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PubMed1993

In-vitro evaluation of the four beta-lactamase inhibitors: BRL42715, clavulanic acid, sulbactam, and tazobactam.

The in-vitro synergic activities of BRL42715, a new beta-lactamase inhibitor, clavulanic acid, sulbactam, and tazobactam combined with ampicillin, piperacillin, cephalothin, or cefoperazone were tested against various bacteria producing known types of beta-lactamase. BRL42715 showed the best synergistic activity among the inhibitors tested against strains producing penicillinases of type I, II, III, V, and that from Klebsiella pneumoniae, cephalosporinases, and oxyiminocephalosporinases (except that from Klebsiella oxytoca). Clavulanic acid combined with the beta-lactams tested showed the best synergic activity of the inhibitors against strains producing type IV penicillinase and oxyiminocephalosporinase from K. oxytoca. The 50% inhibitory doses of BRL42715 were superior to those of clavulanic acid against various types of beta-lactamases except for type IV penicillinase and the oxyiminocephalosporinase from K. oxytoca. The inhibitory activity of BRL42715 against cephalosporinases from various bacteria was 10(4) to 10(6)-fold greater than that of clavulanic acid. The synergic effects of BRL42715 and clavulanic acid on the activity of piperacillin were compared against six clinical isolates of bacteria resistant to piperacillin. The synergic activity of BRL42715 was greater than that of clavulanic acid in all six isolates.

Anti-Bacterial Agents↗
PubMed1994

Characterization of a beta-lactamase from Clostridium clostridioforme.

A beta-lactamase-producing strain of Clostridium clostridioforme isolated from human peritoneal fluid was examined by MIC testing and enzyme characterization. MICs of penicillins (64-512 mg/L) were higher than those of cephalosporins (8-128 mg/L); the strain was susceptible to cefoxitin (8 mg/L) and imipenem (1 mg/L). No enhancement of cephalosporin activity occurred when clavulanate was also added, but a limited degree of enhancement of penicillin activity (resulting in beta-lactam MICs higher than available NCCLS breakpoints) occurred when clavulanate, sulbactam or tazobactam was added simultaneously. By contrast, addition of BRL 42715 with amoxycillin, ticarcillin or piperacillin led to a drop in beta-lactam MICs from 512 to < or = 1 mg/L, with a drop from 64 to 1 mg/L when BRL 42715 was added with cefotaxime. All inhibitors were added at fixed concentrations of 2 mg/L. As determined spectrophotometrically, the enzyme hydrolysed penicillin G, cloxacillin and piperacillin (Vmax values (%) 372, 1816, 1001, respectively relative to cephaloridine) more efficiently than cephalosporins (69-191, with cephaloridine as 100%). Km values (microM) varied between 30-308 microM (penicillins) and 2-20 microM (cephalosporins). Relative enzyme efficiency (relative Vmax/Km with cephaloridine as 100) varied from 21-100 (cephalosporins) and 8-77 (penicillins). IC50 values (microM) with nitrocefin, piperacillin and penicillin G substrates (concentrations 20, 100 and 20 microM, respectively) were > 1000, 7, 3.5 (clavulanate); > 1000, 300, 59 (sulbactam), > 1000, 29, 7.7 (tazobactam); 0.0004, 0.001, 0.0018 (BRL 42715). The enzyme was not inhibited by EDTA, cefoxitin, cloxacillin or aztreonam, but was inhibited by pCMB.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Bacterial Agents↗
PubMed1996

Imipenem and cephem resistant Pseudomonas aeruginosa carrying plasmids coding for class B beta-lactamase.

From October 1988 to January 1992, nine isolates of Pseudomonas aeruginosa carrying transferable plasmids encoding imipenem-hydrolyzing beta-lactamase (pI = c. 9.5) were recovered from nine different patients in a neurosurgical ward of a hospital in Japan. The beta-lactamase activities of the sonicated extracts from the transconjugants were inhibited by EDTA and this was partially reversible by the addition of zinc cation. The substrate specificity and pI of the beta-lactamase were similar to those of the metallo beta-lactamases from P. aeruginosa and Serratia marcescens TN9106. All strains were resistant to imipenem, carbenicillin and antipseudomonal cephems including ceftazidime, cefsulodin, cefpirome, while four and five strains were susceptible to piperacillin and aztreonam, respectively. Both low level imipenem resistance and high level cephem resistance were co-transferred with the production of metallo beta-lactamase, while resistance to piperacillin, aztreonam, and high level imipenem-resistance were not selected. Production of chromosomal cephalosporinase in piperacillin resistant strains was derepressed, and production of outer membrane protein of D2 was diminished in highly imipenem resistant strains. Six strains were isolated in 1991, and the amounts of antipseudomonal agents, especially imipenem, used in the neurosurgical ward increased markedly in this year. Only three of the nine isolates had the same serotype, pyocin type and phage type. Our results suggest that the repeated isolation of imipenem and cephem-resistant P. aeruginosa producing metallo beta-lactamase was related to the high usage of antipseudomonal beta-lactam antibiotics such as imipenem, and was exacerbated by the dissemination of a plasmid.

Anti-Infective Agents↗
PubMed1996

In-vitro susceptibility of Klebsiella oxytoca strains to 13 beta-lactams in the presence and absence of beta-lactamase inhibitors.

The susceptibility of Klebsiella oxytoca isolates was tested by an agar diffusion method (167 strains collected in six countries) and an agar dilution method (38 strains). Multivariate analysis of inhibition zone diameters by principal component analysis clearly individualised four susceptibility patterns, including the phenotype of strains overproducing beta-lactamase and resistant to penicillins, first-generation cephalosporins, cefuroxime and aztreonam, but susceptible to ceftazidime. This phenotype was different from that conferred by plasmid-mediated extended-spectrum beta-lactamases; strains expressing these enzymes were also resistant to ceftazidime and cefotaxime. The bla(oxy) gene from K. oxytoca was introduced into Escherichia coli and K. oxytoca recipients and conferred increased resistance to beta-lactams in the recipient cells. Clavulanic acid was effective in association with piperacillin (MIC decreased 36-fold), ceftriaxone (35-fold) and aztreonam (19-fold) against overproducing strains, in spite of a relatively high IC50 (0.3 microM). Sulbactam (IC50, 400 microM) was ineffective in this context when combined with piperacillin (MIC decreased 1.5-fold), ceftriaxone (1.6-fold) and aztreonam (1.6-fold). The inhibitory activity of tazobactam (IC50, 8.2 microM) was heterogeneous depending on the strain and the beta-lactam with which it was combined. When combined with piperacillin or ceftriaxone little potentiation in antibiotic activity occurred (MIC decreased 3.9-fold and 4.5-fold, respectively); however, tazobactam plus aztreonam resulted in a 50-fold decrease in MIC of antibiotic.

Enzyme Inhibitors↗
PubMed2000

In vitro activities of parenteral beta-lactam antimicrobials against TEM-10-, TEM-26- and SHV-5-derived extended-spectrum beta-lactamases expressed in an isogenic Escherichia coli host.

The in vitro activities were determined and time-kill studies of cefepime, imipenem-cilastatin, meropenem and piperacillin-tazobactam were performed against SHVand TEM-derived extended-spectrum beta-lactamases (ESBLs). Sequence-confirmed SHV-5, TEM-10 and TEM-26 beta-lactamases were transferred into Escherichia coli C600N by conjugation. Imipenem and meropenem were more active (MIC range 0. 0625-0.25 mg/L) than cefepime (MIC range 2-8 mg/L) and piperacillin-tazobactam (MIC range 8-32 mg/L). Regrowth of strains expressing TEM-10 and TEM-26 was noted at all cefepime and piperacillin-tazobactam concentrations studied. Imipenem-cilastatin and meropenem demonstrated rapid, sustained bactericidal activity uninfluenced by the type of ESBL expressed.

Conjugation, Genetic↗
PubMed2004

Pharmacodynamic study of beta-lactams alone and in combination with beta-lactamase inhibitors against Pseudomonas aeruginosa possessing an inducible beta-lactamase.

OBJECTIVES: The antimicrobial efficacies of beta-lactams alone and in combination with beta-lactamase inhibitors were investigated by applying a rabbit tissue cage model against a strain of Pseudomonas aeruginosa with an inducible AmpC (iAmpC) beta-lactamase. METHODS: Two sterilized golf Wiffle balls were surgically implanted in the rabbit dorsal cervical area. After 4 weeks, Wiffle balls had filled with tissue cage fluid (TCF), in which 2 mL of 10(6) cfu/mL of the test isolate were inoculated. To achieve the same T > MIC as in humans, 400 mg/kg of the beta-lactams alone and in combination was administered twice a day via subcutaneous injection. The dosing regimens were as follows: piperacillin alone, 4 g piperacillin/0.5 g tazobactam; ticarcillin alone, 3 g ticarcillin/0.1 g clavulanate; and 3 g ticarcillin/ 0.3 g clavulanate. RESULTS: The changes in bacterial counts (log cfu/mL) after the 3 day treatments were as follows: 1.03 +/- 0.97 (control), -1.31 +/- 0.61 (piperacillin), -2.81 +/- 0.53 (4 g piperacillin/0.5 g tazobactam), -1.61 +/- 0.68 (ticarcillin), -3.42 +/- 0.75 (3 g ticarcillin/0.1 g clavulanate) and -1.65 +/- 1.47 log cfu/mL (3 g ticarcillin/0.3 g clavulanate). AmpC induction by high-dose clavulanate was observed in rabbit TCF, and was confirmed by the in vitro induction study. CONCLUSIONS: The study indicated that tazobactam significantly enhanced the antibacterial activity of piperacillin against iAmpC P. aeruginosa; clavulanate had synergy with the antibacterial activity of ticarcillin at low concentration, but had no effect on ticarcillin at high concentration due to AmpC induction by clavulanate.

Animals↗
PubMed2001

Effect of mono-dose intraperitoneal cecropins in experimental septic shock.

OBJECTIVE: To investigate the efficacy of three cecropins, cecropin A, cecropin B, and cecropin P1, in preventing lethality in a rat model of septic shock. DESIGN: Prospective, randomized, controlled animal study. SETTING: Research laboratory in a university hospital. SUBJECTS: Adult male Wistar rats. INTERVENTIONS: Rats were given an intraperitoneal injection of 2 x 10(10) colony forming units of Escherichia coli, with the exception of the uninfected control group (C0). Animals were randomized to receive, immediately after bacterial challenge, intraperitoneally isotonic sodium chloride solution (untreated control group C1), 1 mg/kg cecropin A (group 2), 1 mg/kg cecropin B (group 3), 1 mg/kg cecropin P1 (group 4), 20 mg/kg imipenem (group 5), or 60 mg/kg piperacillin (group 6). Each group included 15 animals. MEASUREMENTS AND MAIN RESULTS: We measured bacterial growth (quantitative agar culture) in abdominal exudate and plasma, endotoxin and tumor necrosis factor-alpha concentration in plasma, and mortality. Results were evaluated at 48 hrs after inoculation. Cecropins, piperacillin, and imipenem significantly reduced the lethality and the number of E. coli in abdominal fluid compared with saline treatment. In addition, cecropin B significantly decreased the lethality compared with piperacillin treatment. Finally, only cecropins significantly reduced plasma endotoxin concentration. CONCLUSIONS: Mono-dose cecropin treatment prevents bacterial growth, endotoxemia, and mortality in rats with septic shock. Cecropin B was the most effective compound in reducing all variables measured.

Animals↗
PubMed2006

Risk of emergence of Pseudomonas aeruginosa resistance to beta-lactam antibiotics in intensive care units.

OBJECTIVE: The emergence of Pseudomonas aeruginosa resistance to antimicrobial drugs is frequent in intensive care units and may be correlated with the use of some specific drugs. The purpose of our study was to identify a relationship between the use of various beta-lactam antibiotics and the emergence of resistance and to characterize the mechanism of resistance involved. DESIGN: We conducted an open prospective study over a 3-yr period by including all patients in whom P. aeruginosa had been isolated from one or more specimens: bronchial aspiration, blood cultures, catheters, and urinary cultures. SETTING: General intensive care unit. PATIENTS: One hundred and thirty-two intensive care unit patients. INTERVENTIONS: The antibiotics studied were amoxiclav, piperacillin-tazobactam, cefotaxime, ceftazidime, cefepim, and imipenem. The mechanisms of resistance studied were production of penicillinase or cephalosporinase, nonenzymatic mechanisms, and loss of porin OprD2. Analysis was performed using Cox proportional-hazard regression with time-dependant variables. MEASUREMENTS AND MAIN RESULTS: Forty-two strains became resistant, 30 to one antibiotic, nine to two, and three to three, leading to the study of 57 resistant strains. Imipenem (hazard ratio 7.8; 95% confidence interval, 3.4-18.1), piperacillin-tazobactam (hazard ratio 3.9; 95% confidence interval, 1.3-11.9), and cefotaxim (hazard ratio 9.3; 95% confidence interval, 2.9-30.2) were strongly linked to the emergence of resistance. The use of imipenem (p<.0001) was associated with the loss of porin OprD2. Thirty-six strains from nine patients, assayed by pulsed-field gel electrophoresis, showed that for any one patient, all the strains were genetically related. CONCLUSIONS: Our results show that there is a high risk of the emergence of drug resistance during treatment with cefotaxime, imipenem, and piperacillin-tazobactam. This has to be taken into account in the therapeutic choice and in the patient's surveillance.

Aged↗
PubMed2003

Neutralization of endotoxin in vitro and in vivo by Bac7(1-35), a proline-rich antibacterial peptide.

Lipopolysaccharides (LPS), or endotoxins, are structural components of gram-negative bacteria implicated in the pathogenesis of septic shock. In this study the antiendotoxin activity of Bac7(1-35), a synthetic peptide based on the sequence of a proline-rich antibacterial peptide from bovine neutrophils, was investigated in vitro and in an experimental rat model of gram-negative septic shock. The ability of Bac7(1-35) to bind LPS from Escherichia coli O111:B4 was determined using a sensitive Limulus chromogenic assay. In the in vivo study, adult male Wistar rats were given an intraperitoneal injection of 1 x 10(9) colony-forming units of E. coli ATCC 25922. All animals were randomized to receive intraperitoneally 1 mg/kg Bac7(1-35), or isotonic sodium chloride solution (control group C1), 60 mg/kg of piperacillin and 1 mg/kg polymyxin B, 1 mg/kg of polymyxin B plus 60 mg/kg of piperacillin, and 1 mg/kg of Bac7(1-35) plus 60 mg/kg of piperacillin. Each group included 15 animals. Bac7(1-35) was found to completely inhibit the LPS procoagulant activity at approximately 10 microM peptide concentration, as determined by in vitro LAL chromogenic assay. Treatment with Bac7(1-35) resulted in significant decrease in plasma endotoxin levels and lethality rates compared with saline injected control animals. No statistically significant differences were noted between Bac7(1-35) and polymyxin B in reducing all variables measured. These results provide evidence for the ability of Bac7(1-35) to effectively bind LPS and protect animals from lethal effects of this molecule, and point to its potential use for the treatment of endotoxin-induced septic shock.

Amino Acid Sequence↗
PubMed1980

Antigenicity of semisynthetic penicillin preparations to evoke systemic anaphylactic reactions in animal models.

Four commercially available penicillin preparations (benzylpenicillin, aminobenzylpenicillin, carbenicillin and sulbenicillin) and two kinds of the new semisynthetic penicillin preparations (mezlocillin and piperacillin) evoked systemic anaphylactic reactions in guinea pigs immunized with one of the following penicillin-Ascaris extract (As) conjugates in aluminum hydroxide gel (alum), i.e., benzylpenicilloyl (BPO)-As, aminobenzylpenicilloyl (ABPO)-As, carbenicilloyl (CBPO)-As, sulbenicilloyl (SBPO)-As, mezlocillin-As conjugate (MEZ-As) and piperacillin-As conjugate (PIP-As). The tracheal chains prepared from the tracheas of the guinea pigs immunized with BPO-As, MEZ-As, or PIP-As revealed anaphylactic contractions in vitro on addition of benzylpenicillin, mezlocillin, or piperacillin preparations. These results indicated that the semisynthetic penicillin preparations as well as benzylpenicillin preparation have enough antigenicity to evoke systemic anaphylactic reactions in guinea pigs immunized with penicillin-As conjugate. Such guinea pigs seem to be suitable animals for investigations of penicillin allergy.

Allergens↗
PubMed2005

[A case of sphenoid sinusitis which could be diagnosed by orbital computed tomography after detected Strepotococcus pneumoniae from blood culture].

We report a case of sphenoid sinusitis which could be diagnosed by orbital CT after detecting Strepotococcus pneumoniae from blood culture. A previously healthy 47 year-old Japanese male was admitted to our hospital with severe left-sided headache of 2 days duration. From 9 days before hospitalization (1st day), the patient complained of cough and sputum. On physical examination, his neck was supple and his temperature was 38.3 degrees C. The rest of the examination was normal. A chest radiograph, sinus radiograph, and head computed tomographic (CT) scan without contrast material disclosed no abnormalities. Lumbar puncture was done and cerebrospinal fluid was clear and cell counts and the levels of glucose and protein were normal. The peripheral white blood cell count was 14,400/fl, and the C-reactive protein level was 9.6 mg/dl. After blood, urine, pharyngeal mucus and cerebrospinal fluid cultures were obtained, empirical antibiotic therapy with 2 gms of piperacillin twice daily was begun. He complained sever left-sided retro-orbital headahe on the next day too. The lumbar puncture and head CT scan with contrast material was done again but gave no diagnostic clues. The examinations by the otolaryngologist, ophthalmologist and dentist found no abnormal findings. On the 3rd hospitalized day, Strepotococcus pneumoniae was detected from the blood culture taken on the 1st hospitalized day. A CT scan focused on orbita was done and revealed a low density area of the left sphenoid sinus. The dose of piperacillin was increased to 4 gms twice daily and continued for 24 days. The patient's headache improved and piperacillin was changed to oral levofloxacin 100 mg, three times daily on the 26th day. The medication was stopped on the 73th day. Isolated sphenoid sinusitis is rare, but crtitical complications such as cranial nerve involvement, brain abscess, and bacterial meningitis may happen. It is necessary to also think of sphenoid sinusitis in practices of patients with severe headache.

Headache↗
PubMed1982

Comparative in vitro activities of beta-lactam-tobramycin combinations against Pseudomonas aeruginosa and multidrug-resistant gram-negative enteric bacilli.

Piperacillin was more consistently active than tobramycin, carbenicillin, moxalactam, or ceftriaxone against strains of Pseudomonas aeruginosa isolated from blood cultures and against multidrug-resistant strains. Moxalactam and ceftriaxone were more consistently active than tobramycin, carbenicillin, or piperacillin against multidrug-resistant Enterobacteriaceae. Synergy between beta-lactam antibiotics and tobramycin was frequently observed against strains of P. aeruginosa isolated from blood cultures but not against multidrug-resistant organisms. Piperacillin plus tobramycin was the most active antibiotic combination against P. aeruginosa. Moxalactam plus tobramycin and ceftriaxone plus tobramycin were the most active antibiotic combinations against Enterobacteriaceae.

Anti-Bacterial Agents↗
PubMed1983

Stability of gentamicin, tobramycin, and amikacin in combination with four beta-lactam antibiotics.

The stability of the aminoglycosides gentamicin, tobramycin, and amikacin stored in combination with carbenicillin, piperacillin, cefotaxime, and moxalactam was evaluated at four temperatures (25, 4, -8, and -70 degrees C) over a 3-week period. Amikacin was the most stable of the aminoglycosides and demonstrated no loss of activity when stored with either carbenicillin or piperacillin. Gentamicin and tobramycin were inactivated by carbenicillin and piperacillin at 25 and 4 degrees C, with aminoglycoside activity declining substantially after 8 to 48 h of storage; virtually no loss of gentamicin or tobramycin activity occurred with storage at -8 or -70 degrees C. Cefotaxime and moxalactam produced no degradation of any of the three aminoglycosides.

Amikacin↗
PubMed1984

Comparative in vitro activities of cefpiramide and apalcillin against anaerobic bacteria.

The in vitro activities of two new antimicrobial agents, apalcillin and cefpiramide (SM-1652), were evaluated against 324 strains of anaerobic bacteria. Apalcillin (a penicillin derivative) and cefpiramide (a semisynthetic cephalosporin) were compared with piperacillin, moxalactam, and cefoxitin. Organisms studied included the Bacteroides fragilis group, other Bacteroides species, fusobacteria, clostridia, nonsporeforming gram-positive rods, and anaerobic cocci. Piperacillin was found to be the most active overall, inhibiting 96% of the strains tested at its achievable level in serum (128 micrograms/ml). Apalcillin was comparable in activity to piperacillin, inhibiting 93% of anaerobes tested at this concentration. The other antibiotics inhibited ca. 80% of the strains at 32 micrograms/ml. In terms of activities against particular species, apalcillin was active against 75% of B. fragilis group strains and 97 to 100% of all other anaerobes. Cefpiramide inhibited 37% of B. fragilis group strains at 32 micrograms/ml and 68% at 64 micrograms/ml (a level that may be achievable with this drug). Cefpiramide inhibited 92% of all other anaerobes at 32 micrograms/ml and 95% at 64 micrograms/ml. The clostridia other than Clostridium perfringens were the most resistant (84% inhibited at 32 micrograms/ml and 95% inhibited at 64 micrograms/ml).

Ampicillin↗
PubMed1986

Comparative activities of the beta-lactamase inhibitors YTR 830, clavulanate, and sulbactam combined with ampicillin and broad-spectrum penicillins against defined beta-lactamase-producing aerobic gram-negative bacilli.

The in vitro synergistic activities of the beta-lactamase inhibitors YTR 830, clavulanate, and sulbactam, combined with ampicillin, ticarcillin, mezlocillin, azlocillin, piperacillin, and apalcillin, were determined against 34 strains of members of the Enterobacteriaceae family, Pseudomonas aeruginosa, Aeromonas hydrophila, and Haemophilus influenzae with characterized plasmid or chromosomal beta-lactamases or both. Strains were tested against fixed concentrations of beta-lactamase inhibitors (8 micrograms/ml) combined with doubling dilutions of beta-lactams. Synergy was defined as a fourfold or greater decrease in the MIC of the beta-lactam. Against Enterobacteriaceae producing Richmond and Sykes class III and V plasmid-mediated beta-lactamases, synergy was obtained against most strains with YTR 830- and clavulanate-beta-lactam combinations, with sulbactam being less effective. Against Enterobacteriaceae producing class I chromosomal beta-lactamases, combinations containing YTR 830 or sulbactam were more synergistic than combinations containing clavulanate. Against strains producing class V PSE enzymes, all three inhibitors were synergistic with piperacillin and apalcillin against strains producing PSE-1, -3, and -4 enzymes, while the PSE-2-producing strain was resistant to all inhibitors. YTR 830-beta-lactam combinations were also synergistic against strains producing the novel beta-lactamases OHIO-1, TLE-1, AER-1, and ROB-1. Overall, YTR 830 with piperacillin or apalcillin was the most effective combination.

Ampicillin↗
PubMed1989

In vitro activity of ME1228, a new parenteral cephalosporin.

ME1228 is a new cephalosporin with an iminocarboxymethyl moiety on the acyl side chain and a novel pyridiniumthiomethyl group at position 3 of the bicyclic ring. Its activity was compared with those of ceftazidime, imipenem, piperacillin, and gentamicin. ME1228 inhibited most members of the family Enterobacteriaceae, except for some Enterobacter spp. and Citrobacter freundii, at less than or equal to 0.25 micrograms/ml, and it inhibited gentamicin- and piperacillin-resistant isolates. It had MICs for Pseudomonas aeruginosa between 1 and 32 micrograms/ml, comparable to those of ceftazidime, and it inhibited piperacillin- and gentamicin-resistant isolates. Most group A, B, C, and G streptococci and Streptococcus pneumoniae were inhibited by less than or equal to 0.25 micrograms/ml. Enterococci and listeriae were resistant (MICs, 64 to 128 micrograms/ml). The MICs for staphylococci were 4 to 8 micrograms/ml, and methicillin-resistant Staphylococcus aureus was resistant. There was a minimal inoculum effect and no effect of the medium. ME1228 was not hydrolyzed by TEM-1, TEM-2, SHV-1, and S. aureus plasmid beta-lactamases and was stable against hydrolysis by Richmond-Sykes type 1a, 1c, 1d, and IV chromosomal beta-lactamases. It was hydrolyzed by TEM-3 and Xanthomonas maltophilia beta-lactamases. Overall, ME1228 had activity comparable or superior to that of ceftazidime.

Anti-Bacterial Agents↗
PubMed1991

Role of the beta-lactamase of Campylobacter jejuni in resistance to beta-lactam agents.

We studied the role of the beta-lactamase of Campylobacter jejuni in resistance to beta-lactam agents. beta-Lactamase-positive strains were more resistant than beta-lactamase-negative strains to amoxicillin, ampicillin, and ticarcillin (P less than 0.05). With penicillin G, piperacillin, imipenem, and six cephalosporins, the susceptibility levels were similar for both beta-lactamase-positive and -negative strains. By using spectrophotometric and microbiological assays, the beta-lactamase from three strains hydrolyzed ampicillin, amoxicillin, penicillin G, cloxacillin, and, partially, cephalothin. Ticarcillin and piperacillin were partially hydrolyzed in the microbiological assay. There was no activity against five other cephalosporins or imipenem. Isoelectric focusing of the enzyme showed a pI of 8.8. Tazobactam was the best inhibitor of the enzyme, followed by clavulanic acid, sulbactam, and cefoxitin, while EDTA and p-chloromercuribenzoate had no activity. All beta-lactamase-positive strains became susceptible to amoxicillin and ampicillin with 1 micrograms of clavulanic acid per ml. With the same inhibitor, there was a reduced but significant effect for ticarcillin but no effect for penicillin G or piperacillin. Sulbactam had no effect and tazobactam was effective only at 2 micrograms/ml on amoxicillin and ampicillin. The beta-lactamase of C. jejuni seems to be a penicillinase with a role in resistance for only amoxicillin, ampicillin, and ticarcillin.

Anti-Bacterial Agents↗
PubMed1997

In vitro and in vivo antibacterial activities of GV129606, a new broad-spectrum trinem.

GV129606 is a new parenteral trinem antibiotic belonging to the beta-lactam class. It combines broad-spectrum activity (against gram-negative and -positive bacteria, aerobes and anaerobes), with high potency and resistance to beta-lactamases. Comparative in vitro and in vivo antibacterial activities were determined for GV129606 against more than 400 recent clinical isolates (aerobes, including beta-lactamase producers, and anaerobes), using representative antibacterial agents (meropenem, piperacillin, ceftazidime, cefpirome, ciprofloxacin, and gentamicin for aerobes and metronidazole, cefoxitin, piperacillin, and clindamycin for anaerobes). Against methicillin-susceptible staphylococci and streptococci, GV129606 and meropenem were the most active of the drugs tested. GV129606 showed an MIC for 90% of strains tested (MIC90) ranging from < or =0.015 to 0.06 microg/ml against methicillin-susceptible staphylococci and Streptococcus sanguis, Streptococcus pyogenes, and Streptococcus agalactiae. Against penicillin-susceptible and -resistant Streptococcus pneumoniae isolates, GV129606, meropenem, and cefpirome showed MIC90s of < or =0.015 and 1 microg/ml, respectively. Meropenem was the most active compound against members of the family Enterobacteriaceae with MIC90s of < or =0.5 microg/ml. Against these species, GV129606 possessed activity superior to those of piperacillin, ceftazidime, cefpirome, and gentamicin, with MIC90s of < or =8 microg/ml, but its activity was two- to sixfold less than that of ciprofloxacin (with the exception of Proteus rettgeri and Providencia stuartii). Haemophilus spp., Moraxella catarrhalis, Neisseria gonorrhoeae, and Pseudomonas aeruginosa were also included in the spectrum of GV129606. GV129606 showed good antianaerobe activity, similar to metronidazole. It was stable against all clinically relevant beta-lactamases (similar to meropenem). The in vitro activity was confirmed in vivo against septicemia infections induced in mice by selected gram-positive and -negative bacteria with 50% effective doses (ED50s) of < or =0.05 and < or =0.5 mg/kg of body weight/dose, respectively. GV129606 was as effective as meropenem against septicemia in mice caused by ceftazidime-resistant Pseudomonas aeruginosa, exhibiting an ED50 of 0.33 mg/kg/dose.

Animals↗