faropenem should be further evaluated for clinical use in infections with multiply antibioticresistant pneumococci.

Acknowledgments This study was supported by a grant from Bayer, Inc. We thank T. J. Lockhart for excellent technical assistance, Stan Block for providing some of the isolates, and Connie Owens and Vonnetta Byington for help typing the manuscript.

J.A. Black et al. / Diagnostic Microbiology and Infectious Disease 41 (2001) 89 –92

91

Table 2 Comparative activity of all agents against S. pneumoniae Strains

All

No. Tested

181

PenSb

c

PenI

PenRd

45

87

49

Agent

Faropenem Imipenem Penicillin Amox/clav Cefprozil Cefuroxime axetil Azithromycin Clarithromycin Trimethoprim/sulfamethoxazole Faropenem Imipenem Penicillin Amox/clav Cefprozil Cefuroxime axetil Azithromycin Clarithromycin Trimethoprim/sulfamethoxazole Faropenem Imipenem Penicillin Amox/clav Cefprozil Cefuroxime axetil Azithromycin Clarithromycin Trimethoprim/sulfamethoxazole Faropenem Imipenem Penicillin Amox/clav Cefprozil Cefuroxime axetil Azithromycin Clarithromycin Trimethoprim/sulfamethoxazole

Cumulative Percent of Strains Inhibited at Each Concentration (␮g/ml) ⱕ0.002

0.004

0.007

2 12

4 19

18 34

3

9 49

18 76

73 96

13

21

0.015

0.03

0.06

0.12

24 44 14 20

41 46 20 23

9

19

59

63

45 56 25 29 4 20 41 64 2

50 86 38 43 18 27 63 64 10

91 100 58 82

100

38

76

91

91

2 40

54

80 84

33 44

100 98 18 80 82 93 9 43 63

3

10

59

28 59

2

100 67 89 91 93 36 53 100 28 37 3 9 59 59 3 49

0.25

0.5

1

82 96 46 46 31 31 63 65 27

93 98 99 100 51 73 54 83 41 46 42 47 64 65 67 77 28 29

96 96 91 93 69 94

100 98 100 93 93 93 100 71 76 100

44 44 15 15 59 61 18 43 84

55 100 60 95 34 44 37 46 59 61 64 80 20 20 73 92 98 100 45

37

45

29 45

45 47

45 47 2

45 47 4

45 51 4

2

4

8

ⱖ16

100 93 92 52 62 69 92 32

93

97 98 75 90 80 92 41a

97 99 91 97a 92 93

100 100 100 100 100

100

78

80a

100 56 75 68 99 23 100

91 99 86 99 37a

73 69 2 6 47 71 6

88 94 24 63 51 73 12a

100 100 99 99

90 96 67 88a 71 76

100 100

100 100 100 100 100

% of strains inhibited at highest concentration tested i.e. 8 ␮g/mL of cefuroxime, 4/76 ␮g/mL of trimethoprim/sulfamethoxazole (only trimethoprim concentration shown) b Penicillin MIC ⱕ 0.06 ␮g/mL c Penicillin MIC 0.12–1 ␮g/mL d Penicillin MIC ⱖ 2 ␮g/mL a

References Amyes, S. G. B., & Thomson, C. J. (1998). Fluoroquinolones as treatment for patients with lower respiratory tract infections caused by Streptococcus pneumoniae [letter]. Journal of Antimicrobial Chemotherapy, 42, 398 –399. Boken, D. J., Chartrand, S. A., Moland, E. S., & Goering, R. V. (1996). Colonization with penicillin-nonsusceptible Streptococcus pneumoniae in urban and rural child-care centers. Pediatric Infectious Diseases Journal, 15, 667– 672. Cormican, M. G., & Jones, R. N. (1995). Evaluation of the in-vitro activity of furopenem (SY5555 or SUN5555) against respiratory tract pathogens and ␤-lactamase producing bacteria. Journal of Antimicrobial Chemotherapy, 35, 535–539. Davies, T. A., Kelly, L. M., Pankuch, G. A., Credito, K. L., Jacobs, M. R., & Appelbaum, P. C. (2000). Antipneumococcal activities of gemifloxa-

cin compared to those of nine other agents. Antimicrobial Agents Chemotherapy, 44, 304 –310. Friedland, I. R., & McCracken, Jr. G. H. (1994). Management of infections caused by antibiotic-resistant Streptococcus pneumoniae. New England Journal of Medicine, 331, 377–382. Inoue, E., & Mitsuhashi, S. (1994). In vitro antibacterial activity and ␤-Lactamase stability of SY5555, a new oral penem antibiotic. Antimicrobial Agents Chemotherapy, 38, 1974 –1979. Klugman, K., & Wasas, A. (1995). In-vitro activity of the fluoroquinolone trovafloxacin against penicillin-susceptible and -resistant Streptococcus pneumoniae [letter]. Journal of Antimicrobial Chemotherapy, 36, 873– 874. National Committee for Clinical Laboratory Standards. (2000a). Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically-fifth edition; approved standard, M7–A5. Wayne, PA, NCCLS.

92

J.A. Black et al. / Diagnostic Microbiology and Infectious Disease 41 (2001) 89 –92

National Committee for Clinical Laboratory Standards. (2000b). Performance standards for antimicrobial susceptibility testing; tenth informational supplement (aerobic dilution) M100 –S10. Wayne, PA, NCCLS. Okuda, J., Otsuki, M., Oh, T., & Nishino, T. (2000). In vitro activity of DU-6681a, an active form of the new oral carbapenem compound DZ-2640, in comparison with that of R-95867, faropenem and oral cephalosporins. Journal of Antimicrobial Chemotherapy, 46, 101–108.

Reinert, R. R., Lu¨ tticken, R., Lemperle, M., & Bryskier, A. (1999). A comparative study of the in-vitro activity of levofloxacin against Streptococcus pneumoniae. Journal of Antimicrobial Chemotherapy, 43, Suppl. C,5– 8. Schaad, U. B., Salam, M. A., Aujard, Y., Dagan, R., Green, S. D. R., Peltola, H., Rubio, T. T., Smith, A. L., & Adam, D. (1995). Use of fluoroquinolones in pediatrics: consensus report of an International Society of Chemotherapy commission. Pediatric Infectious Diseases Journal, 14, 1–9.