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PubMed2005

Comparative in vitro antimicrobial activity of a new carbapenem, doripenem: tentative disc diffusion criteria and quality control.

OBJECTIVES: To determine the spectrum of activity of doripenem and to propose tentative MIC and disc diffusion breakpoints. METHODS: The in vitro susceptibilities of 2137 bacterial isolates, representing 28 different species, to doripenem, imipenem and meropenem were determined by the NCCLS broth microdilution and disc diffusion testing methods. RESULTS: The doripenem MIC(50)s/(90)s were (in mg/L) for Enterobacteriaceae, 0.06/0.25; Pseudomonas aeruginosa, 0.25/1; Haemophilus influenzae, 0.12/0.5; streptococci, 0.016/0.5 and for staphylococci, 0.06/4. Like other carbapenems tested, doripenem MIC(50)s/(90)s were >32/>32 and 0.5/32 mg/L for the enterococci and non-fermentative Gram-negative bacilli (excluding P. aeruginosa), respectively. Against members of the Enterobacteriaceae and H. influenzae, doripenem was generally more active than imipenem and the same as or slightly less active than meropenem. Values for the non-fermentative Gram-negative bacilli excluding P. aeruginosa were comparable for all three carbapenems. Doripenem MICs increased with increasing resistance to methicillin (staphylococci), penicillin (streptococci) and strains that were beta-lactamase-negative ampicillin-resistant (Haemophilus). Doripenem exhibits excellent activity against extended-spectrum beta-lactamase-producing strains of Escherichia coli and Klebsiella spp. The NCCLS disc diffusion test was performed simultaneously on all organisms. CONCLUSIONS: Assuming the MIC susceptible breakpoints for doripenem are < or =1 mg/L for the streptococci and < or =2 mg/L for all other genera, then disc diffusion zone diameter breakpoints can be proposed. In addition, MIC and/or disc diffusion quality control ranges of doripenem were determined for 10 ATCC reference strains.

Carbapenems↗

PubMed2005

Influence of inoculum size of Staphylococcus aureus and Pseudomonas aeruginosa on in vitro activities and in vivo efficacy of fluoroquinolones and carbapenems.

OBJECTIVES: We investigated the effect of inoculum size on MIC, bactericidal activity and the post-antibiotic effect (PAE) of carbapenems (imipenem, panipenem and meropenem) and injectable quinolones (pazufloxacin and ciprofloxacin) against Staphylococcus aureus and Pseudomonas aeruginosa, and also the relationship between in vivo systemic infection by changing the inoculum size injected in mice. RESULTS: Increasing the bacterial inoculum (10(5)-10(8) cfu/mL) had no significant effect on the MIC of any of the tested antimicrobial agents. With the standard inocula (10(6) cfu/mL) of both test strains, all the antimicrobial agents showed bactericidal activity; however, increasing the inoculum size to >10(8) cfu/mL resulted in a reduction in bactericidal activity of all the antimicrobial agents against S. aureus Smith. In contrast, increasing the inoculum size of P. aeruginosa exerted only a minimal influence on the bactericidal activity of fluoroquinolones, but resulted in a reduction in the bactericidal activity of carbapenems. With the standard inoculum size of S. aureus Smith, pre-incubation with fluoroquinolones and carbapenems, except for meropenem, was sufficient to produce PAEs. When the inoculum was increased, the duration of the PAEs of these antimicrobial agents was reduced; however, those of fluoroquinolones were longer than carbapenems. Inoculum size had a greater influence on the in vivo efficacy of carbapenems than that of fluoroquinolones. CONCLUSIONS: Our results suggest that decreased bactericidal activity, or the in vitro PAE of carbapenems and fluoroquinolones, is related to the reduced in vivo protective effect against infection caused by high inoculum with S. aureus or P. aeruginosa.

Animals↗

PubMed2005

Differential effects of beta-lactams on human IFN-gamma activity.

OBJECTIVES: To investigate whether a range of beta-lactam antibiotics conjugate to and hence reduce the activity of IFN-gamma, as has been shown for penicillin G. A selection of penicillins, cephalosporins, a monobactam (aztreonam), a beta-lactamase inhibitor (clavulanic acid), a carbapenem (meropenem) and the non-beta-lactam penicillin derivative d-penicillamine were tested for their effect on IFN-gamma activity. METHODS: Following exposure to a range of concentrations of these compounds, for varying lengths of time, IFN-gamma activity was assayed by induction of CD54 on the surface of the lung epithelial cell line A549, utilizing an ELISA. RESULTS: Clavulanic acid, cefoxitin and cefaloridine were the most potent inhibitors of IFN-gamma activity, followed by cefotaxime, ceftriaxone and phenoxymethylpenicillin. Ampicillin was less inhibitory than penicillin G, whilst meropenem and aztreonam had the least effect and d-penicillamine had no effect. The modulatory effect of these compounds was not due to a direct effect on CD54 induction. Unlike freshly prepared drugs, aged preparations of penicillin G and clavulanic acid had no significant effect on IFN-gamma activity. CONCLUSIONS: beta-Lactams differ in their capacity to modulate human IFN-gamma activity. This finding may have implications for the immunomodulatory effects of beta-lactams and for the design both of beta-lactams that do not affect the immune system and those which may be used therapeutically to target cytokine action.

Anti-Bacterial Agents↗

PubMed2001

Continuous beta-lactam antibiotic therapy in a double-lung transplanted patient with a multidrug-resistant Pseudomonas aeruginosa infection.

BACKGROUND: It is well known that the bactericidal effect of beta-lactam antibiotics is closely related to the time which the serum concentration of the antibiotic remains above the minimal inhibitory concentration of the target pathogen. Thus, the optimal administration of beta-lactam antibiotics would be the continuous infusion of the drug. METHODS: We present a case report with a critically ill double-lung transplanted patient with pneumonia due to a multidrug-resistant Pseudomonas aeruginosa who received continuously 8 g meropenem/24 hr. Based on a previous pharmacokinetic study showing that continuous infusion of meropenem is at least equivalent to intermittent administration this case report is reported to demonstrate the clinical efficacy of continuous infusion. RESULTS: C-reactive protein and pneumonia decreased rapidly when clinical conditions were improved significantly. Continuous administration of meropenem did not interfere with cyclosporine, no side effects were seen, and the patient's renal function was not impaired during the whole period of treatment. CONCLUSION: The continuous administration of beta-lactam antibiotics is a powerful application in critically ill patients to intensify antimicrobial therapy.

Anti-Bacterial Agents↗

PubMed1999

In vitro assessment of colistin's antipseudomonal antimicrobial interactions with other antibiotics.

OBJECTIVE: To study the interactions of colistin (MIC 2 mg/L) at concentrations of 0.5 and 5 mg/L with ceftazidime (1 and 75 mg/L, MIC 0.5 mg/L), aztreonam (1 and 30 mg/L, MIC 0.12 mg/L), meropenem (1 and 25 mg/L, MIC 0.03 mg/L), gentamicin (1 and 10 mg/L, MIC 2 mg/L), piperacillin (5 and 100 mg/L, MIC 4 mg/L) and ciprofloxacin (0.25 and 4 mg/L, MIC 1 mg/L) using a representative strain of Pseudomonas aeruginosa isolated from a cystic fibrosis patient. METHODS: The method used was a bacterial time kill curve with single agents and combinations. Using inocula of 106 CFU/mL, multiple sampling was performed over 6 h and in triplicate. The AUBKC of the time versus viable count curve, with single agents and combinations of agents, was taken as the endpoint for comparison. RESULTS: For colistin plus ceftazidime, colistin plus aztreonam, colistin plus meropenem and colistin plus ciprofloxacin, the pattern was for all the combinations (high or low concentrations) to produce smaller AUBKCs than single agents. In experiments using a bacteriostatic agent such as ceftazidime, the AUBKCs (log CFU/µL per h) for colistin 0.5 mg/L or 5 mg/L alone were 32.3±0.8 or 12.7±0.5, and for ceftazidime 1 mg/L or 75 mg/L alone they were 24.3±1.5 or 20.9±2.7. Combinations of colistin 0.5 mg/L plus either ceftazidime 1 mg/L or 75 mg/L produced AUBKCs of 23.8±1.8 or 16.1 mg/L. Combinations of colistin 5 mg/L plus ceftazidime 1 mg/L or 75 mg/L produced AUBKCs of 12.2±0.8 or 8.7±1.0. The AUBKCs for colistin 5 mg/L plus 75 mg/L are significantly smaller than those for the single agents, indicating synergy. In experiments using the bactericidal agent ciprofloxacin, the AUBKCs (log CFU/mL per h) for colistin 0.5 mg/L or 5 mg/L alone were 33.6±1.9 or 11.2±2.4, and for ciprofloxacin 0.25 mg/L or 4 mg/L alone they were 32.8±1.3 or 5.0±0.7. Combinations of colistin 0.5 mg/L plus either ciprofloxacin 0.25 mg/L or 4 mg/L produced AUBKCs of 32.2±0.9 or 4.3±1.4. Combinations of colistin 5 mg/L plus ciprofloxacin 0.25 mg/L or 4 mg/L produced AUBKCs of 10.7±1.5 or 4.2±0.6. Although combination AUBKCs were smaller than those for single agents, in no case did this reach statistical significance (p<0.05). CONCLUSIONS: These studies indicate that addition of colistin to other antipseudomonal drugs tends to produce smaller AUBKCs and hence greater killing of Pseudomonas aeruginosa than monotherapy.

Journal Article↗

PubMed2005

Antimicrobial activity of doripenem (S-4661): a global surveillance report (2003).

The spectrum of activity and potency of doripenem, a broad-spectrum parenteral carbapenem currently in clinical development, was evaluated using 16 008 clinical bacterial isolates collected as part of an international surveillance project during 2003. Using reference broth microdilution methods, doripenem was found to be highly active against oxacillin-susceptible Staphylococcus aureus and coagulase-negative staphylococci (2705 and 297 isolates, respectively; MIC90s 0.06 mg/L), with a potency greater than that of other carbapenem antibiotics. Against enterococci (1474 isolates), with the exception of Enterococcus faecium, doripenem displayed modest activity (MIC50 4). Doripenem was among the most potent agents tested against Streptococcus pneumoniae, viridans group streptococci and beta-haemolytic streptococci (885, 140 and 397 isolates; MIC(90)s 0.5, 0.5 and 0.03 mg/L, respectively). For Enterobacteriaceae (> 6200 isolates), doripenem was four- to 32-fold more active than imipenem against wild-type isolates (MIC90s 0.03-0.5 mg/L). MIC90s for confirmed extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae (121 and 155 isolates; 0.06 and 0.12 mg/L, respectively) were two-fold higher than for wild-type isolates. Doripenem was also active against Citrobacter spp., Enterobacter spp. and Serratia spp. (MIC90s 0.06-0.25 mg/L), including ceftazidime-resistant isolates. Doripenem and meropenem were the most active agents among all beta-lactams against Pseudomonas aeruginosa (829 isolates; MIC50/90s 0.5/8 and 0.5/16 mg/L, respectively), whereas doripenem and imipenem were the most active agents against Acinetobacter spp. (155 isolates; MIC50/90s 0.5/4 and <or= 0.5/2 mg/L, respectively). Doripenem was slightly more potent (MIC50 2 mg/L) than ertapenem and imipenem (MIC50 4 mg/L), and had a potency similar to that of meropenem (MIC50 2 mg/L), against Burkholderia cepacia (20 isolates). Both Haemophilus influenzae (1824 isolates) and Moraxella catarrhalis (108 isolates), including beta-lactamase-positive isolates, were susceptible to doripenem (MIC90s 0.25 and 0.03 mg/L, respectively). Doripenem displays the favourable characteristics of other carbapenems, and appears to offer certain advantages in terms of potency, spectrum and beta-lactamase stability when compared with some carbapenems used currently to treat nosocomial infections.

Anti-Bacterial Agents↗

PubMed2007

The contribution of pharmacokinetic-pharmacodynamic modelling with Monte Carlo simulation to the development of susceptibility breakpoints for Neisseria meningitidis.

This study used pharmacokinetic-pharmacodynamic (PK-PD) modelling and MICs of 15 antimicrobial agents, derived from testing a large international culture collection, to assist in the development of interpretative criteria, i.e., breakpoints, for Neisseria meningitidis. PK parameters, protein binding, percentage penetration into cerebrospinal fluid (CSF), and the variability of these values, were extracted from the published literature for the 15 agents. PK-PD parameters have not been developed specifically for N. meningitidis in animal or human studies. Thus, it was necessary to invoke PK-PD targets from other organisms that cause infections at similar sites. The PK-PD targets utilised were: time above the MIC for at least 50% of the dosing interval for all beta-lactams, chloramphenicol, sulphafurazole and trimethoprim-sulphamethoxazole; an AUC/MIC ratio of >or=25 for the tetracyclines and macrolides; and an AUC/MIC ratio of >or=125 for the fluoroquinolones. A 10 000-subject Monte Carlo simulation was designed with the usual dosing regimens of each antimicrobial agent at MIC values of 0.03-64 mg/L in both serum and CSF. The PK-PD breakpoint was defined as the MIC at which the calculated target attainment was >or=95%. Using these assumptions, the proposed PK-PD breakpoints were: azithromycin, 0.125 mg/L; doxycycline, 0.25 mg/L; cefotaxime, ciprofloxacin and levofloxacin, 0.5 mg/L; penicillin G, meropenem, rifampicin, tetracycline and minocycline, 1 mg/L; chloramphenicol and sulphafurazole, 2 mg/L; and ampicillin, ceftriaxone and trimethoprim-sulphamethoxazole, 4 mg/L. Proposed PK-PD breakpoints applicable to CSF were: penicillin and cefotaxime, 0.06 mg/L; rifampicin, 0.125 mg/L; ceftriaxone, meropenem and trimethoprim-sulphamethoxazole, 0.25 mg/L; ampicillin, 0.5 mg/L; and chloramphenicol, 1 mg/L.

Animals↗

PubMed1998

Carbapenem-induced endotoxin release in gram-negative bacterial sepsis rat models.

The carbapenem-induced endotoxin release was evaluated using experimental models of gram-negative bacterial sepsis in Wistar rats. Infections with Escherichia coli, Serratia marcescens, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus vulgaris and Proteus mirabilis resulted in an increase of the plasma endotoxin concentration after treatment with ceftazidime and carbapenems including imipenem, panipenem, meropenem and biapenem. Except for P. aeruginosa, the plasma endotoxin concentrations after carbapenem treatment were significantly lower than those after ceftazidime treatment. It is noteworthy that treatment of P. aeruginosa sepsis with meropenem or biapenem induced significantly more endotoxin release than other carbapenems and the endotoxin concentrations induced by these carbapenems reached those of ceftazidime treatment. The plasma endotoxin concentrations appeared to correlate with the reduction of platelet counts and the elevation of both glutamic oxaloacetic transaminase and glutamic pyruvic transaminase values.

Animals↗

PubMed2004

[Campylobacter fetus subsp. fetus sepsis: a case report and review of the literatures in Japan].

We report a 32-year-old female with eating disorder whose body weight was only 20 kg. She was admitted to the hospital with severe low nutrition, low proteinemia, liver dysfunction, hypokalemia and hypoglycemia. On the third hospital day, she had a high fever and Campylobacter fetus subsp. fetus (C. fetus) was isolated from the blood. After treatment with meropenem (1 g/day) intravenous drip injection, her condition improved. C. fetus sepsis is not common disease in Japan. A review of 37 cases of this disease in Japan revealed that the age range of adult patients was 20 to 60 years old. The male-to-female ratio was 4.6 to 1.0. Seventy-eight percent of the patients had underlying diseases which were composed of 11 patients with liver disease, 6 patients with blood dyscrasia and some with diabetes mellitus, heart disease, other malignant tumor and collagen disease. There was no case with eating disorder. All apparent sources of infection in Japan originate from eating raw food. Gastrointestinal symptoms were observed in only 16% of the patients. Recent recommendations for the treatment of C. fetus sepsis are to use gentamicin, imipenem and meropenem. Some strains of C. fetus have resistance to erythromycin, ciprofloxacin. The mortality of this infection is 14% in Japan.

Adult↗

PubMed2006

Diversity of ampicillin resistance genes and antimicrobial susceptibility patterns in Haemophilus influenzae strains isolated in Korea.

By Etest determination of the susceptibilities of 229 Haemophilus influenzae strains isolated in Korea to 10 antibiotics, the isolates were found to be antibiotic nonsusceptible in the following order: ampicillin (58.1%), trimethoprim-sulfamethoxazole (52%), cefaclor (41.1%), clarithromycin (25.8%), chloramphenicol (14.0%), amoxicillin-clavulanic acid (13.5%), meropenem (11.7%), cefixime (10.9%), cefuroxime (9.2%), and levofloxacin (1.3%). The prevalences of each resistance class were 23.6% for beta-lactamase-negative ampicillin-susceptible (BLNAS) strains; 37.6% for strains with the TEM-1 type beta-lactamase gene; 1.3% for strains with the ROB-1 type beta-lactamase gene; 29.3% for the beta-lactamase-negative ampicillin-resistant (BLNAR) strains with a mutation in the ftsI gene, which encodes PBP 3; and 8.3% for beta-lactamase-positive amoxicillin-clavulanate-resistant (BLPACR) strains, which showed both resistance mechanisms (i.e., a beta-lactamase gene and a mutation in the ftsI gene). The MIC50s of all beta-lactams, including cephem and meropenem agents, for the BLNAR strains were two to three times higher than those for the BLNAS strains. This study confirms that the prevalence of BLNAR and BLPACR strains is relatively high and for the first time confirms the presence of H. influenzae strains carrying blaROB-1 in Korea. Even though mutations in another gene(s) might be involved in beta-lactam resistance, these results suggest that mutations in the ftsI gene are important for the development of resistance to beta-lactams in H. influenzae strains in Korea.

Ampicillin Resistance↗

PubMed1990

Biochemical characterization of a beta-lactamase that hydrolyzes penems and carbapenems from two Serratia marcescens isolates.

Reexamination of Serratia marcescens isolates obtained in 1982 revealed two organisms that were resistant to the penem FCE 22101 (MIC, 512 micrograms/ml) and imipenem (MIC, 16 micrograms/ml) and that had slightly reduced susceptibilities to meropenem (MIC, 0.12 micrograms/ml). MICs of these agents for typical S. marcescens isolates were 1 to 8, 0.25 to 0.5, and 0.03 micrograms/ml, respectively. The two isolates were fully susceptible to broad-spectrum cephalosporins, and only one was highly resistant to ampicillin and carbenicillin (MICs, greater than 1,024 micrograms/ml). Both isolates had beta-lactamases that focused at pIs 8.2 and 9.7. The penicillin-resistant isolate additionally produced the TEM-1 enzyme. The enzymes with pIs of 8.2 and 9.7 were separated by cation-exchange chromatography. The pI 8.2 beta-lactamase was a class I enzyme of the type found in most S. marcescens isolates. It was almost inactive against carbapenems and penems, as was the class I enzyme from another S. marcescens strain. The pI 9.7 enzyme hydrolyzed penems and carbapenems rapidly: kcat (turnover number) values for FCE 22101, imipenem, and meropenem were 3.4, 26, and 1% of the kcat value for cephaloridine, respectively; kcat/Km values were 140, 915, and 150% of the kcat/Km value for cephaloridine, respectively. Otherwise, the pI 9.7 enzyme had predominantly penicillinase activity. It was inhibited more readily by clavulanate than by tazobactam and was inactivated by the chelating agents EDTA and ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. Expression of the pI 9.7 enzyme was not associated with any plasmid, and production was not transferred to Escherichia coli K-12 recipients, even after the mobilizing plasmid pUZ8 was inserted into the S. marcecens donor strains.

Carbapenems↗

PubMed1990

Activities of beta-lactam antibiotics against Escherichia coli strains producing extended-spectrum beta-lactamases.

Seven extended-spectrum beta-lactamases related to TEM and four enzymes derived from SHV-1 were transferred to a common Escherichia coli host so that the activity of a variety of beta-lactams could be tested in a uniform genetic environment. For most derivatives, penicillinase activity was 10% or less than that of strains making TEM-1, TEM-2, or SHV-1 beta-lactamase, suggesting that reduced catalytic efficiency accompanied the broader substrate spectrum. Despite this deficit, resistance to aztreonam, carumonam, cefdinir, cefepime, cefixime, cefmenoxime, cefotaxime, cefotiam, cefpirome, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, and E1040 was enhanced. For strains producing TEM-type enzymes, however, MICs of carumonam, cefepime, cefmenoxime, cefotiam, cefpirome, and ceftibuten were 8 micrograms/ml or less. Susceptibilities of cefmetazole, cefotetan, cefoxitin, flomoxef, imipenem, meropenem, moxalactam, temocillin, FCE 22101, and Sch 34343 were unaffected. FCE 22101, imipenem, meropenem, and Sch 34343 were inhibitory for all strains at 1 microgram/ml or less. In E. coli an OmpF- porin mutation in combination with an extended-spectrum beta-lactamase enhanced resistance to many of these agents, but generally by only fourfold. Hyperproduction of chromosomal AmpC beta-lactamase increased resistance to 7-alpha-methoxy beta-lactams but not that to temocillin. When tested at 8 micrograms/ml, clavulanate was more potent than sulbactam or tazobactam in overcoming resistance to ampicillin, while cefoperazone-sulbactam was more active than ticarcillin-clavulanate or piperacillin-tazobactam, especially against TEM-type extended-spectrum beta-lactamases.

Anti-Bacterial Agents↗

PubMed1992

In vitro activity of L-627, a new carbapenem.

The in vitro activity of L-627, a new parenterally administered carbapenem, was compared with those of imipenem, meropenem, FCE 22101 (a penem), ceftazidime, and ceftriaxone. L-627 was active against members of the family Enterobacteriaceae (MIC for 90% of strains tested [MIC90] ranging from 0.03 to 4 micrograms/ml). L-627 displayed activity equal to that of meropenem against Pseudomonas aeruginosa (MIC90, 2 micrograms/ml), although, as with other carbapenems, the antipseudomonal activity was reduced against D2-deficient strains. Staphylococci and streptococci were susceptible (MIC90 of 1.0 micrograms/ml for Staphylococcus aureus and 0.015 micrograms/ml for group A streptococci). L-627 also had activity against anaerobic bacteria (MIC90, 2.0 micrograms/ml for Bacteroides fragilis). Neisseria gonorrhoeae and Neisseria meningitidis were highly susceptible (MIC90, 0.06 micrograms/ml), and against the common respiratory pathogens (Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis), the MIC90s were less than or equal to 2.0 micrograms/ml. The protein binding of L-627 ranged from 13.8 to 22%, depending on the concentration. The presence of human serum had little effect on the MIC or MBC of L-627. These results suggest that L-627 merits further study in the treatment of infections caused by a wide range of pathogens.

Bacteria↗

PubMed1993

Transient carbapenem resistance induced by salicylate in Pseudomonas aeruginosa associated with suppression of outer membrane protein D2 synthesis.

Pseudomonas aeruginosa PAO1 showed increased phenotypic resistance to imipenem, panipenem, and biapenem specifically in the presence of salicylate. The antipseudomonal activity of carbapenems was reduced in proportion to the concentration of salicylate. This resistance was transient and nonheritable. The synthesis of the outer membrane protein D2 (OprD or OprD2) in P. aeruginosa PAO1 was inhibited by 4 to 32 mM salicylate in the bacterial growth medium, whereas no changes in any other outer membrane proteins were observed. These results indicate that salicylate suppresses the synthesis of OprD and therefore reduces the antipseudomonal activity of carbapenems. Under these conditions, one carbapenem--meropenem--is still active against P. aeruginosa, which indicates that meropenem can pass through the outer membrane via both the D2 channel and another undefined route(s).

Anti-Arrhythmia Agents↗

PubMed1993

Penicillin-binding proteins of Rhodococcus equi: potential role in resistance to imipenem.

Rhodococcus equi is a gram-positive coccobacillus which, like other members of the order Actinomycetales, is increasingly reported as an opportunistic pathogen in patients with AIDS. The use of combinations of antibiotics that include imipenem (IMP) has been suggested for the treatment of patients infected with R. equi. An antagonism between IMP, meropenem, cefoxitin, ceftriaxone, moxalactam, and oxacillin and other beta-lactams, such as penicillin, amoxicillin, cephalothin, and ticarcillin, was detected in vitro both on Mueller-Hinton agar and in broth for all 10 IMP-susceptible R. equi strains examined. To study the mechanism of the antagonism between beta-lactams, a mutant with decreased susceptibility to IMP (isolate IpR) was selected in vitro from a susceptible clinical isolate of R. equi (isolate IpS). IpR exhibited decreased susceptibility to IMP, meropenem, cefoxitin, ceftriaxone, moxalactam, and oxacillin but not to penicillin, amoxicillin, cephalothin, or ticarcillin. No beta-lactamase was found in IpS, IpS cultured with antagonistic beta-lactams, or IpR strains. Labeling of penicillin-binding proteins (PBPs) revealed four PBPs with molecular masses of ca. 59, 56, 43, and 26 kDa in IpS. In IpR, PBP 3 disappeared and was replaced by PBP 3a of 40 kDa. The 50% saturation of PBP 3 and PBP 3a by the carbapenems correlated with the MICs of these antibiotics, respectively, for IpS and IpR strains. However, PBP 3a was not detected in IpS when IpS was cultured in the presence of beta-lactams, with which antagonism was observed. The present work describes the PBPs of R. equi and reports that IMP resistance in R. equi is related to an altered PBP pattern.

Anti-Bacterial Agents↗

PubMed1995

Relationship between structure and convulsant properties of some beta-lactam antibiotics following intracerebroventricular microinjection in rats.

The epileptogenic activities of several beta-lactam antibiotics were compared following their intracerebroventricular administration in rats. Different convulsant potencies were observed among the various beta-lactam antibiotics tested, but the epileptogenic patterns were similar. The patterns consisted of an initial phase characterized by wet-dog shakes followed by head tremor, nodding, and clonic convulsions. After the largest doses of beta-lactam antibiotics injected, clonus of all four limbs and/or the trunk, rearing, jumping, falling down, escape response, transient tonic-clonic seizures, and sometimes generalized seizures were observed, followed by a postictal period with a fatal outcome. At a dose of 0.033 mumol per rat, cefazolin was the most powerful epileptogenic compound among the drugs tested. It was approximately three times more potent than benzylpenicillin in generating a response and much more potent than other cephalosporins, such as ceftriaxone, cefoperazone, and cefamandole. No epileptogenic signs were observed with equimolar doses of cefotaxime, cefonicid, cefixime, and ceftizoxime in this model. The more convulsant compounds (i.e., cefazolin and ceftezole) are both characterized by the presence of a tetrazole nucleus at position 7 and show a marked chemical similarity to pentylenetetrazole. Imipenem and meropenem, the two carbapenems tested, also showed epileptogenic properties, but imipenem was more potent than meropenem, with a convulsant potency similar to those of ceftezole and benzylpenicillin. In addition, the monobactam aztreonam possessed convulsant properties more potent than those of cefoperazone and cefamandole. This suggest that the beta-lactam ring is a possible determinant of production of epileptogenic activity, with likely contributory factors in the substitutions at the 7-aminocephalosporanic or 6-aminopenicillanic acid that may increase or reduce the epileptogenic properties of the beta-lactam antibiotics. While the structure-activity relationship was also investigated, there seem to be no convincing correlations among the rank order of lipophilicities and the convulsant potencies of the compounds studied. The lack of marked convulsant properties of cefixime, cefonicid, cefuroxime, and cephradine suggests that these antibiotics may interact with a binding site which is different from that by which the beta-lactam antibiotics exert their convulsant effects or may demonstrate a reduced affinity for the relevant site(s).

Animals↗

PubMed1995

Target for bacteriostatic and bactericidal activities of beta-lactam antibiotics against Escherichia coli resides in different penicillin-binding proteins.

The relationship between cell-killing kinetics and penicillin-binding protein (PBP) saturation has been evaluated in the permeability mutant Escherichia coli DC2 in which the antimicrobial activity of beta-lactams has been described as being directly related to the extent of saturation of the PBP target(s). Saturation of a single PBP by cefsulodin (PBP 1s), mecillinam (PBP 2), and aztreonam (PBP 3) resulted in a slow rate of killing (2.5-, 1.5-, and 0.8-log-unit decreases in the number of CFU per milliliter, respectively, in 6 h). Saturation of two of the three essential PBPs resulted in a marked increase in the rate of killing, which reached the maximum value when PBPs 1s and 2 were simultaneously saturated by a combination of cefsulodin and mecillinam (4.7-log-unit decrease in the number of CFU per milliliter in 6 h). Inactivation of all three essential PBPs by the combination of cefsulodin, mecillinam, and aztreonam further increased the killing kinetics (5.5-log-unit decrease in the number of CFU per milliliter), and this was not significantly changed upon additional saturation of the nonessential PBPs 5 and 6 by cefoxitin. Similar relationships between PBP saturation and killing kinetics were obtained with imipenem and meropenem at concentrations which inhibited only one PBP (PBP 2), only two PBPs (PBP 1s and 2), or all three essential PBPs. Saturation of one or more PBPs also resulted in a different rate of bacteriolysis, the highest rate being obtained by the cefsulodin-mecillinam combination and by 5 micrograms of either imipenem or meropenem per ml. All of these conditions caused saturation of PBP 2 and saturation or extensive binding of PBP 1s. However, none of these conditions caused determined the fastest possible rate of killing, which occurred only when all three essential PBPs were saturated. It was concluded that the actual killing effect of beta-lactams is reflected by killing rates that approach the fastest possible rate for the given microorganism and that the targets for the bactericidal activity are precisely those PBPs whose saturation or binding occurs under conditions.

Anti-Bacterial Agents↗

PubMed1995

In vitro and in vivo antibacterial activities of BO-2727, a new carbapenem.

BO-2727, a new injectable carbapenem, was evaluated for its in vitro and in vivo antibacterial activities in comparison with those of biapenem, meropenem, imipenem, cefpirome, and ceftazidime. BO-2727 had activity comparable to that of imipenem against methicillin-susceptible staphylococci and streptococci, with MICs at which 90% of strains tested (MIC90s) are inhibited being equal to 0.5 microgram/ml or less. Against methicillin-resistant staphylococci, BO-2727 was the most active among the antibiotics tested, with MIC90s ranging from 4 to 8 micrograms/ml. BO-2727 was highly active against members of the family Enterobacteriaceae, Haemophilus influenzae, and Moraxella catarrhalis, with MIC90s ranging from 0.006 to 2 micrograms/ml. BO-2727 was also highly active against Pseudomonas aeruginosa (imipenem-susceptible strains), for which the MIC90 was 2 micrograms/ml, which was lower than those of imipenem, cefpirome, and ceftazidime and comparable to those of biapenem and meropenem. Differences in activity between BO-2727 and the other carbapenems against imipenem-resistant P. aeruginosa were particularly striking (MIC90, 8 micrograms/ml). Furthermore, BO-2727 displayed a high degree of activity against many of the ceftazidime-, ciprofloxacin-, and/or gentamicin-resistant isolates of P. aeruginosa. The in vivo efficacy of BO-2727 against experimental septicemia caused by gram-positive and gram-negative bacteria, including methicillin-resistant Staphylococcus aureus and imipenem-resistant P. aeruginosa, reflected its potent in vitro activity and high levels in plasma.

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