Antibiotic susceptibility and mechanisms of beta-lactam resistance in 1310 strains of pseudomonas aeruginosa: a French multicentre study (1996).

A total of 1310 consecutive strains of Pseudomonas aeruginosa were collected in 11 French hospitals in 1996. The percentages of susceptible isolates measured by the agar dilution method were: ticarcillin (53%), piperacillin (69%) (MIC 16 mg/L), ceftazidime (77%), cefepime (55%), cefpirome (40%), aztreonam (57.5%), imipenem (81.5%) (MIC 4 mg/L), amikacin (64.5%) (MIC 8 mg/L) and ciprofloxacin (58%) (MIC 1 mg/L). Resistance to beta-lactams was linked to the production of transferable beta-lactamases (30%), overproduction of cephalosporinase (29%) and to non-enzymic mechanisms (38%).

[In vitro antibacterial activity of a new fluoroquinolone, sparfloxacin, against nosocomial bacteria, and concordance curve]. / Activité anti-bactérienne in vitro d'une nouvelle fluoroquinolone, la sparfloxacine sur les bactéries hospitalières et courbe de concordance.

Minimal inhibitory concentrations (MICs) of sparfloxacin (SFX) were determined by agar dilution for 3,164 bacterial strains isolated in 10 university hospitals; in addition, antibiograms by agar diffusion were performed with 5 micrograms disks. Activity of SFX against nalidixic acid (NAL) susceptible (S) Enterobacteriaceae was close to that of other fluoroquinolones (FQ) (MIC 50 and 90: 0.06-0.5 microgram/ml); like for other FQ, this activity was reduced against NAL intermediate and resistant (R) Enterobacteriaceae (2-16). MICs of SFX against P. aeruginosa were between 0.12 and 16 (1-32). SFX had also a good activity against NAL-S A. baumannii (CMI < or = 0.25) but this activity is reduced against NAL-R Acinetobacter (16). SFX was highly active against Haemophilus (0.016-0.06) gonococci (0.008), meningococci (0.008) and B. catarrhalis (0.008-0.03). SFX showed activity superior to the currently available FQ against methicillin susceptible staphylococci (0.06); the resistant strains [8] are usually methicillin resistant. SFX is more effective against enterococci (0.5), streptococci (0.25-0.5) and particularly pneumococci (0.25-0.5) including penicillin-resistant strains. The coefficient correlation of the regression curve is 0.876; for MIC breakpoints of 1 and 2 micrograms/ml, zone diameter breakpoints should be 20 and 16 mm.

In-vitro development of resistance to beta-lactam antibiotics in Streptococcus pneumoniae.

Selection of resistant mutants was induced in broth by exposing pneumococci to serial sub-inhibitory concentrations of various beta-lactam antibiotics. Aminopenicillins selected for resistance to themselves and to cephalosporins although cephalosporins tended to select for resistance to their own class, with the exception of cefixime which seems to select cross-resistant organisms.

In vitro development of resistance of Streptococcus pneumoniae to beta-lactam antibiotics.

In recent years, increasing numbers of Streptococcus pneumoniae strains displaying relative resistance to penicillin have been reported. Epidemiological studies have shown a correlation between aminopenicillin administration and resistance. We investigated the development of resistance in six strains (four sensitive and two intermediate-resistant to penicillin) by serial daily passages in subinhibitory concentrations of amoxicillin (AMX), amoxicillin + clavulanic acid (AMC), imipenem (IMP), cefixime (CFM), cefatrizine (CTZ), cefadroxil (CDX), and cefuroxime (CXM). MICs were determined by the macrodilution method in brain-heart broth for each daily passage. The number of daily passages needed to increase the MIC by a factor of 8 was achieved with AMX, AMC, and CFM for most of the strains after a mean of 24, 20, and 11 passages, respectively, and for one-third of the strains, with CDX, IMP, and CTZ after 11, 11, and 21 passages, respectively. Decreased susceptibility to breakpoints for intermediate-resistant S. pneumoniae populations was noted for all strains with CFM, AMX, and AMC after a mean of 10, 18, and 21 serial passages, respectively, and for four of five strains with IMP and CTZ after 12 and 13 passages. CTZ-, CDX-, and CXM-passaged variants had increased MIC values only for cephalosporins, while AMX-, AMC-, IMP-, and CFM-passaged variants exhibited increased MICs to all antibiotics tested. These in vitro data appear to be in agreement with epidemiological studies and warrant further exploration with respect to possible clinical implications.

Possible prevention of in vitro selection of resistant Streptococcus pneumoniae by beta-lactamase inhibitors.

The development of resistance in vitro in five strains of Streptococcus pneumoniae (3 with full susceptibility and 2 with intermediate susceptibility to penicillin) was investigated by serial passages in the presence of subinhibitory concentrations of amoxicillin and ampicillin. At the end of passaging, MICs of antibiotics for all the strains increased by a factor of four or more, reaching at least intermediate levels. MICs of cephalosporins, ampicillin and amoxicillin increased for almost all variants obtained. Similar results were obtained with amoxicillin plus clavulanic acid at a ratio of 2:1 and at a constant concentration of 2 micrograms/ml, and with ampicillin plus sulbactam at a ratio 2:1. In contrast, no significant modification of MIC was seen with ampicillin plus sulbactam at a constant concentration of 4 micrograms/ml sulbactam. These results suggest interaction of sulbactam with penicillin binding proteins as described previously for other bacterial species, and merit further investigation.

[Current status of resistance of bacteria to pefloxacin in hospital units. Cross resistance with ofloxacin and ciprofloxacin. Results of a multicenter study]. / Etat actuel de la résistance des bactéries à la péfloxacine à l'hôpital. Résistance croisée avec l'ofloxacine et la ciprofloxacine. Résultats d'une étude multicentrique.

The antibacterial activities of pefloxacin (PEF), ofloxacin (OFL), ciprofloxacin (CIP) were measured by agar diffusion (5 micrograms strength disks) against 6370 non duplicate clinical isolates collected in November 1991 in 40 hospitals from various areas in France. The MICs of PEF, OFL and CIP were determined by agar dilution against intermediate or resistant strains to one of the three antibiotics (inhibition zone < 16 mm for PEF, OFL, < 19 mm for CIP). In the Enterobacteriaceae the overall incidence of resistance to PEF (MIC > 4 mg/l) was 8% with important variations between the different species: E. coli 2%, Salmonella 0%, E. cloacae 9%, K. pneumoniae 21%, P. mirabilis 13%, P. vulgaris 3%, M. morganii 5%, Providencia 61%, S. marcescens 55%. Among S. aureus, the incidence of resistance was 3% for the methicillin-susceptible strains and 86% for the methicillin-resistant strains. The same applied to coagulase negative Staphylococci: methicillin-susceptible 9%, methicillin-resistant 62%. The frequency of the resistant strains was high among P. aeruginosa: 40% and A. baumanii: 83%. A high degree of correlation was observed between the MICs of PEF, OFL and CIP for all the bacterial species: r = 0.8 - 0.9. No major discrepancies were noted between the clinical categorizations of the activities of the three antibiotics for the different species except for P. aeruginosa: 4% of the strains were resistant to pefloxacin and susceptible to ciprofloxacin.

Conditions for the emergence of resistance to cefpirome and ceftazidime in experimental endocarditis due to Pseudomonas aeruginosa.

The conditions for the emergence of resistance to cefpirome and ceftazidime were studied in rabbits with experimental aortic endocarditis due to Pseudomonas aeruginosa. The MIC of cefpirome was 16 mg/L and that of ceftazidime was 4 mg/L. Resistant mutants with MICs of > or = 64 mg/L were obtained in vitro to cefpirome after a single passage and to ceftazidime after five passages. A single dose of 50 mg/kg intramuscularly gave mean peak serum concentrations of 110.0 +/- 31.7 mg/L for cefpirome compared with 67.7 +/- 21.4 mg/L for ceftazidime and the half-lives were 1.2 +/- 0.1 h and 2.1 +/- 0.4 h, respectively. After treating infected rabbits for 4 days with various dosing regimens, resistant strains were only detected in those animals in which the time that the serum concentration exceeded the MIC was less than half of the dosing interval. There was no evidence of emergent resistance when the serum concentrations exceeded the MIC for a longer period nor when amikican was combined with the cephalosporins on the first day of therapy. Moreover, once differences in MICs and pharmacokinetics were taken into account, both antibiotics had a similar propensity to induce resistance.

Comparison of phenotypic methods and DNA hybridization for detection of methicillin-resistant Staphylococcus aureus.

One hundred thirty-eight Staphylococcus aureus isolates from patients with severe staphylococcal infections were collected in 15 French hospitals. Detection of the mec gene was performed by dot blot hybridization with a specific DNA probe. Dot blot results were used to characterize the isolates as methicillin susceptible (77 isolates) or resistant (61 isolates). The isolates were screened for methicillin resistance by an agar spread method on Mueller-Hinton plates containing oxacillin (2 and 10 micrograms/ml) and were incubated at 37 degrees C, with 10(8) CFU as the inoculum. MICs of oxacillin and methicillin were determined by the agar dilution method on Mueller-Hinton plates without NaCl, by using 10(5) CFU per spot, after 24 and 48h of incubation at 30 or 37 degrees C. Moderately elevated MICs were found for 20 isolates (14.5%). The mec gene was detected in six (30%) of the isolates expressing a low level of resistance to methicillin and/or oxacillin. As determined by comparison with probe hybridization results, the spread plate method with oxacillin at 2 micrograms/ml was more sensitive (sensitivity, 100%) and specific (specificity, 100%) than agar dilution with either methicillin or oxacillin in identifying methicillin resistance or susceptibility. Determinations of methicillin and oxacillin MICs by the agar dilution method had a specificity of 99 to 100% depending on the conditions of incubation, but the sensitivity was below 85% whatever the duration or temperature of incubation.

Interactions of ceftibuten with extended-spectrum beta-lactamases: a bacteriological and enzymatic analysis.

The authors analysed the antibacterial activity of ceftibuten, cefotaxime, ceftazidime and aztreonam against Klebsiella pneumoniae strains, including those which produced novel extended-spectrum beta-lactamases. These molecules were also tested for their susceptibility to cell-free extracts of the corresponding beta-lactamases. Both approaches showed that ceftibuten was not hydrolysed by the CTX-1/TEM-3, SHV-2 and SHV-3 beta-lactamases, while cefotaxime, ceftazidime and aztreonam were hydrolysed. Nevertheless all compounds were substrates for the SHV-4 and SHV-5 beta-lactamases, and the organisms which produced these beta-lactamases showed increased MICs.

In-vitro antibacterial activity of cefepime: a multicentre study.

The antimicrobial activity of cefepime, a new broad-spectrum parenteral cephalosporin, was evaluated in vitro against 1757 recent clinical Gram-positive and Gram-negative isolates. Cefepime was active at low concentrations (MIC50 values < or = 0.06 mg/L and MIC90 values < or = 0.12 mg/L) against non-cephalosporinase-producing Enterobacteriaceae (Escherichia coli, Proteus mirabilis, Salmonella spp. and Shigella spp.). For Klebsiella pneumoniae, MICs were between 0.016 and 16 mg/L; the highest MIC values were observed for extended-spectrum beta-lactamase-producing strains. Against Enterobacteriaceae, such as cephalosporinase producing Enterobacter cloacae, MICs were < or = 0.5 mg/L, but MICs against cephalosporinase hyperproducing strains were generally higher. Ticarcillin-sensitive strains of Pseudomonas aeruginosa were inhibited by cefepime concentrations of 0.5-16 mg/L, while cefepime MICs were 8-64 mg/L for strains resistant to ticarcillin. The cefepime MIC50 value for Haemophilus spp. including many resistant to amoxycillin, was 0.03 mg/L. Against methicillin-sensitive strains of Staphylococcus aureus, cefepime MICs were 0.5-16 mg/L; MICs against methicillin-resistant staphylococci were 16- > 128 mg/L). Against methicillin-sensitive coagulase-negative staphylococci, cefepime MIC values were 0.03-16 mg/L; corresponding values for methicillin-resistant strains were 2-128 mg/L. Streptococci (Groups A, C and G) were sensitive to cefepime with MICs ranging from < or = 0.008-2 mg/L (MIC50, 0.03 mg/L; MIC90, 0.25 mg/L). The activity of cefepime against Group B streptococci and pneumococci were comparable, with MIC50 values of 0.12 and 0.25 mg/L, respectively, and MIC90 values of 0.03 and 0.25 mg/L, respectively. Most enterococci and all Listeria monocytogenes strains had MICs > or = 32 mg/L.(ABSTRACT TRUNCATED AT 250 WORDS)

A collaborative study of the in-vitro sensitivity to RP 59500 of bacteria isolated in seven hospitals in France.

The in-vitro activity of RP 59500 was determined against 1051 recent clinical bacterial isolates. The susceptibility to RP 59500 was determined with an agar dilution technique for all the isolates, while MICs and MBCs were determined for 82 selected strains in broth. Isolates of both Staphylococcus aureus and coagulase-negative staphylococci appeared to be potentially susceptible to RP 59500, independent of susceptibility to methicillin or MLS resistance. (S. aureus: methicillin-sensitive, MIC90, 1.0 mg/L; methicillin-resistant, MIC90 1.0 mg/L; coagulase-negative staphylococci: methicillin-sensitive, MIC90 0.5 mg/L). Lancefield group A, B, C and G streptococci (MIC50 0.5 and MIC90 1.0 mg/L) and Streptococcus pneumoniae (MIC50 0.5 and MIC90 1.0 mg/L) appeared to be susceptible to RP 59500. Some Streptococcus spp. and enterococci as well as Listeria monocytogenes were inhibited by a higher concentration of RP 59500 (enterococci: MIC90 4 mg/L, range 0.125-16 mg/L). Comparatively low MICs were seen when Legionella spp., Neisseria gonorrhoeae and Gardnerella vaginalis were tested. Broth dilution MIC/MBC determinations showed no evidence of tolerance, as MIC values were within two dilutions of MBC values. RP 59500 might be a useful compound in the treatment of infections caused by a range of Gram-negative and Gram-positive bacteria, including those resistant to methicillin and/or macrolides.

[In vitro activity of beta-lactam antibiotics in combination with sulbactam against enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter. Results of a multicenter study]. / Activité des bêtalactamines en association avec le sulbactam chez les entérobactéries Pseudomonas aeruginosa et Acinetobacter. Résultats d'une étude multicentrique.

The in vitro antimicrobial activity of ticarcillin (TICAR), mezlocillin (MEZLO), piperacillin (PIPER), cefoperazone (CPZ), cefotaxime (CTX) and ceftazidime (CAZ), alone and in combination with 8 micrograms/ml of sulbactam (SULB), was studied by agar dilution against TICAR resistant strains isolated in 8 hospitals over a period of 3 months in 1989 (747 enterobacteria, 110 Ps. aeruginosa and 48 Acinetobacter sp.). SULB did not modify the activity of beta-lactam antibiotics against Ps. aeruginosa. The 6 beta-lactam antibiotics SULB combinations were only active for 27% of Acinetobacter SULB sensitive. SULB restored the activity of: MEZLO, PIPER, CPZ in Enterobacteria producing a penicillinase; PIPER, CTX and CAZ in Enterobacteria producing a broad-spectrum beta-lactamase; MEZLO, PIPER, CTX and CAZ in M. morganii producing a derepressed cephalosporinase.

[Comparative activities of 15 beta-lactam antibiotics against 590 strains of Klebsiella pneumoniae according to the production of beta-lactamase]. / Activité comparée de 15 bêtalactamines sur 590 souches de Klebsiella pneumoniae en fonction de la production de bêtalactamase.

In October 1988, all non repetitive strains of K. pneumoniae isolated in 17 hospitals have been studied. Among these 590 strains: 451 (76%) only produce the specific beta-lactamase of the species SHV-1 (pI 7,7) or SHV-1 type (pI 7,1), while 74 (12.5%) produce a TEM-1 or TEM-2 type beta-lactamase, and 65 (11%) an extended broad spectrum beta-lactamase: 22 CTX-1, 5 SHV-2, 4 SHV-3, 26 SHV-4, 8 SHV-5. The minimum inhibitory concentrations of the following antibiotics were performed by a liquid micro dilution technic: amoxicillin (AMX), amoxicillin + clavulanic acid (CL), 5 mg/l, ticarcillin (TIC), piperacillin (PIP), cefazolin (CEZ), cefamandole (CFM), cefoperazone (CFP), cefotaxime (CTX), cefotaxime + clavulanic acid 5 mg/l, cefotaxime + sulbactam (SUL) 5 mg/l, cefpirome (CPI), ceftazidime (CAZ), azthreonam (AZT), latamoxef (MOX), cefoxitin (FOX), cefotetan (CTT), temocillin (TMO), imipenem (IMI). The "wild" strains with SHV-1 beta-lactamase are resistant to AMX and have a decreased susceptibility to TIC and PIP, but are susceptible to other antibiotics. The TEM producing strains are more resistant to PIP and TIC, have a decreased susceptibility to CEZ and CFM but are susceptible to other antibiotics. For the extended broad-spectrum beta-lactamase producing strains, the MIC of penicillin antibiotics (AMX, TIC, PIP) are very high and also the MIC of CEZ, CFM and CFP. The MIC of CTX are higher for CTX-1 or SHV-4 producing strains, than for SHV-2, SHV-3, or SHV-5 producing strains. The combination with CL is more efficacious than the one with SUL to reduce the MIC of CTX in susceptibility area.(ABSTRACT TRUNCATED AT 250 WORDS)

[In vitro activity of tazobactam and piperacillin combination against 224 strains of Pseudomonas aeruginosa according to the production of beta-lactamase]. / Activité in vitro de l'association pipéracilline-tazobactam sur 224 souches de Pseudomonas aeruginosa en fonction de la production de bêtalactamase.

Piperacillin (PIP) alone and combined with 4 mg/l, 8 mg/l of tazobactam (TAZ) were tested by MIC determination on Mueller-Hinton agar against 224 clinical strains of P. aeruginosa: "wild type" (BLA-), 32 producing a constitutive cephalosporinase (CEP), 41 producing the PSE-1 type beta-lactamase, 7 PSE-2, 8 PSE-3, 9 PSE-4, 13 TEM-1, 24 TEM-2, 13 OXA-1, 22 OXA-2, 5 OXA-3. The combination with 8 mg/l was more effective than that one with 4 mg/l. Combinations of PIP-TAZ 8 mg/l reduced the MICs of PIP for the resistant strains (MICs greater than 64 mg/l) to the susceptible ot the moderately susceptible range (MICs less than or equal to 64 mg/l) for 31% of the CEP producing strains, 63% of the PSE-1, 15% of the PSE-2, none of the PSE-3, 34% of the PSE-4, 39% of the TEM-1, 30% of the TEM-2, 23% of the OXA-1, 14% of the OXA-2, 27% of the OXA-3, TAZ is the first beta-lactamase inhibitor effective against the constitutive cephalosporinase of P. aeruginosa; it is also very effective against the most frequently found PSE-1 beta-lactamase in P. aeruginosa.

[Comparative antibacterial activity of ceftibuten (SH 39 720) against 150 K. pneumoniae strains producing different beta-lactamases]. / Activité antibactérienne comparée du ceftibutène (SH 39 720) sur 150 souches de K. pneumoniae productrices de différentes bêta-lactamases.

Comparative antibacterial activity of ceftibuten (SH 39 720) on 150 K. pneumoniae strains producing different beta-lactamases. MICs of ceftibuten, cefotaxime + clavulanic acid (10 mg/l), ceftazidime and azthreonam were determined for 150 clinical isolates of K. pneumoniae: 15 "wild" type producing only the SHV-1 type beta-lactamase, 15 TEM-1 and 120 producing new "extended spectrum" beta-lactamases (48 CTX-1, 9 SHV-2, 4 SHV-3, 35 SHV-4, 24 SHV-5). Against SHV-1 and TEM-1 strains the bacteriostatic activity of ceftibuten was close to that of the other beta-lactams tested. This activity was preserved against strains producing CTX-1, SHV-2, SHV-3 beta-lactamases and MICs were comparable to those of cefotaxime + clavulanic acid. The MICs of ceftibuten against strains producing SHV-4 and SHV-5 beta-lactamases were higher (1 to 8 mg/l) but this level of antibacterial activity was superior to that of the other beta-lactam antibiotics. The bactericidal activity of ceftibuten was evaluated by kill kinetic studies: this activity was preserved against the CTX-A and SHV-2 strains--with concentrations equal to 2 or 4 x CMI a 4 log10 reduction of the bacterial inoculum was obtained at 24 h. A such reduction was not obtained with cefotaxime. This preserved antibacterial activity of ceftibuten against K. pneumoniae producing some new "extended spectrum" beta-lactamases need further studies to state the structure-activity relation-ships of this antibiotic.

[In vitro antibacterial activity of lomefloxacin, a new fluoroquinolone, against hospital strains. Results of a multicenter study]. / Activité antibactérienne in vitro d'une nouvelle fluoroquinolone, la loméfloxacine, sur les bactéries hospitalières. Résultats d'une étude multicentrique.

Minimal inhibitory concentrations (MICs) of lomefloxacin (LOM) was determined by agar dilution for 2,819 bacterial strains isolated in 1988 in 9 university hospitals. Activity of LOM against nalidixic acid (NAL) susceptible (S) Enterobacteriaceae was close to that of pefloxacin (PEF) (mode MIC: 0.12-0.25 micrograms/ml); like for PEF, this activity was reduced against NAL resistant (R) Enterobacteriaceae (mode MIC: 4). MICs of LOM against P. aeruginosa were between 0.5 and 16 (mode: 2). LOM had also a good activity against NAL S A. baumannii (mode MIC: 0.5) but this activity is reduced against NAL R Acinetobacter (MICs : 4 to 128). LOM was highly active against Haemophilus (mode MIC: 0.06), Gonococci (mode MIC: 0.008), Meningococci (mode MIC: 0.03), Branhamella (mode MIC: 0.12-0.25). LOM showed activity similar to PEF against methicillin susceptible Staphylococci (mode MIC: 0.5-1); the resistant strains are usually methicillin resistant. Similar to the currently available quinolones, LOM is less effective against L. monocytogenes (mode MIC: 8), Enterococci (mode MIC: 4), Streptococci (mode MIC: 4) and Pneumococci (mode MIC: 8). Finally, for the anaerobic bacteria, LOM is more active against Clostridium perfringens (mode MIC: 1) than against Bacteroides fragilis (mode MIC: 32).

[Frequency and distribution of beta-lactamases in 1792 strains of Klebsiella pneumoniae in France between 1985 and 1988]. / Fréquence et distribution des bêta-lactamases chez 1,792 souches de Klebsiella pneumoniae isolées en France entre 1985 et 1988.

In october 1985, 1987 and 1988, all the clinical isolates of K. pneumoniae (respectively 530, 654, 590 strains) were collected in 20 hospitals. The beta-lactamases were identified by analytical isoelectrofocusing and by substrate and inhibition profiles. 76 to 81% of the strains produced only one beta-lactamase: SHV-1 type, pI 7.7 (61 to 65%) or PI 7.1 (14%). The TEM-1 betalactamase (pI 5.4) was produced in 1985 by 21% of the strains, 9% in 1987, and 11% in 1988: TEM-2, pI 5.6 by 2% in 1985-87-88. The extended broad spectrum beta-lactamases, able to hydrolyse amino-thiazol-oximino-beta-lactam antibiotics, TEM or SHV type enzymes (SHV-2, pI 7.7, SHV-3, pI 7.1; SHV-4/CAZ-5, pI 7.8; SHV-5/CAZ-4 pI 8.2; CTX-1/TEM-3, pI 6.3) were also detected: 0.75% of the strain (3 strains) in 1985, 8.4% (55 strains) in 1987, 11% (65 strains) in 1988. These extended broad spectrum beta-lactamases were found in 2 hospitals in 1985, 10 in 1987 and 9 in 1988.

[Bactericidal activity of imipenem]. / L'activité bactéricide de l'imipénème.

The bactericidal activity of imipenem against Pseudomonas aeruginosa, Enterobacteriaceae and Staphylococcus aureus was compared with that of other antibiotics, using the time-related kill rate curve method. The activity of imipenem was found to be less rapid and less intense than that of aminoglycosides, similar to that of fluoroquinolones and more rapid than that of beta-lactam antibiotics, notably ticarcillin and ceftazidime against P. aeruginosa and cefotaxime against Enterobacteriaceae. As with aminoglycosides, this bactericidal activity was concentration-dependent against Enterobacteriaceae and S. aureus but not against P. aeruginosa. Unlike the beta-lactam antibiotics, but like aminoglycosides and fluoroquinolones, imipenem remained active against "quiescent" P. aeruginosa, though not against Enterobacteriaceae. Successive transfers into liquid media rapidly produced resistant variants among P. aeruginosa strains and methicillin-resistant S. aureus strains, but not among Enterobacteriaceae. This shows that the bactericidal activity of imipenem is markedly different from that of other beta-lactam antibiotics.