Antibacterial activity of carbapenems against clinically isolated respiratory bacterial pathogens in Japan between 2005 and 2006

International Journal of Antimicrobial Agents 29 (2007) 586–592

Short communication

Antibacterial activity of carbapenems against clinically isolated respiratory bacterial pathogens in Japan between 2005 and 2006 Kazunori Gomi a , Akira Watanabe a,∗ , Shizuka Aoki a , Toshiaki Kikuchi a , Katsuhiro Fuse a , Toshihiro Nukiwa a , Iku Kurokawa b , Shigeru Fujimura c a

Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging and Cancer, Tohoku University, 4-1, Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan b Department of Laboratory Medicine, Tohoku Rosai Hospital, 4-3-21 Dainohara, Aoba-ku, Sendai 981-8563, Japan c Department of Microbiology, Miyagi University, 1 Gakuen, Taiwa-cho, Miyagi 981-3298, Japan Received 4 September 2006; accepted 13 November 2006

Abstract The current status of the susceptibility of the main respiratory bacterial pathogens was evaluated by analysing the antibacterial activity of 21 drugs, including four carbapenems, against five species of the pathogens isolated between January 2005 and January 2006. A total of 157 strains were studied. Carbapenems inhibited the growth of all of the tested strains of Moraxella catarrhalis, Streptococcus pneumoniae and methicillin-susceptible Staphylococcus aureus strains at concentrations that were below the breakpoints set by the Japanese Society of Chemotherapy (2 and 1 ␮g/mL for pneumonia and chronic respiratory tract infection, respectively). However, the majority of methicillin-resistant Staphylococcus aureus strains were resistant to carbapenems. Meropenem, but not the other carbapenems, inhibited the growth of all of the tested strains of Haemophilus influenzae isolates, including ␤-lactamase-non-producing ampicillin-resistant strains, at concentrations of ≤1 ␮g/mL. The MIC50 and MIC90 of meropenem, 0.25 and 4 ␮g/mL, against Pseudomonas aeruginosa were the lowest of the carbapenems. By comparing these results with our previous data, it was found that there was no increase in resistance to carbapenems in any of the species tested. Thus, it can be stated that carbapenems have retained their position as key drugs for severe respiratory tract infections. © 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Antibacterial activity; Carbapenems; Japan; Respiratory pathogens

1. Introduction Increasing numbers of resistant strains among the respiratory bacterial pathogens, such as ␤-lactamase-non-producing ampicillin-resistant (BLNAR), Haemophilus influenzae and penicillin-resistant Streptococcus pneumoniae (PRSP), have been recently reported [1]. Carbapenems possess a broad antibacterial spectrum and potent antibacterial activity, exceeding those of penicillins and cephems. Therefore,

∗

Corresponding author. Tel.: +81 22 717 8540; fax: +81 22 717 8540. E-mail address: [email protected] (A. Watanabe).

they have been used mainly for infections such as nosocomial pneumonia and severe community-acquired pneumonia [2,3]. However, it is inevitable that clinical isolates develop resistance to any antibiotics, including the carbapenems. Thus, it is of major clinical importance to continuously monitor the susceptibility of clinical isolates to antibiotics. In this study, we investigated the antibacterial activity of a total of 21 drugs (focusing primarily on carbapenems) against common respiratory bacterial pathogens that were isolated between 2005 and 2006 at a large core hospital in Sendai city, Japan, and compared the results with those obtained in our previous studies [4,5].

0924-8579/$ – see front matter © 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2006.11.030

K. Gomi et al. / International Journal of Antimicrobial Agents 29 (2007) 586–592

587

2. Materials and methods

2.4. Test to confirm β-lactamase production

2.1. Antibiotics

For H. influenzae, a qualitative test of ␤-lactamase production was carried out using the nitrocefin spot plate method [6]. For P. aeruginosa, a confirmatory test for metallo-␤lactamase-producing bacteria was carried out by the disk diffusion method using sodium mercaptoacetate [7].

Susceptibility to the following drugs was tested: meropenem (Dainippon Sumitomo Pharma, Osaka, Japan), imipenem (Banyu Pharmaceutical, Tokyo, Japan), panipenem (Sankyo, Tokyo, Japan), biapenem (Meiji Seika, Tokyo, Japan), cefotiam (Takeda Pharmaceutical, Osaka, Japan), ceftazidime (GlaxoSmithKline, Tokyo, Japan), cefpirome (Aventis Pharma, Tokyo, Japan), cefozopran (Takeda Pharmaceutical), cefepime (Bristol Myers, Tokyo, Japan), flomoxef (Shionogi, Osaka, Japan), ampicillin (Meiji Seika), piperacillin (Taisho Toyama Pharmaceutical, Tokyo, Japan), sulbactam/ampicillin (Pfizer Japan, Tokyo, Japan), sulbactam/cefoperazone (Pfizer Japan), aztreonam (Eisai, Tokyo, Japan), amikacin (Banyu Pharmaceutical), arbekacin (Meiji Seika), vancomycin (Shionogi), teicoplanin (Astellas Pharma, Tokyo, Japan), ciprofloxacin (Bayer Yakuhin, Osaka, Japan), pazufloxacin (Taisho Toyama Pharmaceutical). 2.2. Bacterial strains The bacterial strains used in the study were isolated between January 2005 and January 2006 from patients with respiratory tract infections treated at a large core hospital in Sendai city, Japan. The strains tested were presumed to be causative organisms by the physician in charge. A total of 157 strains were studied, including 29 strains of methicillin-susceptible Staphylococcus aureus (MSSA), 30 strains of methicillin-resistant S. aureus (MRSA), 24 strains of S. pneumoniae, 19 strains of Pseudomonas aeruginosa, 26 strains of Moraxella catarrhalis, and 29 strains of H. influenzae. If more than one strain of the same species was isolated from a single patient, the first isolate was used.

2.5. Genetic analysis Genetic analysis was carried out on strains that were stored after MIC measurement and then recultured; 29 strains of H. influenzae and 18 strains of S. pneumoniae were analysed. Three PBP genes (pbp1a, pbp2x and pbp2b) in S. pneumoniae and ftsI gene encoding PBP3 in H. influenzae were identified by the polymerase chain reaction kit (Wakunaga Pharmaceutical, Osaka, Japan) constructed by Ubukata et al. [8,9].

3. Results 3.1. Antibacterial activity of carbapenems and control drugs The MIC values (MIC range, MIC50 and MIC90 ) for the various bacterial species are shown in Table 1. The susceptibility rates to the four carbapenems were estimated using the breakpoints for respiratory tract infection (RTI) set by the Japanese Society of Chemotherapy (2 ␮g/mL for pneumonia and 1 ␮g/mL for chronic respiratory tract infection (CRTI)) (Table 2) [10]. CRTI is defined as acute exacerbation or chronic persistent infection in chronic respiratory lesions, such as panbronchiolitis, bronchiectasis and chronic bronchitis. In the following section, the results for the carbapenems are reviewed, using MIC90 and the susceptibility rates as the main indicators of antibacterial activity.

2.3. Susceptibility testing The minimum inhibitory concentration (MIC) was measured using the broth microdilution method in 0.1 mL cation-adjusted Mueller–Hinton broth (Difco, Detroit, MI, USA), according to the Standard Method for Measuring Minimum Inhibitory Concentrations recommended by the Japanese Society of Chemotherapy. Strepto–Haemo Supplement (Eiken, Tokyo, Japan) was added to Mueller–Hinton broth for the culture of S. pneumoniae, H. influenzae and M. catarrhalis. Microdilution plates received an inoculum of about 5 × 105 cfu (colony-forming units)/mL delivered by means of an automatic pin inoculator (MDS 1300; Dainippon Seiki, Kyoto, Japan). The MIC was defined as the lowest antibiotic concentration that inhibited the visible growth after incubation for 20 h at 37 ◦ C. S. pneumoniae, H. influenzae and M. catarrhalis were grown in a 7% CO2 incubator for 20 h at 32, 35 and 37 ◦ C, respectively.

3.1.1. H. influenzae (29 strains) The MIC90 values of the four carbapenems were 0.5 ␮g/mL for meropenem and 2 ␮g/mL for imipenem, panipenem and biapenem. All of the strains were susceptible to meropenem at both breakpoints. The susceptibility rates for the other carbapenems were 100% for imipenem and panipenem, 96.6% for biapenem at the pneumonia breakpoint, while the susceptibility rate was 75.9% for imipenem and panipenem, and 79.3% for biapenem at the breakpoint for CRTI. Among the other drugs, ciprofloxacin showed the lowest MIC90 value of ≤0.015 ␮g/mL. 3.1.2. M. catarrhalis (26 strains) The MIC90 values of the four carbapenems were ≤0.015 ␮g/mL for meropenem, 0.06 ␮g/mL for panipenem and biapenem, and 0.12 ␮g/mL for imipenem. All of the strains were susceptible to all four carbapenems at both the

588

Table 1 Comparison of MIC range, MIC50 and MIC90 of meropenem, other ␤-lactams, aminoglycosides and other antibiotics against five major species of respiratory pathogens isolated between 2005 and 2006 Organism (no. tested)

Drugsa

MIC (␮g/mL) Range

Organism (no. tested) 50%

Drugsa

90%

MIC (␮g/mL) Range

50%

90%

0.015–0.25 0.015–0.25 0.015–0.12 0.015–0.25 0.06–2 0.015–0.5 0.015–1 0.015–2 0.03–2 0.03–0.5 0.015–1 0.015–1 0.015–0.5 16–>32 8–>32 0.015–1 0.015–0.06 0.25–2 0.06–4

0.12 0.06 0.06 0.06 0.5 0.12 0.25 0.25 0.25 0.25 0.5 0.5 0.25 32 32 0.5 0.03 1 2

0.25 0.25 0.12 0.12 2 0.25 0.5 1 1 0.5 1 0.5 0.5 >32 >32 0.5 0.06 2 2

0.03–0.06 0.03 0.03 0.03–0.06 0.25–1 0.25–1 1–2 0.5–2 0.25–0.5 0.06–8 0.5–16 0.5–2 0.06–4 0.25–4 0.12–0.5 0.5–1 0.25–1 0.06–0.5 0.06–0.12

0.06 0.03 0.03 0.03 0.5 0.5 2 1 0.25 1 4 2 1 0.5 0.25 0.5 0.5 0.12 0.12

0.06 0.03 0.03 0.06 1 0.5 2 1 0.25 4 8 2 2 2 0.5 1 1 0.25 0.12

8 4 4 8 32

16 16 8 16 >64

MEPM IPM PAPM BIPM CTM CAZ CPR CFPM CZOP FMOX ABPC PIPC SBT/CPZ SBT/ABPC AZT AMK ABK CPFX PZFX

0.03–1 0.25–2 0.12–2 0.06–4 0.5–>32 0.03–0.25 0.03–1 0.015–4 0.06–16 0.25–8 0.25–4 0.015–0.25 0.015–0.5 0.25–4 0.03–4 1–32 1–16 0.015–0.12 0.03–0.25

0.12 1 1 0.5 2 0.12 0.06 0.25 0.5 4 1 0.06 0.12 0.5 0.12 8 8 0.015 0.03

0.5 2 2 2 16 0.25 1 4 8 8 4 0.25 0.5 4 1 16 16 0.015 0.03

Moraxella catarrhalis (26)

MEPM IPM PAPM BIPM CTM CAZ CPR CFPM CZOP FMOX ABPC PIPC SBT/CPZ SBT/ABPC AZT AMK ABK CPFX PZFX

0.015 0.015–0.12 0.015–0.12 0.015–0.12 0.5–4 0.015–0.25 0.12–4 0.03–4 0.5–8 0.015–0.5 0.12–8 0.12–0.5 0.03–0.25 0.06–0.5 0.5–>32 0.5–4 0.12–2 0.015–0.06 0.03–0.06

0.015 0.12 0.06 0.06 2 0.06 1 1 4 0.25 2 0.25 0.12 0.12 2 2 0.5 0.03 0.03

0.015 0.12 0.06 0.06 2 0.12 2 2 4 0.5 4 0.5 0.25 0.25 >32 4 2 0.06 0.06

Staphylococcus aureus (MSSA) (29)

MEPM IPM PAPM BIPM CTM CPR CFPM CZOP FMOX ABPC PIPC SBT/CPZ SBT/ABPC AMK ABK VCM TEIC CPFX PZFX

Pseudomonas aeruginosa (19)

MEPM IPM PAPM BIPM CTM

0.03–>64 0.5–>64 0.5–>64 0.25–>64 >64

0.25 1 2 0.5 >64

4 16 16 8 >64

Staphylococcus aureus (MRSA) (30)

MEPM IPM PAPM BIPM CTM

1–64 0.06–64 0.12–64 0.25–64 2–>64

K. Gomi et al. / International Journal of Antimicrobial Agents 29 (2007) 586–592

MEPM IPM PAPM BIPM CTM CPR CFPM CZOP FMOX ABPC PIPC SBT/CPZ SBT/ABPC AMK ABK VCM TEIC CPFX PZFX

Haemophilus influenzae (29)

Streptococcus pneumoniae (24)

>64 >64 64 >64 32 >64 >64 32 16 1 1 1 >64 >64 >64 >64 32 >64 16 64 32 16 4 0.5 1 0.5 64 4 8–>64 >64 4–>64 >64 8–32 16–>64 8–>64 4–32 0.5–64 0.12–2 0.25–2 0.25–2 0.25–>64 0.12–>64 CPR CFPM CZOP FMOX ABPC PIPC SBT/CPZ SBT/ABPC AMK ABK VCM TEIC CPFX PZFX

Range

4 8 4 4 >64 >64 32 32 >64 >64 8 4 2 2 2 2 2 1 >64 >64 4 4 >64 64 2 2 0.12 0.25 1–>64 0.5–>64 0.25–>64 0.25–>64 >64 32–>64 0.25–64 0.25–>64 8–>64 4–>64 0.25–>64 0.25–8 0.03–64 0.06–>64 CAZ CPR CFPM CZOP FMOX ABPC PIPC SBT/CPZ SBT/ABPC AZT AMK ABK CPFX PZFX

50% Range

a MEPM, meropenem; IPM, imipenem; PAPM, panipenem; BIPM, biapenem; CTM, cefotiam; CAZ, ceftazidime; CPR, cefpirome; CFPM, cefepime; CZOP, cefozopran; FMOX, flomoxef; ABPC, ampicillin; PIPC, piperacillin; SBT/CPZ, sulbactam/cefoperazone; SBT/ABPC, sulbactam/ampicillin; AZT, aztreonam; AMK, amikacin; ABK, arbekacin; VCM, vancomycin; TEIC, teicoplanin; CPFX, ciprofloxacin; PZFX, pazufloxacin.

Organism (no. tested)

Table 1 ( Continued )

Drugsa

MIC (␮g/mL)

90%

Organism (no. tested)

Drugsa

MIC (␮g/mL)

50%

90%

K. Gomi et al. / International Journal of Antimicrobial Agents 29 (2007) 586–592

589

breakpoints. Among the other drugs, ciprofloxacin and pazufloxacin showed the lowest MIC90 value of 0.06 ␮g/mL. 3.1.3. P. aeruginosa (19 strains) The MIC90 values of the four carbapenems were 4 ␮g/mL for meropenem, 8 ␮g/mL for biapenem, and 16 ␮g/mL for imipenem and panipenem. The susceptibility rate for meropenem was 84.2% at the pneumonia breakpoint and 78.9% at the CRTI breakpoint. The susceptibility rates for biapenem were the next highest, with a rate of 78.9% at the breakpoints for pneumonia and CRTI. Among the other drugs, ciprofloxacin and pazufloxacin showed the lowest MIC90 value of 2 ␮g/mL. One metallo-␤-lactamaseproducing strain was detected. The MIC values against the strain were 8 ␮g/mL for arbekacin, 64 ␮g/mL for piperacillin, ciprofloxacin and pazufloxacin, and >64 ␮g/mL for the other drugs. 3.1.4. S. pneumoniae (24 strains) The MIC90 values of the four carbapenems were 0.12 ␮g/mL for panipenem and biapenem, and 0.25 ␮g/mL for meropenem and imipenem. All of the strains were susceptible to all four carbapenems at both breakpoints. Among the other drugs, teicoplanin showed the lowest MIC90 value of 0.06 ␮g/mL. 3.1.5. MSSA (29 strains) The MIC90 values were ≤0.03 ␮g/mL for imipenem and panipenem, and 0.06 ␮g/mL for meropenem and biapenem. All of the strains were susceptible to all four carbapenems at both breakpoints. Among the other drugs, clindamycin showed the lowest MIC90 value of 0.06 ␮g/mL. 3.1.6. MRSA (30 strains) The MIC90 values were 8 ␮g/mL for panipenem, and 16 ␮g/mL for meropenem, imipenem and biapenem. The susceptibility rates for all four carbapenems were <40%, and the majority of strains were resistant. Among the other drugs, arbekacin, vancomycin and teicoplanin showed the lowest MIC90 value of 1 ␮g/mL. 3.2. Genetic analysis Genetic analysis of 29 H. influenzae strains showed that five strains did not carry resistance genes (genotypic ␤-lactamase-non-producing ampicillin-susceptible H. influenzae (gBLNAS) strains), 18 strains had a resistancerelated mutation at one site within the ftsI gene that codes for PBP3 (gLow-BLNAR strains), six strains had resistancerelated mutations at two sites on the ftsI gene (gBLNAR strains), and no strains carried the ␤-lactamase gene. The MIC values of carbapenems, excluding meropenem, against gLow-BLNAR (five strains) and gBLNAR (three strains) were above the RTI breakpoint [10]. Genetic analysis of the 18 S. pneumoniae strains showed that four strains had mutations of pbp2x and pbp2b or pbp1a

590

K. Gomi et al. / International Journal of Antimicrobial Agents 29 (2007) 586–592

Table 2 Susceptibility rate to carbapenems in five major species of respiratory pathogens isolated between 2005 and 2006 Susceptibility ratea (%)

Organism (no. tested)

MEPMb

IPMb

PAPMb

BIPMb

Haemophilus influenzae (n = 29)

Pneumonia CRTIc

100 100

100 75.9

100 75.9

Moraxella catarrhalis (n = 26)

Pneumonia CRTI

100 100

100 100

100 100

Pseudomonas aeruginosa (n = 19)

Pneumonia CRTI

Streptococcus pneumoniae (n = 24)

Pneumonia CRTI

100 100

100 100

100 100

100 100

MSSAd (n = 29)

Pneumonia CRTI Pneumonia CRTI

100 100 10.0 6.7

100 100 33.3 20.0

100 100 36.7 16.7

100 100 16.7 6.7

MRSAe (n = 30)

84.2 78.9

78.9 73.7

96.6 79.3 100 100

63.2 15.8

78.9 78.9

a Susceptible: MIC≤2 ␮g/mL (breakpoint of carbapenems for pneumonia, stated by the Japanese Society of Chemotherapy); MIC≤1 ␮g/mL (breakpoint of carbapenems for chronic respiratory tract infections, stated by the Japanese Society of Chemotherapy). b MEPM; meropenem, IPM; imipenem, PAPM; panipenem, BIPM; biapenem. c Chronic respiratory tract infections. d Methicillin-susceptible Staphylococcus aureus. e Methicillin-resistant Staphylococcus aureus.

Table 3 Changes in MIC50 and MIC90 of carbapenems against five major species of respiratory pathogens in 1993, 1997, 1999–2000, and 2005–2006 Organism

Yearsa

n

MIC50 (␮g/mL)

MIC90 (␮g/mL)

MEPMd

IPMd

PAPMd

BIPMd

MEPMd

IPMd

PAPMd

BIPMd

Haemophilus influenzae

1993 1997 1999–2000 2005–2006

20 26 25 29

1 0.12 0.12 0.12

1 0.5 1 1

0.5 0.5 1 1

1 0.5 2 0.5

4 0.25 0.25 0.5

2 2 4 2

1 2 4 2

4 8 4 2

Moraxella catarrhalis

1993 1997 1999–2000 2005–2006

20 19 14 26

0.06 0.03 0.015 0.015

0.06 0.03 0.06 0.12

0.06 0.03 0.03 0.06

0.06 0.03 0.06 0.06

0.06 0.03 0.06 0.015

0.06 0.06 0.06 0.12

0.06 0.03 0.06 0.06

0.06 0.06 0.12 0.06

Pseudomonas aeruginosa

1993 1997 1999–2000 2005-2006

20 53 30 19

1 0.25 0.5 0.25

2 1 1 1

4 8 8 16

16 16 8 16

4 4 16 8

Streptococcus pneumoniae

1993 1997 1999–2000 2005–2006

– 32 40 24

– 0.06 0.12 0.12

– 0.03 0.06 0.06

– 0.03 0.03 0.06

– 0.03 0.06 0.06

– 0.25 0.5 0.25

– 0.12 0.12 0.25

– 0.06 0.06 0.12

– 0.25 0.25 0.12

MSSAb

1993 1997 1999–2000 2005–2006

20 38 30 29

0.06 0.06 0.12 0.06

0.06 0.03 0.06 0.03

0.06 0.03 0.12 0.03

0.06 0.06 0.12 0.03

0.12 0.12 0.25 0.06

0.06 0.03 0.25 0.03

0.06 0.06 0.25 0.03

0.12 0.12 0.25 0.06

MRSAc

1993 1997 1999–2000 2005–2006

20 32 28 30

16 16 16 8

32 8 16 4

16 4 16 4

32 8 8 8

64 32 32 16

64 16 32 8

a b c d

16 4 2 2

1 0.5 2 0.5

4 2 2 4

64 32 32 16

MIC data for isolates obtained in 1993, 1997 and 1999–2000 are quoted from published literature [4,5]. Methicillin-susceptible Staphylococcus aureus. Methicillin-resistant Staphylococcus aureus. MEPM; meropenem, IPM; imipenem, PAPM; panipenem, BIPM; biapenem.

64 32 32 16

K. Gomi et al. / International Journal of Antimicrobial Agents 29 (2007) 586–592

and pbp2x (genotypic penicillin-intermediate S. pneumoniae (gPISP) strains), and 14 strains had mutations of pbp1a, pbp2x and pbp2b (gPRSP strains). 3.3. Changes in carbapenem susceptibility during 1993 and 2006 Table 3 compares the MIC50 and MIC90 values of the carbapenems in the present study with those obtained in our previous studies [4,5]. There was almost no change in the MIC50 and MIC90 of the carbapenems between 1993 and 2006 against all of the tested species.

4. Discussion This study reviewed the current susceptibility to parenteral antibiotics (focusing primarily on the carbapenems) of the main respiratory bacterial pathogens at a large core hospital in Sendai city, Japan. Carbapenems had excellent antibacterial activity against S. pneumoniae, including PRSP, MSSA and M. catarrhalis, since growth of all of the tested strains was inhibited at concentrations below the RTI breakpoints [10]. On the other hand, since the majority of MRSA isolates were beyond the RTI breakpoints [10], carbapenem antibacterial activity against MRSA was inadequate. Vancomycin, teicoplanin and arbekacin were found to be useful candidates for MRSA infection. In Japan, despite the large proportion of MRSA as causative organism of hospital-acquired pneumonia, the ratio of first-line use of glycopeptides is low [11]. Considering that both the clinical effect and prognosis are poor in cases of MRSA pneumonia [11], first-line treatment in combination with anti-MRSA agents such as glycopeptides appears to be necessary for cases with a risk of MRSA. Care should be exercised when administering glycopeptides if the patient has renal insufficiency. Therapeutic drug monitoring should be performed as much as possible, and the occurrence of toxicity should be minimised, while keeping the blood level of the drug within the therapeutic range. For H. influenzae, the frequency of the resistant strains, gLow-BLNAR and gBLNAR, was 62.1 and 20.7%, respectively. In Japan, Ubukata et al. reported that the prevalence of gBLNAR and gLow-BLNAR was 28.8 and 23.6%, respectively [1]. In contrast, as the percentage of BLNAR strains is <10% in Europe [12] and the United States [13], there may be discrepancies in the frequency of BLNAR strains between Japan and other countries. In this study, as the percentage of gLow-BLNAR strains tended to increase further compared with that in previous studies [1], the prevalence of non-susceptible strains was considered to be remarkable in recent years. Irrespective of the high frequency of resistance, meropenem inhibited the strains at concentrations at or below the RTI breakpoints [10]. As for the other carbapenems, MICs above the RTI breakpoint [10] were observed mainly against the gLow-BLNAR and gBLNAR strains. Therefore, it is sug-

591

gested that the antibacterial activity of the other carbapenems against H. influenzae may have further declined due to a recent increase in the number of BLNAR strains. Differences in the binding affinity of carbapenems to H. influenzae PBP3A and PBP3B are considered to play a role in the differences in their antibacterial activity against H. influenzae [14]. Meropenem also showed the lowest MIC50 , MIC90 and resistance of all four carbapenems against P. aeruginosa. Unlike the other carbapenems, meropenem is not readily affected by a decreased level or deficiency of OprD [15]. It is therefore likely that most of the strains that were susceptible to meropenem, but resistant to other carbapenems, had a decreased level or deficiency of OprD. However, the carbepenem MIC90 values are above the RTI breakpoints [10]. In Japan, the usual adult dosage (meropenem 0.25–0.5 g twice daily), which is less than the approved maximum dosage (2 g/day), is used in most cases of hospital-acquired pneumonia, whose main causative organism is P. aeruginosa [11]. As for ␤-lactams, the most important pharmacokinetic/pharmacodynamic parameter that correlates with therapeutic efficacy is the time that serum concentration is above the MIC. Considering the MIC data obtained in this study, higher doses with higher frequency (such as 0.5–1 g three times daily) are considered to be preferable for cases with a risk of P. aeruginosa. In this study, one metallo-␤-lactamase-producing strain, classified as multi-drug-resistant (imipenem, amikacin and ciprofloxacin), was detected. In recent years, hospital outbreaks of carbapenem-resistant P. aeruginosa, such as the metallo-␤-lactamase-producing strain, have occasionally been reported. Therefore, this situation should be monitored to determine if a trend is developing. Compared to results obtained in our previous studies [4,5], our current data show that there has been no marked progression in resistance for any of the bacterial species that were tested. Therefore, the carbapenems continue to be useful for treating severe infections. In particular, meropenem is advantageous because it has excellent antibacterial activity, even against H. influenzae, including the BLNAR strains.

Acknowledgments This study was supported partially by a grant from Dainippon Sumitomo Pharma.

References [1] Ubukata K. Problems associated with high prevalence of multidrugresistant bacteria in patients with community-acquired infections. J Infect Chemother 2003;9:285–91. [2] The Committee for the Japanese Respiratory Society guidelines in the management of respiratory infections. The Japanese Respiratory Society guidelines for the management of hospital-acquired pneumonia in adults. Respirology 2004;9(Suppl.):S1–62.

592

K. Gomi et al. / International Journal of Antimicrobial Agents 29 (2007) 586–592

[3] The Committee for the Japanese Respiratory Society guidelines in the management of respiratory infections. The Japanese Respiratory Society guidelines for the management of hospital-acquired pneumonia in adults. Respirology 2006;11(Suppl. 3):S1–133. [4] Watanabe A, Kikuchi H, Kikuchi T, et al. Comparative in vitro activity of carbapenem antibiotics against respiratory pathogens isolated in recent years. J Infect Chemother 1999;5:171–5. [5] Watanabe A, Kikuchi H, Kikuchi T, et al. Comparative in vitro activity of carbapenem antibiotics against respiratory pathogens isolated between 1999 and 2000. J Infect Chemother 2001;7:267– 71. [6] O’Callaghan CH, Morris A, Kirby SM, et al. Novel method for detection of ␤-lactamases by using a chromogenic cephalosporin substrate. Antimicrob Agents Chemother 1972;1:283–8. [7] Arakawa Y, Shibata N, Shibayama K, et al. Convenient test for screening metallo-␤-lactamase-producing gram-negative bacteria by using thiol compounds. J Clin Microbiol 2000;38:40–3. [8] Hasegawa K, Yamamoto K, Chiba N, et al. Diversity of ampicillinresistance genes in Haemophilus influenzae in Japan and the United States. Microb Drug Resist 2003;9:39–46. [9] Ubukata K, Chiba N, Hasegawa K, Kobayashi R, Iwata S, Sunakawa K. Antibiotic susceptibility in relation to penicillin-binding protein genes and serotype distribution of Streptococcus pneumoniae strains

[10]

[11]

[12]

[13]

[14]

[15]

responsible for meningitis in Japan, 1999 to 2002. Antimicrob Agents Chemother 2004;48:1488–94. Saito A, Inamatsu T, Okada J, et al. Clinical breakpoints in pulmonary infections and sepsis: new antimicrobial agents and supplemental information for some agents already released. J Infect Chemother 1999;5:223–6. Kohno S, Watanabe A, Matsushima T, et al. Multicenter survey on pathophysiology of hospital-acquired pneumonia and clinical efficacy of first-line antibiotics. In: American Thoracic Society 2005 International Conference. 2005. p. 622. Jansen WTM, Verel A, Beitsma M, et al. Longitudinal European surveillance study of antibiotic resistance of Haemophilus influenzae. J Antimicrob Chemother 2006;58:873–7. Heilmann KP, Rice CL, Miller AL, et al. Decreasing prevalence of ßlactamase production among respiratory tract isolates of Haemophilus influenzae in the United States. Antimicrob Agents Chemother 2005;49:2561–4. Kanazawa K, Nouda K, Sunagawa M. Structure-activity relationships of carbapenem compounds to anti-Haemophilus influenzae activity and affinity for penicillin-binding proteins: effect of 1-methyl group and C-2 side chain. J Antibiotics 1997;50:162–8. Sumita Y, Fukasawa M. Meropenem resistance in Pseudomonas aeruginosa. Chemotherapy 1996;42:47–56.