Antibacterial effects of meropenem and imipenem against Haemophilus influenzae

Phase contrast microscopy, killing curves and turbidimetric growth curves were used in a comparative study of the antibacterial effects of imipenem and meropenem on Haemophilus influenzae. The minimal inhibitory concentrations (MICs) and their ranges of meropenem and imipenem using five beta-lactamase-producing strains of H. influenzae were 0.03 (0.015-0.06) and 0.6 (0.5-1) micrograms/ml, respectively. Imipenem and meropenem induced spheroplast formation in cultures. Killing curves showed a bacteriostatic activity for meropenem and imipenem for MIC values, and a lag of 2 h in killing for MIC x 2 to MIC x 64. For these concentrations the killing rates of the two antibiotics were similar. Turbidimetric growth curves showed a higher early increase in optical density for meropenem. As far as the MIC value of meropenem was 10 times lower than the MIC value of imipenem, we may conclude that meropenem was more active than imipenem on beta-lactamase-producing strains of H. influenzae.     

Antibacterial effect of meropenem and imipenem on Proteus mirabilis

Phase-contrast microscopy, killing-curves and turbidimetric growth-curves were used in a comparative study of the antibacterial effects of a new carbapenem, meropenem (SM 7338) and imipenem on five strains of Proteus mirabilis. Despite the low MIC (0.2 mg/l) of imipenem for the five strains included in our study, the MBC remained relatively high (4.4 mg/l). During the first few hours of incubation, imipenem induced large lemon-shaped cells while the turbidity increased without substantial changes in culture viability. Later, most of the cell-wall deficient bacteria generated small spheroplasts until the antibiotic concentration exceeded 32 times the MIC. The MIC of meropenem was lower (0.03 mg/l) with an MBC (0.08 mg/l) very close to the MIC. Meropenem also induced large bodies but these cell-wall deficient bacteria did not generate small round bodies as observed with imipenem. In conclusion, imipenem produced in strains of Pr. mirabilis an amdinocillin-like change in cell morphology, responsible for the discrepancies observed between MIC and MBC. This effect was not observed with meropenem.     

Ro 17-2301: in vitro comparison with aztreonam, imipenem, ceftazidime, cefotaxime and netilmicin

The in vitro activity of the novel monobactam antibiotic, Ro 17-2301 has been compared with those of aztreonam, imipenem, ceftazidime, cefotaxime and netilmicin. A total of 438 clinical isolates of aerobic gram-negative rods were employed and an agar dilution method was used for measurement of MIC. Ro 17-2301 was highly active against a wide variety of Enterobacteriaceae species (MIC range less than or equal to 0.03-8, MIC50 less than or equal to 0.03, MIC90 0.06 mg/l). The activity of aztreonam parallelled that of Ro 17-2301 although the latter seemed to have more uniformly high activity against Klebsiella sp. The other agents showed generally high activity against Enterobacteriaceae except netilmicin against Providencia stuartii (MIC50 4, MIC90 greater than or equal to 16 mg/l). Activity against Pseudomonas aeruginosa. was more variable. Ro 17-2301 and aztreonam were moderately active (MIC50 2, MIC90 8 and 16 mg/l, respectively). Imipenem was the most active agent against Acinetobacter, whereas Ro 17-2301 was moderately active. In conclusion, Ro 17-2301 shows impressive activity against Enterobacteriaceae and moderate activity against Acinetobacter and P. aeruginosa. Ro 17-2301 may well prove to be a useful agent in the treatment of gram-negative infections.     

In vitro activities of aztreonam, imipenem, and amoxycillin-clavulanate against ampicillin-resistant Haemophilus influenzae.

Two hundred and fifty-seven ampicillin-resistant clinical isolates of Haemophilus influenzae were tested by disk diffusion and MIC determination for susceptibility to aztreonam, imipenem, and amoxycillin combined with clavulanate. The modal MICs and MICs for 50 and 90% of isolates of all three antimicrobial agents for the 157 beta-lactamase-positive strains did not differ significantly from figures obtained with 2,201 ampicillin-susceptible H. influenzae by the same methods. Aztreonam and amoxycillin-clavulanate were less active, as reflected by an increase in these parameters, against 38 beta-lactamase-negative isolates requiring greater than or equal to 4 micrograms of ampicillin per ml for inhibition and 62 strains considered to have an intermediate degree of nonenzymic (intrinsic) resistance to ampicillin (zone diameters of less than 20 mm with 2-micrograms ampicillin disks and MICs of 1 or 2 micrograms/ml). There was no detectable difference in imipenem activity against these 100 strains compared with that observed against the ampicillin-susceptible group. Of the 24 strains requiring at least 4 micrograms of imipenem per ml for inhibition, 13 also showed reduced susceptibility to ampicillin (5 beta-lactamase-positive and 8 beta-lactamase-negative isolates). A lack of correlation between reduced susceptibility to imipenem and the other beta-lactams was observed.     

In vitro antibacterial activities of doripenem, imipenem, and meropenem against recent Streptococcus pneumoniae isolates

We investigated the in vitro activities of carbapenems against 347 Streptococcus pneumoniae isolates from Korea. While doripenem and imipenem resistance was displayed by only 1.2% and 3.2%, respectively, 21.3% of the isolates were resistant to meropenem. One isolate displaying very high carbapenem MICs and susceptibility only to vancomycin was also identified.     

New antibiotics: carbapenems, monobactams and quinolones

New beta lactams and the quinolone class of antibiotics represent major improvements in the therapy of moderate to severe infections. These newer antibiotics have an extended spectrum of antimicrobial activity, excellent pharmacokinetic properties and low toxicity. The beta lactams include carbapenems, represented by imipenem-cilastatin, and monobactams, represented by aztreonam. Norfloxacin and ciprofloxacin are potent quinolones.     

Predicting doripenem susceptibility based on meropenem and imipenem interpretation for Pseudomonas aeruginosa

Doripenem is not available on many automated susceptibility testing panels. We evaluated the surrogate predictive value (SPV) of meropenem and imipenem in predicting doripenem susceptibility using the different breakpoint definitions available globally. MIC data for 736 Pseudomonas aeruginosa were extracted, and categorical interpretations were performed using Clinical and Laboratory Standards Institute (CLSI) proposed 2012, European Committee on Antimicrobial Susceptibility Testing (EUCAST), and Food and Drug Administration (FDA) breakpoints. Regardless of the breakpoint applied, very major and major errors were observed in only 0.1-0.8% and 0.1-4.5% of isolates, respectively. Meropenem's SPV was 98.6% for CLSI 2012 breakpoints, 94.0% for EUCAST, and 95.0% for FDA. Imipenem's SPV was 98.6%, 90.9%, and 97.2%, respectively. These data indicate that meropenem and imipenem would be reliable surrogate markers of doripenem susceptibility when using CLSI 2012 and FDA breakpoints. Meropenem would be recommended over imipenem for EUCAST breakpoints. However, meropenem and imipenem nonsusceptible isolates should be directly tested against doripenem since the latter antibiotic may still retain susceptibility against these isolates.     

Mutation prevention concentration of ceftriaxone,meropenem, imipenem,and ertapenem against three strains of Streptococcus pneumoniae

This investigation tested the mutation prevention concentration (MPC) concept using imipenem, meropenem, ceftriaxone, and ertapenem against three strains of Streptococcus pneumoniae (PCN MIC = 0.012, 1, 8 mg/L, respectively). MIC, MBC, and MPC values for each of the beta-lactams did not differ by more than one tube dilution. While an interesting concept, MPC may not apply to antimicrobials that do not utilize a dual targeting system, such as beta-lactams, or to bacteria that exhibit multiple mechanisms of resistance and/or mutate at a rate where the frequency would likely be captured by the standard inoculum size used in routine MIC testing.     

Comparative in vitro pharmacodynamics of imipenem and meropenem against Pseudomonas aeruginosa.

MICs are commonly used to assess the in vitro activities of antimicrobial agents; however, they provide minimal information on the pattern of bacterial activities. Time-kill studies with extensive sampling allow assessment of both the rate and extent of bacterial killing and regrowth. We compared imipenem and meropenem by both MIC-MBC testing and a time-kill study with P. aeruginosa 27853. In the time-kill study, concentration/MIC ratios ranging from 0.0625 to 32 times the MIC were studied. The kill rate, time to 99.9% kill, doubling time of regrowth, and area under the bacterial killing curve (AUKC) were evaluated. Degradation during the testing procedure was accounted for by assessing actual drug exposure as determined by the area under the concentration-time curve. Pharmacodynamic parameters were compared by using the Wilcoxon signed-rank test. The modal MIC and MBC for imipenem were 2 and 4 micrograms/ml, respectively, and those for meropenem were 0.25 and 0.5 microgram/ml, respectively. In the time-kill study, both agents displayed concentration-dependent activity over a range of 0.25 to 4 times the MIC. Initial killing (0 to 1 h) was faster with imipenem at the same concentration/MIC ratios (P = 0.0506). The time to 99.9% kill was approximately 5 h for both agents. When regrowth occurred, the doubling rate for imipenem, which was the same as that for the growth control, was twice as rapid as that for meropenem. At the same concentrations, the AUKCs over 24 h were lower for meropenem than for imipenem (P = 0.0280); however, when normalized by MIC, imipenem resulted in smaller AUKCs. Comparison of plots of area under the concentration-time curve versus AUKC, which accounted for drug degradation and actual drug exposure, revealed that meropenem was three times more active than imipenem, rather than the eightfold difference suggested by MICs. Time-kill curves with extensive sampling and measurement of actual drug exposure, rather than traditional MIC testing, may more accurately assess differences in the in vitro activities of antimicrobial agents.     

The effect of amphotericin B, aztreonam, imipenem and cephalosporins on the bone marrow progenitor cell activity

The effects of certain antibiotics on the colony forming activity of human bone marrow cells in semisolid methylcellulose medium in vitro and on murine BM cells in spleen colony forming units (cfu-s) in vivo were evaluated. Amikacin, gentamicin, piperacillin, co-trimoxazole and pentamidine had little or no effect on human bone marrow progenitor cell function; amphotericin B, aztreonam, ceftazidime and imipenem caused significant suppression of human colony forming unit-erythroid (cfu-e), burst forming unit-erythroid (bfu-e) and colony forming unit-granulocyte macrophage (cfu-gm) at both peak and trough serum concentrations. At molar equivalent concentrations ceftazidime, cefotaxime and cefoperazone caused significant decreases in human cfu-e, bfu-e and cfu-gm in vitro (P less than 0.01) and murine cfu-s in vivo (P less than 0.05); cefoxitin, cefuroxime, ceftizoxime and ceftriaxone did not suppress human bone marrow progenitor cell activity. Gentamicin, piperacillin and ceftriaxone had no effect on murine cfu-s formation. Further studies to evaluate the effect of these antibiotics on human bone marrow in vivo are suggested.     

Comparative in vivo efficacy of meropenem, imipenem, and cefepime against Pseudomonas aeruginosa expressing MexA-MexB-OprM efflux pumps

To identify the optimal pharmacodynamic exposures of meropenem, imipenem, and cefepime, and the emergence of resistance in vivo for Pseudomonas aeruginosa overexpressing MexA-MexB-OprM efflux pumps, we used the murine thigh model. Mice were challenged with P. aeruginosa isolates: PAO1 (K767 wild type), K767+ (MexA-MexB-OprM efflux mutant), and DeltaK767 (knockout strain). Efficacy (Delta log colony-forming unit [CFU]) was determined at various exposures of %T > MIC at both standard (10(5) CFU/thigh) and high (10(7) CFU/thigh) inoculums. At 10(5) CFU/thigh, meropenem and imipenem produced a maximal activity against PAO1 (-2.82, -1.88) and K767+ (-2.24, -2.68) at 40%T > MIC; cefepime at 70%T > MIC produced a comparable kill (-2.74 and -2.19, respectively). Similar magnitudes of kill were observed at the 10(7) inocula. Except for DeltaK767 with cefepime, no development of resistance emerged at various %T > MIC. All agents exhibited reduced activity against DeltaK767. DeltaK767 cefepime-resistant strains were isolated up to 100%T > MIC. The overexpression of MexA-MexB-OprM efflux pumps did not result in the loss of efficacy of the antibiotics tested regardless of the amount of bacterial inocula; however, their presence also did not lead to increased selection for resistance. The effects of efflux mechanisms on beta-lactam agents in vivo warrant further research.     

Carbapenems: past, present, and future

In this review, we summarize the current "state of the art" of carbapenem antibiotics and their role in our antimicrobial armamentarium. Among the β-lactams currently available, carbapenems are unique because they are relatively resistant to hydrolysis by most β-lactamases, in some cases act as "slow substrates" or inhibitors of β-lactamases, and still target penicillin binding proteins. This "value-added feature" of inhibiting β-lactamases serves as a major rationale for expansion of this class of β-lactams. We describe the initial discovery and development of the carbapenem family of β-lactams. Of the early carbapenems evaluated, thienamycin demonstrated the greatest antimicrobial activity and became the parent compound for all subsequent carbapenems. To date, more than 80 compounds with mostly improved antimicrobial properties, compared to those of thienamycin, are described in the literature. We also highlight important features of the carbapenems that are presently in clinical use: imipenem-cilastatin, meropenem, ertapenem, doripenem, panipenem-betamipron, and biapenem. In closing, we emphasize some major challenges and urge the medicinal chemist to continue development of these versatile and potent compounds, as they have served us well for more than 3 decades.     

Quality control limits for microdilution susceptibility tests with aztreonam, imipenem, ceftriaxone, ceftazidime, ceftizoxime, cefuroxime, and cefonicid

A six-laboratory collaborative study was performed in order to define quality control limits for microdilution tests with seven new beta-lactams (aztreonam, imipenem, ceftriaxone, ceftazidime, ceftizoxime, cefuroxime, and cefonicid). Four standard control strains were tested and the expected MIC limits for each of the appropriate drug-microorganism combinations were defined.     

In vitro activity of meropenem, imipenem, cefepime and ceftazidime against Pseudomonas aeruginosa isolates from cystic fibrosis patients

We studied 67 Pseudomonas aeruginosa isolates from cystic fibrosis patients, and compared their in vitro susceptibility to two carbapenems (meropenem and imipenem) and two cephalosporins (cefepime and ceftazidime). The carbapenems were more effective in vitro than the cephalosporins: 92.5% of isolates were susceptible to the former and 77.6% to the latter. Essentially no difference was found between meropenem and imipenem. More discrepancies were seen between cefepime and ceftazidime: four of 67 isolates (6.0%) were more susceptible to cefepime than to ceftazidime, while eight (11. 9%) were more susceptible to ceftazidime than to cefepime.     

In-vitro activity of new carbapenem antibiotics: comparative studies with meropenem, L-627 and imipenem against pathogenic Nocardia spp.

MICs of two new carbapenems, meropenem and L-627, and imipenem were determined against 98 strains of the Nocardia asteroides group (i.e. N. asteroides sensu stricto, Nocardia farcinica and Nocardia nova), 46 strains of Nocardia brasiliensis and 17 strains of Nocardia otitidiscaviarum. Meropenem and L-627 were less active against the N. asteroides group than imipenem. Among the three species of the N. asteroides group, N. nova was the most sensitive to all the carbapenems. Meropenem was more active than imipenem against both N. brasiliensis and N. otitidiscaviarum with MIC50 values of 28.3-53.3 mg/L. L-627 was less active than meropenem.     

A comparison of aztreonam and imipenem induction of class I beta-lactamase in Enterobacter cloacae ATCC 13047

Aztreonam and imipenem were shown to induce Class I beta-lactamase in Enterobacter cloacae ATCC 13047 to a similar extent. Quantitatively, however, aztreonam was far less efficient as an inducer than imipenem. Optimum induction by aztreonam required a concentration of 200 mg/l, which was 800-fold greater than the concentration of 0.25 mg/l of imipenem which resulted in the optimum induction. The differences in the concentrations of aztreonam and imipenem that gave optimum induction were related to the inherent antibacterial activities of the antibiotics when these were determined under the conditions of broth culture. The beta-lactamase activity of sonicated cell samples following induction was inhibited by the presence of aztreonam but not by imipenem. The inhibition was overcome by first washing the cell samples from induced cultures and then incubating the sonicates for a prolonged period at 4 degrees C. It is proposed that the phenomena of an optimum inducing concentration and the interference with the assay of beta-lactamase by the presence of residual antibiotic demonstrated in this study with aztreonam and imipenem would be of relevance when applied more broadly to studies of beta-lactamase induction. In particular these would have a profound effect on the results of studies which attempt to compare the efficacy of beta-lactams as inducers of Class I beta-lactamase.     

In vitro activity of meropenem (SM-7338), imipenem, and five other antibiotics against anaerobic clinical isolates

The in vitro susceptibility of 513 recent anaerobic clinical isolates was evaluated against meropenem (SM-7338), a new carbapenem, and six other antibiotics. Virtually all Gram-positive and Gram-negative anaerobic bacteria tested were susceptible to meropenem (defined as MICs less than or equal to 8 micrograms/ml) with 99.8% of the isolates inhibited by less than or equal to 4 micrograms/ml. The activity of meropenem was comparable to imipenem for most clinical isolates. Minor differences were observed for Clostridium and Veillonella (meropenem more active) and other Gram-positive bacilli (imipenem more active). Meropenem inhibited all anaerobes resistant to clindamycin and metronidazole. Bactericidal tests performed with meropenem demonstrated killing activity against all isolates except Clostridium and Lactobacillus.     

Comparative in vitro pharmacodynamics of imipenem and meropenem against ATCC strains of Escherichia coli, Staphylococcus aureus and Bacteroides fragilis

We evaluated the pharmacodynamics of imipenem and meropenem, utilizing time-kill studies over a concentration/MIC (C/MIC) range of 0.0625-1024 for E. coli ATCC 35218 (EC) and S. aureus ATCC 29213 (SA) and from 0.125-512 for B. fragilis ATCC 25285 (BF). Area under the time-kill curves were converted to percent response (%R). AUCs were calculated from drug concentrations corrected for degradation and %R vs. C/MIC and AUC/MIC were fit to a sigmoidal Emax model. Emax was similar for both agents for all organisms. Meropenem was 4x more potent than imipenem against EC based on the MIC and required 7 and 13.5-fold lower AUCs to achieve E50 and E90, (50% and 90% of the maximal response, respectively) respectively, whereas imipenem was 8x more potent than meropenem against SA based on the MIC and required 8 and 13-fold lower AUCs to achieve E50 and E90, respectively. The C/MIC and AUC/MIC to achieve E50 and E90 with imipenem were 2- and fourfold higher, respectively than meropenem against EC. There was less than a twofold difference in C/MICs and AUC/MIC between imipenem and meropenem for both E50 and E90 against SA. Against BF, concentrations and AUCs at E50 were similar for both agents; however, imipenem required 4 to 6-fold higher concentrations and AUC to achieve E90. Although there are differences in the potency of these agents as assessed by the MIC or AUC vs. response, when normalized by the MIC and corrected for drug degradation, these agents displayed similar pharmacodynamic parameter-response relationships.