Uncomplicated Urinary Tract Infections and Antibiotic Resistance-Epidemiological and Mechanistic Aspects.

Uncomplicated urinary tract infections are typically monobacterial and are predominantly caused by Escherichia coli. Although several effective treatment options are available, the rates of antibiotic resistance in urinary isolates of E. coli have increased during the last decade. Knowledge of the actual local rates of antibiotic resistant pathogens as well as the underlying mechanisms are important factors in addition to the geographical location and the health state of the patient for choosing the most effective antibiotic treatment. Recommended treatment options include trimethoprim alone or in combination with sulfamethoxazol, fluoroquinolones, ß-lactams, fosfomycin-trometamol, and nitrofurantoin. Three basic mechanisms of resistance to all antibiotics are known, i.e., target alteration, reduced drug concentration and inactivation of the drug. These mechanisms-alone or in combination-contribute to resistance against the different antibiotic classes. With increasing prevalence, combinations of resistance mechanisms leading to multiple drug resistant (mdr) pathogens are being detected and have been associated with reduced fitness under in vitro situations. However, mdr clones among clinical isolates such as E. coli sequence type 131 (ST131) have successfully adapted in fitness and growth rate and are rapidly spreading as a worldwide predominating clone of extraintestinal pathogenic E. coli.

Induction of beta-lactamase production in Aeromonas hydrophila is responsive to beta-lactam-mediated changes in peptidoglycan composition.

We have studied the mechanism by which beta-lactam challenge leads to beta-lactamase induction in Aeromonas hydrophila through transposon-insertion mutagenesis. Disruption of the dd-carboxypeptidases/endopeptidases, penicillin-binding protein 4 or BlrY leads to elevated monomer-disaccharide-pentapeptide levels in A. hydrophila peptidoglycan and concomitant overproduction of beta-lactamase through activation of the BlrAB two-component regulatory system. During beta-lactam challenge, monomer-disaccharide-pentapeptide levels increase proportionately with beta-lactamase production and beta-lactamase induction is inhibited by vancomycin, which binds muro-pentapeptides. Taken together, these data strongly suggest that the Aeromonas spp. beta-lactamase regulatory sensor kinase, BlrB, responds to the concentration of monomer-disaccharide-pentapeptide in peptidoglycan.

Development of resistance in wild-type and hypermutable Pseudomonas aeruginosa strains exposed to clinical pharmacokinetic profiles of meropenem and ceftazidime simulated in vitro.

In this study we investigated the interplay of antibiotic pharmacokinetic profiles and the development of mutation-mediated resistance in wild-type and hypermutable Pseudomonas aeruginosa strains. We used in vitro models simulating profiles of the commonly used therapeutic drugs meropenem and ceftazidime, two agents with high levels of antipseudomonal activity said to have different potentials for stimulating resistance development. During ceftazidime treatment of the wild-type strain (PAO1), fully resistant mutants overproducing AmpC were selected rapidly and they completely replaced wild-type cells in the population. During treatment with meropenem, mutants of PAO1 were not selected as rapidly and showed only intermediate resistance due to the loss of OprD. These mutants also replaced the parent strain in the population. During the treatment of the mutator P. aeruginosa strain with meropenem, the slowly selected mutants did not accumulate several resistance mechanisms but only lost OprD and did not completely replace the parent strain in the population. Our results indicate that the commonly used dosing regimens for meropenem and ceftazidime cannot avoid the selection of mutants of wild-type and hypermutable P. aeruginosa strains. For the treatment outcome, including the prevention of resistance development, it would be beneficial for the antibiotic concentration to remain above the mutant prevention concentration for a longer period of time than it does in present regimens.

Biochemical and genetic characterization of the beta-lactamases of Y. aldovae, Y. bercovieri, Y. frederiksenii and "Y. ruckeri" strains.

The beta-lactamases of five strains each of Y. aldovae and "Y. ruckeri", and 10 strains each of Y. bercovieri and Y. frederiksenii were examined phenotypically and genetically. Beta-lactamase activity and induction assays and SDS-PAGE were applied for phenotypic characterization of these enzymes. Genotypically, PCR experiments applying degenerated primer pairs for the detection of AmpC beta-lactamase genes were performed. All yersiniae yielded specific amplification products for ampC and all these strains expressed beta-lactamases. Each species produced its own, species-specific AmpC beta-lactamase. Inducibility of these enzymes was shown for Y. bercovieri, but not for the low-level enzyme producing species Y. aldovae and "Y. ruckeri". In contrast to these species, induction tests for Y. frederiksenii revealed heterogeneous results. Whereas the beta-lactamases of 6 of 10 strains were inducible, the enzyme activities after induction in the remaining four were similar to those measured without an inducer. In addition to the AmpC enzyme, all Y. frederiksenii strains expressed a second beta-lactamase belonging to Ambler class A. The present study enlarges the knowledge about the beta-lactamases of four novel Yersinia species that are likely to be involved in human disease. Beta-lactamases of Y. aldovae and "Y. ruckeri" have been characterized for the first time.

Natural antimicrobial susceptibility patterns and biochemical identification of Escherichia albertii and Hafnia alvei strains.

Bangladeshi diarrheagenic Hafnia alvei-like strains have been described recently as the new species Escherichia albertii (Int J Syst Evolut Microbiol. 2003;53:807-810). The natural susceptibility of 21 E. albertii and 76 H. alvei strains to 69 antimicrobial agents was examined, applying a microdilution procedure in IsoSensitest broth (for all the strains) and cation-adjusted Mueller-Hinton broth (for some strains). Examining the phenotypic features of both taxa with commercial identification systems and conventional tests, a database for an accurate biochemical separation of E. albertii from H. alvei was also established. Both taxa were naturally sensitive or sensitive and of intermediate susceptibility to aminoglycosides, acylureidopenicillins, ticarcillin, several cephalosporins, carbapenems, aztreonam, quinolones, folate pathway inhibitors, and nitrofurantoin. They were naturally resistant to tetracycline, penicillin G, oxacillin, all macrolides except for azithromycin, lincosamides, streptogramins, glycopeptides, rifampicin, and fusidic acid. Taxon-related differences in natural susceptibility affecting clinical assessment criteria were seen with doxycycline, minocycline, aminopenicillins, some cephalosporins, azithromycin, and fosfomycin. E. albertii was more susceptible than H. alvei to these agents and was naturally sensitive to all beta-lactams (except for penicillin G and oxacillin), azithromycin, and fosfomycin. H. alvei was naturally resistant or of intermediate susceptibility to all tetracyclines, amoxicillin, amoxicillin-clavulanate, ampicillin-sulbactam, narrow-spectrum cephalosporins, azithromycin, and fosfomycin. Motile malonate-negative Hafnia strains (indicating genospecies 2 of the H. alvei complex) were less susceptible to some cephalosporins than nonmotile, malonate-positive hafniae (indicating genospecies 1). Proline deaminase, hydroxyproline amidase, tripeptidase, chitinase, Voges-Proskauer reaction, and assimilation of histidine as well as acid production from glycerol, rhamnose, and xylose were suitable tests to separate strains of E. albertii from those of the H. alvei complex. Although out of the scope of this study, it should be noted that several strains of E. albertii showed acquired resistances to some penicillins and antifolates.

Feasibility and safety of needle catheter jejunostomy for enteral nutrition in surgically treated severe acute pancreatitis.

BACKGROUND: The role of the gut in the development of septic complications and promising clinical results have led to a shift from the parenteral to the enteral route for nutrition support of patients with acute pancreatitis. In patients undergoing surgery for severe necrotizing pancreatitis, the application of a needle catheter jejunostomy might be useful. However, there is a shortage of clinical data on its feasibility and possible harmful effect. METHODS: Between January 1999 and December 2002, 13 patients were operated for severe acute necrotizing pancreatitis. At the time of surgery, needle catheter jejunostomy was performed using a standard technique. Enteral nutrition was initiated without a strict protocol by feeding small amounts of a standard diet and carefully monitoring patient tolerance. As long as necessary, patients were also fed parenterally in order to achieve target caloric goals. RESULTS: No major tube- or feeding-related complications were observed. A single case of tube dislodgement caused by manipulation during relaparotomy for lavage occurred and was rectified during the same operation. CONCLUSIONS: In patients undergoing surgery for severe acute pancreatitis, needle catheter jejunostomy for long-term enteral nutrition can be applied with no additional risk.

High prevalence of the ermB gene among erythromycin-resistant streptococcus pneumoniae isolates in Germany during the winter of 2000-2001 and in vitro activity of telithromycin.

Of 595 isolates of Streptococcus pneumoniae from outpatients with respiratory tract infections, collected from 17 microbiology laboratories, 14.1% were resistant to erythromycin. Eighty-three erythromycin-resistant isolates were genetically analyzed, 83.1% of which harbored the ermB gene. Only four isolates (4.8%) harbored the mefA gene. Telithromycin exhibited potent activity against all isolates.

Extension of in-use stability of preservative-free nasalia.

Nasal drops and nasal sprays are commonly supplied in multi-dose containers that usually include suitable levels of an appropriate preservative in order to kill or prevent growth of any microorganisms which might enter the dispensing system. Preservatives should both protect the patient from infection and prevent spoilage of the product. Unfortunately, preservatives often cause unwanted side effects; in particular, the nasal mucosa is irritated frequently. Consequently, the use of preservatives in nasal preparations should be avoided. The technical design of the 3K system, a new multi-dose container, combines several microbiological safety features and therefore allows use without preservatives. Earlier tests have shown its safety for 6 weeks after the first opening. In order to test the microbiological safety of this multi-dose system over longer time periods, an in-use stability test was designed. The results revealed that the first dose as well as the contents complied with the requirements of the European Pharmacopoeia. Therefore, from a microbiological point of view for the tested nasalia in the 3K system, the stability after opening could be extended from 6 weeks up to several months without loss of microbiological quality.

Antimicrobial susceptibility patterns, beta-lactamases, and biochemical identification of Yokenella regensburgei strains.

Yokenella regensburgei is an opportunistic human pathogen that phenotypically resembles Hafnia alvei. The susceptibility of 10 Y. regensburgei strains to 75 antimicrobial agents was examined, applying a microdilution procedure in cation-adjusted Mueller-Hinton broth (CAMHB) and IsoSensitest broth (ISB). beta-Lactamases were characterized phenotypically with beta-lactamase activity and induction assays. Genotypically, PCR experiments applying degenerated primer pairs for the detection of AmpC beta-lactamase genes were performed. Examining the phenotypic properties of Yokenella and 76 H. alvei strains with commercial identification systems and conventional tests, a database for an accurate biochemical separation of Y. regensburgei from H. alvei was established. In CAMHB, all tested yokenellae were resistant or at least of intermediate susceptibility to penicillin G, oxacillin, amoxicillin, amoxicillin-clavulanate, cefaclor, cefazoline, loracarbef, cefoxitin, all tested macrolides, lincosamides, streptogramins, ketolides, fusidic acid, glycopeptides, linezolid, and rifampicin. All Yokenella strains were sensitive to several beta-lactams, all tested aminoglycosides, chloramphenicol, folate-pathway inhibitors, fosfomycin, nitrofurantion, quinolones, and tetracyclines. In ISB, the minimum inhibitory concentration (MIC) values of several beta-lactams were one to four MIC doubling dilution steps lower than those found in CAMHB (depending on the beta-lactam). All yokenellae yielded specific amplification products for ampC, and all of these strains expressed beta-lactamases that were strongly inducible. Hydroxyproline amidase, maltosidase, tri-peptidase, proline deaminase, catalase reaction, Voges-Proskauer test, and fermentation of glycerol, melibiose and myo-inositol were suitable parameters to separate Y. regensburgei from H. alvei.

Pharmacological indices in antibiotic therapy.

After 60 years of antibiotic treatment, attempts to rationalize it have culminated in the use of pharmacological indices. These indices facilitate comparison of the activity of different antibiotics and serve as a sound basis for antibiotic dosing. Pharmacokinetic parameters (e.g. AUC, Cmax) and pharmacodynamic parameters (mostly MIC) are used for this purpose. For the so-called concentration-dependent antibiotics, the pharmacological indices AUC/MIC and Cmax/MIC are used, whereas for time-dependent antibiotics, the pharmacological index T>MIC is used. Some authors believe that the index AUC/MIC can be used as a universal index, but, not all experts accept this generalization. As the various pharmacological indices have been defined inconsistently in the literature, the International Society for Anti-Infective Pharmacology (ISAP) has published a paper on the terminology of pharmacokinetic and pharmacodynamic parameters and the pharmacological indices. This paper will help to ensure uniform use of terminology. In addition, we point out that the use of pharmacological indices should consider the differences in pharmacokinetics (patient characteristics and localization of the infection) and the differences in pharmacodynamics of antibiotics (beyond MICs) with different pathogens (e.g. Gram-positive and Gram-negative).

Natural antimicrobial susceptibilities and biochemical profiles of Yersinia enterocolitica-like strains: Y. frederiksenii, Y. intermedia, Y. kristensenii and Y. rohdei.

The natural susceptibility of 131 Yersinia strains of Y. frederiksenii (n=38), Y. intermedia (n=48), Y. kristensenii (n=26) and Y. rohdei (n=19) to 70 antibiotics was tested. Minimum inhibitory concentration (MIC) values were determined with a microdilution procedure in IsoSensitest broth (all strains) and cation-adjusted Mueller Hinton broth (some strains). All species were naturally sensitive or sensitive and of intermediate susceptibility to tetracyclines, aminoglycosides, acylureidopenicillins, numerous cephalosporins, carbapenems, aztreonam, quinolones, chloramphenicol, folate-pathway inhibitors, nitrofurantoin, and fosfomycin. Uniform natural resistance was found with penicillin G, oxacillin, several macrolides, lincosamides, streptogramins, glycopeptides, rifampicin and fusidic acid. Species-specific differences in susceptibility affecting clinical assessment criteria were seen with aminopenicillins (in the presence and absence of beta-lactamase inhibitors), ticarcillin and some cephalosporins. Major medium-dependent susceptibilities were found with fosfomycin. beta-Lactam MIC susceptibility patterns suggested that most strains of the species tested produce both class A and class C (AmpC) beta-lactamases that are characteristic for the species. The present study describes a database concerning the natural susceptibility of some Y. enterocolitica-like species to a wide range of antibiotics, which can be applied to validate forthcoming antibiotic susceptibility tests of these strains and might contribute to their identification. An evaluation of 30 biochemical tests that secured phenotypic identification to the Yersinia species level is presented.

Natural antimicrobial susceptibilities of strains of 'unusual' Serratia species: S. ficaria, S. fonticola, S. odorifera, S. plymuthica and S. rubidaea.

The natural susceptibility to 71 antibiotics of 104 Serratia strains of Serratia ficaria (n = 15), Serratia fonticola (n = 18), Serratia odorifera (n = 16), Serratia plymuthica (n = 32) and Serratia rubidaea (n = 23) was examined. MICs were determined using a microdilution procedure in IsoSensitest broth for all the strains and in cation-adjusted Mueller-Hinton broth for some strains. With few exceptions, all species tested were uniformly naturally resistant to penicillin G, oxacillin, cefazolin, cefuroxime, all tested macrolides, lincosamides, streptogramins, glycopeptides, fusidic acid and rifampicin, and naturally sensitive to several aminoglycosides, piperacillin, piperacillin/tazobactam, carbapenems, some cephalosporins, fluoroquinolones and folate-pathway inhibitors. Major species-related differences in natural susceptibility affecting clinical assessment criteria were seen with tetracyclines, some aminoglycosides, aminopenicillins, ticarcillin, cefaclor, loracarbef, cefoxitin, pipemidic acid, chloramphenicol, nitrofurantoin and fosfomycin. Differences in susceptibility dependent on the medium were seen with macrolides, tetracycline, fosfomycin and some beta-lactams. The natural antibiotic susceptibility patterns suggest novel species-specific mechanisms of antibiotic resistance. Uncharacterized species-specific aminoglycoside-modifying enzymes and multidrug efflux systems affecting tetracyclines, quinolones and chloramphenicol are probably responsible for some of the phenotypes observed. The natural amoxicillin sensitivity of several strains of some species combined with natural resistance to some narrow-spectrum cephalosporins indicate the expression of naturally occurring beta-lactamases with unique substrate profiles. beta-Lactamases of representative strains of each species were characterized phenotypically and genotypically. It was shown that all species expressed naturally occurring AmpC beta-lactamases and, with respect to S. fonticola, also a species-specific class A beta-lactamase. Inducibility of these enzymes was shown in all species with the exception of S. rubidaea and four of five strains of S. plymuthica.

Moellerella wisconsensis: identification, natural antibiotic susceptibility and its dependency on the medium applied.

The present study establishes a data compilation on biochemical features and natural antibiotic susceptibilities of Moellerella wisconsensis strains. 17 moellerellae isolated from humans (n = 11), food (n = 5) and water (n = 1) were tested. Identification was carried out using two commercially available systems and conventional tests. MIC determinations of 74 antibiotics were performed applying a microdilution procedure in Cation-adjusted Mueller Hinton broth and IsoSensitest broth. M. wisconsensis was naturally sensitive to doxycycline, minocycline, all tested aminoglycosides, numerous beta-lactams, all fluoroquinolones, folate-pathway inhibitors, chloramphenicol and nitrofurantoin. Natural resistance was found with oxacillin, penicillin G, all tested macrolides, lincomycin, streptogramins, ketolides, glycopeptides, fusidic acid, linezolid and rifampicin. Medium-dependent differences in susceptibility affecting clinical assessment criteria were seen with tetracycline, clindamycin and fosfomycin. From the data of the present study it is possible that some moellerellae are misidentified as Klebsiella pneumoniae subsp. ozaenae.

Natural antibiotic susceptibility and biochemical profiles of Yersinia enterocolitica-like strains: Y. bercovieri, Y. mollaretii, Y. aldovae and 'Y. ruckeri'.

The natural susceptibility of 54 Yersinia enterocolitica-like strains of Y. bercovieri (formerly Y. enterocolitica biovar 3B, n = 17), Y. mollaretii (formerly Y enterocolitica biovar 3A, n = 12), Y. aldovae (formerly Y. enterocolitica-like group chi2, n = 10) and 'Y ruckeri' (n = 15) was tested to 69 antibiotics. MIC values were determined with a microdilution procedure in IsoSensitest broth for all strains and in cation-adjusted Mueller Hinton broth for some strains. All yersiniae tested showed uniform MIC distributions to most antibiotics and were naturally sensitive or intermediate to aminoglycosides, several cephalosporins, and penicillins, carbapenems, aztreonam, quinolones, tetracyclines, antifolates, chloramphenicol and nitrofurantoin, and naturally resistant to benzylpenicillin, oxacillin, all macrolides except azithromycin, lincosamides, streptogramins, glycopeptides, rifampicin and fusidic acid. Significant differences in susceptibility affecting clinical assessment criteria were seen with aminopenicillins (in the presence and absence of beta-lactamase inhibitors), some cephalosporins (e.g., cefoxitin) and fosfomycin. Whereas strains of Y. aldovae and 'Y. ruckeri' were naturally sensitive or intermediate to amoxicillin and amoxicillin/clavulanate, strains of Y. bercovieri and Y. mollaretii were naturally resistant or naturally resistant or intermediate, respectively. Strains of the two latter species were also highly susceptible to fosfomycin. These data can be valuable for the validation of routine susceptibility test results. beta-Lactam MICs suggest that Y bercovieri and Y. mollaretii strains express chromosomally encoded AmpC beta-lactamases and that most Y. aldovae and 'Y. ruckeri' strains express no, or only small amounts, of enzyme. An evaluation of 30 biochemical tests that determined phenotypic identification to the Yersinia species level is presented.

Natural antibiotic susceptibility of Klebsiella pneumoniae, K. oxytoca, K. planticola, K. ornithinolytica and K. terrigena strains.

The natural susceptibility of 221 Klebsiella strains to 71 antibiotics was examined. The strains were isolated from clinical specimens and the environment, and belonged to K. pneumoniae subsp. pneumoniae (n = 40), K. pneumoniae subsp. ozaenae (37), K. pneumoniae subsp. rhinoscleromatis (10), K. oxytoca (44), K. planticola (40), K. ornithinolytica (25) and K. terrigena (25). MIC values were determined by a microdilution procedure in IsoSensitest broth according to the German standard (DIN). All Klebsiella spp. were naturally resistant or intermediate to amoxicillin, ticarcillin and to antibiotics to which other Enterobacteriaceae are also intrinsically resistant. Klebsiella spp. were naturally sensitive or intermediate to several penicillins, all tested cephalosporins, aminoglycosides, quinolones, tetracyclines, trimethoprim, cotrimoxazole, chloramphenicol and nitrofurantoin. K. pneumoniae subsp. ozaenae and subsp. rhinoscleromatis strains were generally more susceptible to antibiotics than strains of other Klebsiella taxa. K pneumoniae subsp. rhinoscleromatis was the most susceptible taxon, being highly susceptible to cefuroxime, anti-folates and naturally intermediate to erythromycin and clarithromycin. K. pneumoniae subsp. ozaenae was most susceptible to glycopeptides. K. oxytoca and K. terrigena strains were least susceptible to cefazoline, cefoperazone and fosfomycin, respectively. The results of the present study describe a database of the natural antimicrobial susceptibility of Klebsiella spp., which can be used for the validation of antibiotic susceptibility results of these bacteria. MIC patterns to beta-lactams indicate the expression of chromosomally encoded class A gamma-lactamases in all the species, including the subspecies of K. pneumoniae. Similar natural susceptibility patterns of K. planticola and K. ornithinolytica to all tested antibiotics support the status of K. ornithinolytica as a biovar of K. planticola.

Beta-lactamase expression in Yersinia enterocolitica biovars 1A, 1B, and 3.

Characteristic patterns of beta-lactam susceptibility are associated with different biovars of Yersinia enterocolitica. In a previous study differences in beta-lactam susceptibility among biovar 2, 4 and 5 strains were largely attributed to differences in expression of beta-lactamase A (BlaA) and beta-lactamase B (BlaB). The basis for differences in beta-lactam susceptibility of strains of biovars 1A, 1B and 3 is now considered. All the strains examined had blaB; nine of 31 biovar 3 strains and two of 13 biovar 1B strains had blaA, but PCR did not amplify blaA from biovar 1A strains. Nevertheless, inhibition data indicated that the majority of uninduced biovar 1A strains expressed BlaA and BlaB in similar amounts. Strong inducibility was seen in all these strains. Biovar 1B strains (which were less inducible than strains of biovar 1A) predominantly produced BlaA without induction; ticarcillin-sensitive strains of biovar 3 produced only BlaB but were not inducible; without induction biovar 3 strains resistant to ticarcillin and amoxycillin/clavulanate produced either predominantly BlaA, predominantly BlaB or exclusively BlaB and induction was demonstrated except for strains producing BlaB alone; biovar 3 strains resistant to ticarcillin but sensitive to amoxycillin/clavulanate predominantly produced BlaA without induction and were inducible for beta-lactamase activity. After induction, nearly all strains predominantly or exclusively produced BlaB. Although PCR amplification fragments with primers specific for blaA were obtained only from some strains, the induction and inhibition data suggest that all Y. enterocolitica strains possess enzymes related to BlaA- as well as BlaB. Nevertheless, expression of the beta-lactamase is regulated differently in different biovars and varies within most biovars. Failure to predict beta-lactamase expression profiles from MIC data indicates the presence of additional mechanisms contributing to differences in susceptibility.

Expression of beta-lactamases in Yersinia enterocolitica strains of biovars 2, 4 and 5.

Characteristic patterns of susceptibility to beta-lactam antibiotics are associated with different biovars of Yersinia enterocolitica. To elucidate the basis for these differences, the beta-lactamases of strains of Y. enterocolitica biovars 4 (n = 63), 2 (n = 12) and 5 (n = 10) were characterised. PCR fragments were generated from the beta-lactamase A (blaA) and B (blaB) genes; in addition, beta-lactamase induction tests were performed with imipenem as the inducer and beta-lactamase inhibition assays were undertaken with aztreonam and clavulanic acid. All the strains yielded PCR amplification fragments with primers to blaA and blaB. Biovar 4 strains had uniform patterns of beta-lactamase induction and inhibition: uninduced biovar 4 strains predominantly expressed BlaA, but low-level expression of BlaB was also detected; after induction, biovar 4 strains predominantly produced BlaB. Beta-lactamase expression varied between and within biovars 2 and 5: uninduced strains predominantly expressed either BlaA or BlaB, or exclusively BlaB; after induction BlaB was predominantly or exclusively expressed. Both the basal and induced levels of beta-lactamase varied within biovars 2 and 5. Some biovar 5 strains were not inducible; these predominantly produced BlaA. The results of this study show that biovar 2, 4 and 5 strains contain both blaA and blaB, but that the expression of the enzymes is regulated differently between the biovars, and varies within biovars 2 and 5. There was some correlation between antibiogram and the clusters defined from the beta-lactamase induction and inhibition tests, but it was not possible to predict beta-lactamase expression profiles from MIC data.