Introduction
Meropenem is a new antimicrobial agent belonging to the carbapenem group. Imipenem and panipenem were the first representatives of this group of antibiotics available for clinical use. Both imipenem and meropenem are now marketed in The Netherlands and were introduced in July 1986 and August 1995, respectively. Other carbapenem antibiotics, such as biapanem,1are currently under
inves-tigation but not yet available for clinical use.
Imipenem and panipenem are readily hydrolysed
in vivo by human renal dehydropeptidase-I (DHP-I)
and therefore have to be co-administered with
de-hydropeptidase inhibitors like cilastatin2 or -mipron.3
Meropenem, however, is stable to DHP-I and therefore does not have to be co-administered with dehydropepti-dase inhibitors.
Earlier studies have shown that meropenem is stable to many -lactamases.4–6 Small-scale in-vitro studies
per-formed in The Netherlands in the mid-1980s demon-strated excellent activity of meropenem against several microorganisms.7,8The main objective of this study was to
compare the in-vitro activity of meropenem, before its release on the Dutch market, with 15 commonly used antimicrobial agents against selected, relevant clinical isolates from hospitalized patients in The Netherlands.
149
Comparative in-vitro activity of meropenem against selected
pathogens from hospitalized patients in
The Netherlands
H. P. Endtz
a*, W. C. van Dijk
b, H. A. Verbrugh
aand the MASTIN Study Group
†aDepartment of Clinical Microbiology, Erasmus University and University Hospital, Rotterdam; bDepartment of Medical Microbiology, Slotervaart Hospital, Amsterdam, The Netherlands
Thirty laboratories evaluated the in-vitro activity of meropenem and 15 commonly used antibiotics against selected microorganisms isolated in 1994–95 from hospitalized patients with serious infections requiring antibacterial treatment. Isolates (2169) from blood, sputum, pus or CSF were included. MICs were determined with Etest and NCCLS breakpoints were used. In general, the MICs of meropenem for Gram-positive isolates were found to be one- to six-fold higher than those of imipenem, except for Enterococcus faecalis. The MIC90 of
meropenem for E. faecalis was high (32 mg/L) and distinctly higher than the MIC90 of
imipenem (2 mg/L). The MICs of meropenem for Gram-negative isolates were two- to 24-fold lower, with the exception of Acinetobacter spp. Gram-negative fermentative strains,
Entero-bacter spp. in particular, isolated from patients in intensive care units (ICU) were more
resis-tant to the -lactam antibiotics than those isolated from patients in non-intensive care wards. However, all Enterobacteriaceae, with and without inducible -lactamases, isolated from ICU patients were susceptible to meropenem.
*Corresponding address. Department of Clinical Microbiology, University Hospital, Rotterdam, Dr Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. Fax: 31-10-4633875; E-mail: endtz bacl.azr.nl
†Meropenem and other Antibiotics Susceptibility Testing in the Netherlands (MASTIN) Study Group: L. J. Bakker (Den Bosch), A. T. Bernards (Leiden), R. W. Brimicombe (Den Haag), A. G. M. Buiting (Tilburg), J. Dankert (Amsterdam), Y. Debets-Ossenkopp (Amsterdam), J. E. Degener (Leeuwarden), R. J. A. Diepersloot (Utrecht), B. J. van Dijke (Roermond), G. T. J. Fabius
(Sittard), J. A. A. Hoogkamp-Korstanje (Nijmegan), B. T. Lim (Dordrecht), W. L. Manson (Groningen), M. K. E. Nohlmans (Arnhem), B. P. Overbeek (Nieuwegein), G. J. H. M. Ruijs (Zwolle), L. J. M. Sabbe (Goes), H. Schreuder (Amersfoort),
F. W. Sebens (Deventer), W. P. J. Severin (Enschede), E. Stobberingh (Maastricht), E. A. P. M. Thewessen (Gouda), C. P. Timmerman (Hilversum), E. P. F. Yzerman (Haarlem), J. H. T. Wagenvoort (Heerlen), M. J. H. M. Wolfhagen (Zwolle),
M. R. Visser (Utrecht), R. W. Vreede (Delft) and J. A. van Zeijl (Roermond).
Materials and methods
Thirty microbiology laboratories throughout The Nether-lands collaborated in this survey, which included 2169 strains. Only isolates from blood (n 516), sputum, including broncho-alveolar lavage (n 839), pus, includ-ing intra-abdominal, pleural, skin and soft tissue and bone aspirates (n 789), and cerebrospinal fluid (n 25) were included in the study. All strains were isolated from the focus of infection of hospitalized patients with serious in-fections requiring antimicrobial treatment. Only one iso-late per species per patient was included, with a maximum of eight isolates per species per centre.
All isolates were collected between October 1994 and April 1995 and belonged to the following species:
Escherichia coli (n 174), Proteus mirabilis (n 134),
Proteus vulgaris (n 24), Morganella morganii (n 124),
Klebsiella oxytoca (n 72), Klebsiella pneumoniae (n 106), Enterobacter cloacae (n 142), Enterobacter
aero-genes (n 26), Citrobacter freundii (n 90), Citrobacter
diversus (n 34), Serratia marcescens (n 120), Serratia
liquefaciens (n 18), Pseudomonas aeruginosa (n 171),
Acinetobacter spp. (n 87), Haemophilus influenzae (n 173), methicillin-susceptible Staphylococcus aureus (n 179), coagulase-negative staphylococci (CNS) (n 166),
Enterococcus faecalis (n 153), Enterococcus faecium (n 10) and Streptococcus pneumoniae (n 166).
The following antimicrobial agents were tested for Gram-negative organisms: meropenem, imipenem, ticar-cillin/clavulanic acid, piperacillin/tazobactam, co-amoxi-clav, ciprofloxacin, gentamicin, cefuroxime, cefotaxime and ceftazidime; the following were tested for Gram-positive organisms: meropenem, imipenem, piperacillin/ tazobactam, ciprofloxacin, gentamicin, erythromycin, clin-damycin, vancomycin, penicillin, oxacillin (for staphylo-cocci) and amoxycillin (for streptostaphylo-cocci).
All media were purchased from one manufacturer (Oxoid Ltd, Basingstoke, UK) and distributed to the par-ticipating centres. PDM agar was chosen as standard test medium. Five per cent sheep blood was added for testing
S. pneumoniae; 1% haemoglobin and Isovitalex (Oxoid
Ltd) were added for testing H. influenzae; Mueller–Hin-ton agar supplemented with 2% NaCl was used for testing of all staphylococci for oxacillin, penicillin, meropenem, imipenem and piperacillin/tazobactam.9The antimicrobial
activity was measured with the Etest (AB Biodisk, Solna, Sweden). Extended-spectrum -lactamase (ESBL) pro-duction in E. coli and K. pneumoniae was tested at the coordinating laboratory with the Etest. ESBL production was suggested when reversal of resistance to ceftazidime by clavulanic acid was found. The standard inoculum was 0.5 McFarland except for oxacillin, penicillin, meropenem, imipenem and piperacillin/tazobactam test-ing of staphylococci. For these susceptibility tests an inoculum of 1 McFarland was prepared.9 Plates were
incubated at 35–37°C for 18–24 h. The National
Commit-tee for Clinical Laboratory Standards breakpoints for susceptibility and resistance were used.10The meropenem
breakpoints for all species were: 4 mg/L, susceptible; 16 mg/L, resistant, except for H. influenzae and S.
pneu-moniae. For H. influenzae the breakpoints used were: 4,
susceptible; 8 resistant; and for S. pneumoniae: 0.12, susceptible; 1, resistant. These are the same as the val-ues recommended for imipenem by the NCCLS. Etest strips are marked in 0.5 log2concentrations. The NCCLS
reference methods and breakpoints are based on two-fold dilutions. Therefore, for the calculation of percentage of susceptible and resistant strains (Tables I–III) using the NCCLS breakpoints, the Etest MIC was rounded to the nearest higher log2dilution.
The MICs were determined for the following reference strains by all participating laboratories: E. coli ATCC 25922, P. aeruginosa ATCC 27853, S. aureus ATCC 29213 on all testing days. The MICs received from the partici-pating centres were included in the study database only when the MICs of the reference strains were in agreement with accepted quality control ranges of MICs. For valida-tion of MICs for H. influenzae and S. pneumoniae, two strains per species per centre were randomly selected and retested at the Rotterdam co-ordinating laboratory using
H. influenzae ATCC 49247 and S. pneumoniae ATCC
40619 as control strains. The MICs for all H. influenzae and S. pneumoniae from a participating laboratory were included in the database when the MICs for the strains retested at the co-ordinating laboratory were within two log2dilution steps of the MICs performed at the
particip-ating laboratory, and the MICs for reference strains fell within the accepted quality control ranges of MICs.
The chi-square test with the Yates’ correction was used to analyse differences in the frequency of resistances (Table III).
Results
The activity of meropenem and 15 other antimicrobial agents against 1437 Gram-negative microorganisms (Table I) and 674 Gram-positive (Table II) were com-pared. The MICs obtained for P. vulgaris (n 24) were almost identical to those obtained for M. morganii. C.
diversus (n 34) was more susceptible to co-amoxiclav than C. freundii: 76% versus 21%, respectively. E.
fae-cium (n 10) was in general more resistant to several antimicrobial agents when compared with E. faecalis: imipenem MIC90, 32 versus 2 mg/L; piperacillin/
tazobac-tam MIC90, 256 versus 12 mg/L; amoxicillin MIC90, 8
ver-sus 1.5 mg/L, but not for meropenem: meropenem MIC90,
32 versus 32 mg/L.
A group of Enterobacteriaceae that share chromo-somal Class I -lactamases was pooled in a subgroup called ‘potentially inducible’ Enterobacteriaceae (E.
Table I. MICs (mg/L) against 1437 Gram-negative microorganisms
Sensitive Resistant
Organism (n) Antibiotic Range MIC50 MIC90 (%) (%)
E. coli meropenem 0.002–0.125 0.032 0.047 100 0 (174) imipenem 0.064–4 0.19 0.25 100 0 ticarcillin/clavulanic acid 0.5–256 3 96 76 9 piperacillin/tazobactam 0.19–256 3 16 92 4 co-amoxiclav 1–256 4 16 77 8 cefuroxime 0.5–256 4 12 90 5 cefotaxime 0.016–256 0.064 0.19 99 1 ceftazidime 0.094–256 0.25 0.5 99 1 ciprofloxacin 0.002–64 0.016 0.047 98 2 gentamicin 0.19–512 0.5 1 99 1 Klebsiella spp. meropenem 0.016–0.125 0.047 0.064 100 0 (178) imipenem 0.064–1 0.19 0.38 100 0 ticarcillin/clavulanic acid 0.75–512 3 32 89 8 piperacillin/tazobactam 0.38–512 3 24 90 8 co-amoxiclav 0.5–48 2 12 89 4 cefuroxime 0.5–512 2 12 90 8 cefotaxime 0.008–256 0.032 0.19 98 1 ceftazidime 0.047–256 0.19 0.75 98 2 ciprofloxacin 0.008–32 0.032 0.094 98 2 gentamicin 0.125–256 0.5 1.5 97 3 C. freundii meropenem 0.008–0.25 0.032 0.094 100 0 (90) imipenem 0.064–6 0.25 0.75 99 0 ticarcillin/clavulanic acid 0.19–512 2 256 77 19 piperacillin/tazobactam 0.19–512 3 256 81 17 co-amoxiclav 0.19–512 48 256 21 72 cefuroxime 0.38–512 4 256 73 22 cefotaxime 0.016–256 0.125 48 82 11 ceftazidime 0.064–512 0.5 256 81 18 ciprofloxacin 0.006–32 0.023 0.25 93 4 gentamicin 0.094–512 0.5 8 87 10 P. mirabilis meropenem 0.032–2 0.094 0.19 100 0 (134) imipenem 0.094–32 0.38 3 98 1 ticarcillin/clavulanic acid 0.19–256 0.75 1.5 98 1 piperacillin/tazobactam 0.125–256 0.5 1 99 1 co-amoxiclav 0.25–512 1 6 95 2 cefuroxime 0.38–512 1 2 95 4 cefotaxime 0.016–256 0.016 0.032 99 1 ceftazidime 0.016–8 0.094 0.19 100 0 ciprofloxacin 0.012–8 0.032 0.064 99 1 gentamicin 0.125–256 0.75 1.5 99 1 M. morganii meropenem 0.032–0.38 0.125 0.25 100 0 (124) imipenem 0.38–32 2 6 89 3 ticarcillin/clavulanic acid 0.125–256 1 8 95 3 piperacillin/tazobactam 0.016–256 0.38 0.75 98 2 co-amoxiclav 0.38–512 0.38 0.75 3 97 cefuroxime 1–512 48 256 10 76 cefotaxime 0.008–24 0.023 0.38 99 0 ceftazidime 0.016–256 0.094 0.75 94 3 ciprofloxacin 0.004–6 0.016 0.032 98 1 gentamicin 0.016–128 0.5 1 97 1
Table I. Continued
Sensitive Resistant
Organism (n) Antibiotic Range MIC50 MIC90 (%) (%)
Enterobacter meropenem 0.012–2 0.064 0.125 100 0 spp. imipenem 0.094–6 0.38 1 99 0 (168) ticarcillin/clavulanic acid 0.75–512 3 256 71 27 piperacillin/tazobactam 0.38–512 4 256 76 18 co-amoxiclav 0.75–512 128 256 8 90 cefuroxime 0.75–512 12 256 46 40 cefotaxime 0.016–512 0.25 256 79 17 ceftazidime 0.064–512 0.5 256 78 18 ciprofloxacin 0.006–32 0.023 0.094 97 3 gentamicin 0.064–96 0.5 1 98 2 Serratia spp. meropenem 0.031–0.125 0.064 0.094 100 0 (138) imipenem 0.19–1 0.38 0.5 100 0 ticarcillin/clavulanic acid 1–256 4 12 96 1 piperacillin/tazobactam 0.5–48 3 6 99 0 co-amoxiclav 2–512 96 256 26 70 cefuroxime 0.064–512 128 256 3 93 cefotaxime 0.031–6 0.25 0.75 100 0 ceftazidime 0.047–6 0.38 0.75 100 0 ciprofloxacin 0.008–2 0.094 0.25 96 0 gentamicin 0.125–64 0.75 1 99 1 Acinetobacter meropenem 0.016–32 0.38 2 98 1 spp. imipenem 0.001–64 0.19 0.38 94 5 (87) ticarcillin/clavulanic acid 0.008–512 6 48 72 5 piperacillin/tazobactam 0.008–256 12 128 62 16 co-amoxiclav 0.031–512 8 48 65 26 cefuroxime 0.031–512 32 256 28 63 cefotaxime 0.023–256 8 24 66 3 ceftazidime 0.064–256 4 12 77 1 ciprofloxacin 0.001–64 0.19 32 82 14 gentamicin 0.016–512 0.38 48 82 14 P. aeruginosa meropenem 0.023–32 0.38 2 95 2 (171) imipenem 0.094–32 1 3 93 5 ticarcillin/clavulanic acid 0.25–512 16 256 76 24 piperacillin/tazobactam 0.25–512 6 256 85 15 co-amoxiclav 4–512 256 512 2 97 cefuroxime 6–512 256 512 2 97 cefotaxime 0.25–256 12 256 40 21 ceftazidime 0.38–256 2 16 88 9 ciprofloxacin 0.006–32 0.19 2 84 10 gentamicin 0.047–512 2 6 88 7 H. influenzae meropenem 0.008–3 0.094 0.19 100 0 (173) imipenem 0.094–32 0.5 1.5 99 1 ticarcillin/clavulanic acid 0.023–2 0.125 0.25 100 0 piperacillin/tazobactam 0.008–256 0.016 0.047 99 1 co-amoxiclav 0.125–3 0.5 0.75 100 0 cefuroxime 0.016–12 0.75 1 99 1 cefotaxime 0.008–1 0.016 0.016 100 0 ceftazidime 0.016–6 0.125 0.25 99 1 ciprofloxacin 0.003–6 0.016 0.032 99 1 gentamicin 0.19–8 3 4 90 0
cloacae, E. aerogenes, P. vulgaris, M. morganii, S. marcescens and C. freundii). The resistance percentages
of 526 inducible Enterobacteriaceae and 486 non-inducible Enterobacteriaceae (E. coli, K. oxytoca, K.
pneu-m o n i a e and P. pneu-mirabilis) fropneu-m ICU and non-ICU patients
are shown in Table III.
Discussion
This study differs from several others in that stringent selection criteria for inclusion of strains were used. The collection of isolates represents well-defined clinically relevant isolates, since neither contaminant nor colonizing Table II. MICs (mg/L) against 674 Gram-positive microorganisms
Sensitive Resistant
Organism (n) Antibiotic Range MIC50 MIC90 (%) (%)
S. aureus meropenem 0.031–0.38 0.125 0.19 100 0 (179) imipenem 0.008–0.064 0.023 0.032 100 0 piperacillin/tazobactam 0.38–12 2 4 99 1 penicillin 0.002–32 0.75 6 25 75 oxacillin 0.047–2 0.25 0.75 100 0 vancomycin 0.064–4 1 1.5 100 0 erythromycin 0.047–512 0.19 0.38 94 3 clindamycin 0.023–512 0.064 0.125 99 1 ciprofloxacin 0.125–32 0.38 0.75 97 2 gentamicin 0.023–1 0.25 0.5 100 0 Coagulase- meropenem 0.016–64 0.5 32 66 30 negative imipenem 0.006–64 0.064 32 75 22 staphylococci piperacillin/tazobactam 0.064–256 1.5 256 77 23 (166) penicillin 0.012–64 0.75 32 23 77 oxacillin 0.016–512 1 256 58 42 vancomycin 0.064–3 2 2 100 0 erythromycin 0.016–512 0.25 256 57 42 clindamycin 0.016–512 0.094 256 74 25 ciprofloxacin 0.023–64 0.25 32 69 28 gentamicin 0.016–256 0.094 96 59 33 S. pneumoniae meropenem 0.002–0.125 0.008 0.016 100 0 (166) imipenem 0.001–0.25 0.003 0.012 99 0 piperacillin/tazobactam 0.008–1 0.016 0.023 100 0 penicillin 0.002–0.5 0.016 0.032 98 0 amoxicillin 0.008–6 0.016 0.016 97 1 vancomycin 0.094–8 0.75 1 95 5 erythromycin 0.016–256 0.064 0.19 95 3 clindamycin 0.016–256 0.094 0.125 98 1 ciprofloxacin 0.064–24 1.5 3 43 19 gentamicin 2–96 16 48 4 80 E. faecalis meropenem 1–64 8 32 36 38 (153) imipenem 0.125–64 0.75 2 97 2 piperacillin/tazobactam 0.38–256 4 12 96 2 penicillin 0.38–64 3 12 89 11 amoxicillin 0.125–4 0.5 1.5 100 0 vancomycin 0.38–6 2 3 99 0 erythromycin 0.047–512 2 256 11 37 clindamycin 0.064–512 24 256 2 93 ciprofloxacin 0.125–64 1.5 32 33 29 gentamicin 1–512 8 256 22 40
or double isolates from the same patient were included in the study.
In general, in comparison with imipenem, meropenem was one- to six-fold less active against Gram-positive organisms with the exception of E. faecalis. In contrast, against Gram-negative organisms meropenem was found to be two- to 24-fold more active with the exception of
Acinetobacter spp. This is roughly in agreement with
the compiled data presented by Edwards11, except for E. faecalis and Acinetobacter spp. Surprisingly, the
meropenem MIC90 for E. faecalis was 32 mg/L and
four-fold higher than that in other studies.11,12 Therefore, the
MIC as well as the identification of all enterococci was retested at the co-ordinating laboratory using Etest and standard identification criteria.13 The high MIC
90 for E. faecalis was confirmed. Further studies into the
mecha-nism of meropenem resistance in enterococci is currently in progress. The high MICs of meropenem and imipenem (MIC90 32 mg/L) for E. faecium are in agreement with
previous studies.11,12
No difference in susceptibility was observed between strains isolated from blood and CSF compared with those isolated from sputum and pus.
The prevalence of MRSA is very low in The Nether-lands. Therefore, no methicillin-resistant S. aureus isolates were included but 25% of the S. aureus strains were susceptible to penicillin. In a recent Dutch survey including 57144 S. aureus isolates, 22% were penicillin susceptible.14 Meropenem showed good activity against
methicillin-susceptible S. aureus (MIC90 0.19 mg/L),
although it was less active than imipenem (MIC90 0.032
mg/L). The percentage meropenem-susceptible CNS was low (66%) and parallelled the low percentage of oxacillin-susceptible CNS (58%).
Three S. pneumoniae strains were relatively resistant (MIC 0.1–1 mg/L) to penicillin. No high-level penicillin-resistance (MIC 2 mg/L) was found. The low preva-lence of penicillin-resistance in S. pneumoniae is in agreement with the results of a recent survey in seven Dutch public health laboratories.14 Meropenem was
highly active against S. pneumoniae (meropenem MIC90
0.016 mg/L). One S. pneumoniae strain had a high vancomycin MIC of 8 mg/L. Unfortunately, this strain was lost and the MIC could not be confirmed. Seven other
S. pneumoniae strains had MICs of vancomycin of
1.5 mg/L. The MIC90 was 1 mg/L, precisely the NCCLS
vancomycin breakpoint for S. pneumoniae. Therefore, a selection of S. pneumoniae were retested at the co-ordinating laboratory with Etest and the reference NCCLS method (microdilution in Mueller–Hinton with 5% lysed horse blood). The MICs of vancomycin obtained with Etest were reproducible. However, the MICs of vancomycin obtained with the microdilution method were in general two two-fold dilution steps lower (data not shown). Hashemi et al.15have recently described
similar discrepancies between results of Etest and
refer-ence methods. This is of great importance in view of the NCCLS breakpoint for susceptibility for S. pneumoniae of 1 mg/L, although most European commissions or working parties, including the Dutch, have proposed a breakpoint of 4 mg/L. Further studies to clarify this problem are currently in progress.
Two H. influenzae strains were noted resistant to imipenem, while susceptible to meropenem. Another strain was reported as resistant to piperacillin/ tazobactam and ceftazidime. Unfortunately, these strains were no longer viable for retesting with a reference method.
The percentage of inducible Enterobacteriaceae resistant to co-amoxiclav and cefuroxime was very high, reflecting the presence of chromosomal Class I -lactamases (Table III). The percentage of E. coli that were not susceptible (thus resistant or intermediate) to co-amoxiclav was high (23%).
We screened for ESBL-producing E. coli or K.
pneu-moniae isolated from ICU patients using ceftazidime
resistance as the selection criterion.16,17 Three (1.7%)
ESBL-producing K. pneumoniae strains obtained from three different hospitals were found. No ESBL-producing
E. coli was found. The true prevalence is probably
under-estimated because of difficulties in their detection.17,18
Inducible and non-inducible Enterobacteriaceae from ICU patients were more resistant to multiple antimicro-bial agents than Enterobacteriaceae from non-ICU patients. This is particularly true for the inducible Entero-bacteriaceae (Table III). However, all inducible and non-inducible Enterobacteriaceae isolated from ICU patients were susceptible to meropenem.
Nine per cent of the P. aeruginosa isolated in ICU patients were resistant or moderately susceptible to meropenem, in comparison with 11%, 14%, 14%, 21%, 25% and 34% for imipenem, ciprofloxacin, gentamicin, ceftazidime, piperacillin/tazobactam and ticarcillin/clavu-lanic acid, respectively.
The combination piperacillin/tazobactam was generally slightly more active than the combination ticarcillin/clavu-lanic acid except for Acinetobacter spp. With the latter exception, this is in agreement with a recent Dutch study.19 Resistance percentages to gentamicin and
ciprofloxacin were relatively low.
In conclusion, meropenem and imipenem had a wide spectrum of antimicrobial activity and were the most potent drugs evaluated in this study. It appears that meropenem is more active than imipenem against most Gram-negative bacteria. Both drugs showed good activity against the Gram-positive organisms tested with the exception of methicillin-resistant CNS and, in the case of meropenem in particular, enterococci. Plasmid-mediated carbapenemases have recently been described in clinical isolates of S. marcescens in Japan.20 Therefore,
post-marketing surveillance of resistance to the carbapenem antibiotics is indicated to monitor any change in suscepti-bility in the future.
Acknowledgements
We are very indebted to Bert van Klingeren for helpful comments, Leonard Guldemond, Herman Thijs and Ton Smeets for their logistical help and Zeneca Pharma for financial support. We thank Marian Humphrey for read-ing the English version. Part of this study was presented at the 35th ICAAC (1995) in San Francisco, USA.
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Table III. Resistance percentages of inducible and non-inducible Enterobacteriaceae isolated from intensive-care patients compared with non-intensive-care patients
Inducible Non-inducible
ICU non-ICU ICU non-ICU
Antibiotic (n 169) (n 356) (n 105) (n 381) Meropenem 0 0 0 0 Imipenem 1 1 0 1 Ticarcillin/clavulanic acid 20a 9 9 6 Piperacillin/tazobactam 17a 6 6 4 Co-amoxiclav 82 81 6 5 Cefuroxime 67a 56 10b 4 Cefotaxime 13a 5 2 1 Ceftazidime 17a 6 2 1 Ciprofloxacin 4a 1 1 2 Gentamicin 7a 1 2 2
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Received 22 February 1996; returned 4 April 1996; revised 4 July 1996; accepted 21 August 1996
