In vitro activity of N-formimidoyl-thienamycin in comparison to that of moxalactam and cefotaxime against gentamicin-resistant gram-negative bacteria

The inhibitory and bactericidal activity of N-formimidoyl-thienamycin in vitro against 131 clinical isolates selected for their gentamicin resistance was compared with that of cefotaxime and moxalactam. All strains were inhibited by N-formimidoyl-thienamycin concentrations within a range of 0.12–4 mg/l. N-formimidoyl-thienamycin was less active than cefotaxime and moxalactam againstEscherichia coli andKlebsiella spp., and more active than all other antibiotics tested againstSerratia spp.,Enterobacter cloacae, Pseudomonas aeruginosa andAcinetobacter spp. In contrast to the other antibiotics N-formimidoyl-thienamycin showed a narrow margin of difference between minimal inhibitory and minimal bactericidal concentrations. N-formimidoyl-thienamycin is a promising antibiotic for the treatment of hospital infections with multi-resistant organisms.     

In vitro activity of cefoperazone-sulbactam combinations against cefoperazone-resistant clinical bacterial isolates

From July 1987 to January 1988, 452 cefoperazone-resistant bacterial isolates were identified among strains subjected to routine susceptibility testing in a clinical microbiology laboratory. The 452 isolates were tested for susceptibility to cefoperazone, sulbactam, and a 2:1 combination of these drugs by agar dilution techniques. The greatest benefit of the cefoperazone-sulbactam combination was noted againstBacteroides spp. andAcinetobacter spp. The combination demonstrated clinically significant synergism against approximately 20% of strains ofPseudomonas aeruginosa.     

Comparative in vitro activity of cefpirome and cefepime,two new cephalosporins

In in vitro tests the broad-spectrum cephalosporins cefpirome and cefepime were highly active againstEnterobacteriaceae, although often less so against strains resistant to amoxicillin-clavulanate and ticarcillin-clavulanate, and against most strains ofAcinetobacter spp. andAeromonas hydrophila. They were also active againstPseudomonas aeruginosa, although strains with non-plasmid mediated beta-lactam resistance were sometimes less sensitive. OtherPseudomonas spp. varied in their sensitivity. Both agents were highly active againstHaemophilus influenzae, but beta-lactamase-producingBranhamella catarrhalis were somewhat less sensitive.Neisseria gonorrhoeae were susceptible, although non-beta-lactamase producing penicillin-resistant strains had higher MICs.Gardnerella vaginalis was also susceptible andCampylobacter coli/jejuni usually susceptible. Both antibiotics had good activity againstStaphylococcus aureus and coagulase-negative staphylococci except for methicillin-resistant strains andStaphylococcus haemolyticus which were of borderline sensitivity. All streptococci were sensitive, with the exception of highly penicillin-resistant pneumococci and enterococci against which cefpirome had greater activity than cefepime. Both antibiotics had little useful activity against theBacteroides fragilis group orBacteroides oralis group but were active against most other anaerobes.Clostridium difficile and some otherClostridium species were resistant.     

Comparative synergistic activity of ceftriaxone-piperacillin versus ceftriaxone-netilmicin

The effect of combination of ceftriaxone with piperacillin or netilmicin was studied in a total of 119 clinical isolates using the checkerboard titration technique. The isolates includedPseudomonas aeruginosa, Staphylococcus aureus, enterococci and variousEnterobacteriaceae. Synergy was observed in allStreptococcus faecalis strains with both combinations. Whereas the ceftriaxone/ netilmicin combination showed a higher rate of synergy againstPseudomonas aeruginosa, the rate of synergy againstEnterobacteriaceae was the same for the two combinations. In no instance was antagonism encountered.     

Sensitivity of 341 non-fermentative gram-negative bacteria to seven beta-lactam antibiotics

Susceptibility of 341 isolates of non-fermentative gram-negative bacteria to carbenicillin, piperacillin, cefoperazone, moxalactam, cefotaxime, ceftizoxime, and N-formimidoyl thienamycin was determined by the agar dilution and disc diffusion methods. Piperacillin was the most active agent againstPseudomonas aeruginosa, thienamycin the most active againstPseudomonas fluorescens andPseudomonas putida, and moxalactam the most active againstPseudomonas maltophilia. Piperacillin and thienamycin were the most active agents against the otherPseudomonas species studied. Thienamycin proved to have excellent activity againstAcinetobacter calcoaceticus ? 90 % of strains were inhibited by ? 1μg/ml. The two most active drugs againstAlcaligenes species were piperacillin and thienamycin, both of which inhibited 90 % of isolates at a concentration of 2μg/ ml. All drugs were active againstMoraxella species. The broad sensitivity spectrum of piperacillin, thienamycin, and the third-generation cephalosporins against non-fermentative gram-negative bacteria indicates their potential use in infections caused by these organisms.     

In vitro antibacterial properties of cefetamet and in vivo activity of its orally absorbable ester derivative,cefetamet pivoxil

The in vitro activity of cefetamet, the microbiologically active metabolite of the orally administered prodrug cefetamet pivoxil, was compared with that of cephalexin, cefaclor, cefuroxime and amoxicillin. Cefetamet was highly active againstEnterobacteriaceae, Neisseria spp.,Vibrio spp.,Haemophilus influenzae and streptococci other than enterococci. Cefetamet inhibited cefaclor-resistant species such asProteus vulgaris, Providencia stuartii, Providencia rettgeri andSerratia marcescens. Staphylococci,Pseudomonas aeruginosa and cephalosporinase-overproducing strains ofEnterobacter cloacae were resistant to cefetamet. The superior activity of cefetamet compared with older oral beta-lactam antibiotics against a large number of gram-negative pathogens correlated with enhanced stability towards betalactamases. In accordance with the in vitro findings, cefetamet pivoxil showed good activity in experimental infections in the mouse and rat, suggesting satisfactory bioavailability in these animals after oral administration.     

In vitro activity of HR 810, a new broad-spectrum cephalosporin

HR 810, 3-〈(2,3-cyclopenteno-l -pyridinium)methyl〉-7-〈2-syn-methoximino-2-(2-aminothiazole-4-yl)-acetamido〉 ceph-3-em-4-carboxylate, is a new semisynthetic cephalosporin derivative. The in vitro activity of HR810 was compared with that of cefotaxime, ceftazidime, piperacillin and gentamicin using 368 strains of gram-negative and gram-positive bacteria. HR 810 was highly active againstEnterobacteriaceae, being the most active of the cephalosporins againstEnterobacter, Serratia andCitrobacter spp.; the MICs ranged from ≤0.06 to 8mg/l. The activity of HR 810 againstPseudomonas aeruginosa andAcinetobacter spp. was almost as good as that of ceftazidime. The new compound was superior to the other cephalosporins againstStaphylococcus aureus and inhibited allStreptococcus faecalis strains at a concentration of 16 mg/l.     

3-0-demethyl fortimicin A: In vitro activity and interpretive zone standards for disk diffusion susceptibility tests

The in vitro activity of 3-0-demethyl fortimicin A was compared to that of amikacin and tobramycin against 5,230 clinical isolates in four institutions. Amikacin and tobramycin were more active than 3-0-demethyl fortimicin A againstPseudomonas aeruginosa andAcinetobacter spp., but all three drugs had similar activity against theEnterobacteriaceae andStaphylococcus aureus. Additional tests with 335 representative gram-negative bacilli compared five different aminoglycosides, demonstrating differences with some isolates. Standardized disk diffusion tests were also performed with 30μg 3-0-demethyl fortimicin A disks, according to the National Committee for Clinical Laboratory Standards. The following interpretive breakpoints are proposed: ? 11 mm for resistant (MIC ?32μg/ml) and ? 15 mm for susceptible (MIC ? 16μg/ml).     

Newly documented antimicrobial activity of quinolones

The improved antimicrobial activity of newer fluoroquinolones and novel applications recently found for the drugs already marketed are reviewed. Several new compounds are more active against gram-positive bacteria than the presently marketed fluoroquinolones. WIN 57273, the most potent compound in vitro on a weight basis, is 16 to 128 times more active than ciprofloxacin against various staphylococci, streptococci,Enterococcus spp.,Corynebacterium spp.,Listeria monocytogenes andBacillus spp. BMY 40062, PD 117558, PD 127391, sparfloxacin, temafloxacin and tosufloxacin also show enhanced in vitro efficacy against these species. These drugs also possess increased activity against various anaerobes, notablyClostridium perfringens, Clostridium difficile and theBacteroides fragilis group.Mycobacterium tuberculosis, rapidly growing mycobacteria other thanMycobacterium chelonae, andMycobacterium leprae are often susceptible to quinolones displaying bactericidal activity which is potentially useful for curing difficult-to-treat mycobacteriosis. In addition, a number of new products, notably those containing a cyclopropyl group, are more active than reference fluoroquinolones againstMycobacterium leprae. Sparfloxacin, BMY 40062 and WIN 57273 compare favorably with older fluoroquinolones in the killing of intracellularLegionella spp., and several of the newer compounds have greater antichlamydial potency. Improved antibacterial activity has also been found againstMycoplasma hominis, Ureaplasma urealyticum, Acinetobacter spp. andPseudomonas maltophilia. By contrast, the newer quinolones have similar or less activity againstPseudomonas aeruginosa andEnterobacteriaceae. Recently, pefloxacin, ofloxacin and ciprofloxacin were found to be active against protozoa, includingPlasmodium spp.,Trypanosoma cruzi andLeishmania donovani, but not againstToxoplasma gondii. In the near future, more specific research testing unusual pathogens may lead to the identification of quinolones with more selective activity.     

Dactimicin,a new aminoglycoside: In vitro activity,post-antibiotic effect and interaction with other antibiotics

The in vitro activity of the new aminoglycoside dactimicin in comparison to amikacin was tested alone and in combination with piperacillin, mezlocillin and ceftazidime against freshly isolated clinical pathogens. Dactimicin was more active than amikacin againstEnterobacter cloacae, Providencia rettgeri and Salmonella spp., and less active than amikacin againstEscherichia coli, Pseudomonas aeruginosa andAcinetobacter anitratus. Using the checkerboard technique, the combination of either dactimicin or amikacin with the other drugs was shown to result in synergistic interaction against most of the 23 strains tested. Dactimicin-ceftazidime and amikacin-ceftazidime were the most effective combinations, demonstrating synergism against 91 % and 95 % of the isolates respectively. Antagonism was not encountered. Using the time-kill method, synergism was seen in most cases, indifference rarely being seen; antagonism was not observed. Dactimicin induced a post-antibiotic effect which ranged from 1 h forEnterobacter cloacae to 2.4 h forEscherichia coli. An average post-antibiotic effect of 0.6 h was also seen when dactimicin was combined with piperacillin, mezlocillin and ceftazidime. The findings indicate that dactimicin compares favorably in vitro with amikacin and suggest that clinical trials with this drug alone or in combination are warranted.     

In vitro activity of imipenem — A review

A review is given of the microbiological properties of imipenem, a new carbapenem antibiotic with an exceptionally broad spectrum of antibacterial activity. An evaluation of results of numerous in vitro studies reveals that imipenem effectively inhibited growth of 53 of 55 bacterial species, the mean MIC90 being less than 8 mg/l. The MIC 90 for cocci, with the exception ofStaphylococcus epidermidis, is in the range of 0.01–3.1 mg/1. The MIC 90 for allEnterobacteriaceae is equal to or less than 8 mg/l.Pseudomonas aeruginosa and other non-fermentative gram-negative bacteria are generally susceptible to imipenem, onlyPseudomonas maltophilia andPseudomonas cepacia showing intrinsic resistance. Imipenem is currently the most active drug available against anaerobic bacteria, the MIC usually being below 1 mg/l even forBacteroides fragilis. Rare bacteria such asNocardia asteroides, Listeria monocytogenes or fast growingMycobacterium spp. which cause difficult-to-treat infections are also susceptible to imipenem. Increases in inoculum size have only a minimal effect on activity of the drug. In most species the MBC only slightly exceeded the MIC; however in the case ofStreptococcus faecalis the MBC value was many times the MIC value. Synergism has been observed in combinations of imipenem with aminoglycosides, and antagonism in combinations with other beta-lactam antibiotics againstPseudomonas aeruginosa andSerratia marcescens. Imipenem is stable in the presence of the common chromosomal and plasmid-mediated enzymes. Induction of inactivating enzymes was observed in staphylococci,Pseudomonas aeruginosa andSerratia marcescem.     

Antibacterial activity of the new carbapenem meropenem (SM-7338) against clinical isolates

The in vitro antibacterial activity of the new carbapenem antibiotic meropenem (SM-7338) against 567 clinical isolates was evaluated. SM-7338 exhibited activity against a broad spectrum of organisms, including aerobes and anaerobes, and was superior to the other beta-lactam drugs tested (piperacillin, cefotaxime, ceftazidime, ceftriaxone, cefoxitin). SM-7338 was more active than imipenem, gentamicin and amikacin againstEnterobacter cloacae andPseudomonas aeruginosa. SM-7338 was less potent than imipenem against staphylococci and enterococci, but the activity of the two antibiotics against anaerobes was similar. SM-7338 and imipenem showed a high bactericidal activity at a concentration of 2–4 x MIC.     

In vitro activity of FK-037, a novel parenteral cephalosporin,against bacterial isolates from neutropenic cancer patients

The in vitro activity of FK-037, a novel parenteral cephalosporin, was compared to that of ceftazidime, aztreonam and piperacillin (agents often used in empiric regimens in cancer patients) against recent bacterial isolates from patients with cancer. FK-037 was either equal to or 2 to 16-fold more active than the comparative agents against members of theEnterobacteriaceae. It was also active againstAcinetobacter spp.,Aeromonas spp.,Pseudomonas aeruginosa, and otherPseudomonas spp.Xanthomonas maltophilia andAlcaligenes denitrificans were relatively resistant to all four agents. FK-037 was also 4 to 16-fold more active against most gram-positive organisms (including some methicillin-resistant staphylococci) than was ceftazidime.Enterococcus spp.,Listeria monocytogenes andStaphylococcus haemolyticus were relatively resistant to FK-037 and ceftazidime. Overall, FK-037 has a broad antimicrobial spectrum that includes the majority of gram-positive and gram-negative isolates.     

Serum bactericidal activity after administration of four cephalosporins in healthy volunteers

Serum bactericidal activity (SBA) was determined against ten strains each ofStaphylococcus aureus, Klebsiella pneumoniae, Proteus vulgaris andEnterobacter cloacae in six volunteers 1 h and 4 h after intravenous infusion of 1 g and 2 g cefotaxime and cefmenoxime, and 2 g flomoxef, and against ten strains ofPseudomonas aeruginosa after infusion of 1 g and 2 g ceftazidime. Flomoxef showed the highest SBA against methicillin-susceptibleStaphylococcus aureus. All cephalosporins had high SBA against gram-negative rods. Cefotaxime had the highest SBA againstKlebsiella pneumoniae andEnterobacter cloacae. The SBA againstPseudomonas aeruginosa after 1 g and 2 g doses of ceftazidime was very similar.     

Pharmacokinetic and microbial susceptibility studies of ceftriaxone

The in vitro activity of ceftriaxone, a new parenteral cephalosporin, was tested against 450 strains isolated from blood cultures and compared with that of various other antibiotics. The compound was comparable to cefotaxime for all species tested. Its was more potent than cefoperazone, cefamandole and ticarcillin in inhibitingEnterobacteriaceae (Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, indole-positiveProteus spp. andSerratia marcescens). The MIC₉₅ of ceftriaxone for these strains was 0.5Μg/ml. The drug was less active againstStaphylococcus aureus than cefamandole, cloxacillin and vancomycin, but most isolates were inhibited by 4Μg/ml. AgainstPseudomonas aeruginosa, ceftriaxone was comparable in activity to ticarcillin (MIC₉₅=64Μg/ml), and inferior to cefoperazone, ceftazidime and cefsulodine. Levels of ceftriaxone in serum and various body fluids were determined by bio-assays. Due to its very long half-life (8 h), ceftriaxone serum levels 24 h after i.v. or i.m. injection of 1 and 2 g were still above the MIC₉₅ of all strains tested exceptPseudomonas aeruginosa. Levels in bile, synovial and cerebro-spinal fluids were high.     

In vitro phagocytic interaction betweenTrichomonas vaginalis isolates and bacteria

The phagocytic activity of 12Trichomonas vaginalis isolates against both gram-positive bacteria (Staphylococcus aureus ATCC 25923,Lactobacillus spp.) and gram-negative bacteria(Enterobacter cloacae ATCC 13047, 5 strains ofEscherichia coli, Pseudomonas aeruginosa ATCC 27853) was studied. Results showed that all the isolates were able to ingestStaphylococcus aureus to a variable degree, and almost all of them showed phagocytic activity againstPseudomonas aeruginosa. Furthermore, experiments with a restricted number of isolates ofTrichomonas vaginalis showed that they phagocytized, often very effectively, human vaginal lactobacilli. Only in some cases was the addition of serum essential for bacteria ingestion. Phagocytic uptake ofEscherichia coli andEnterobacter cloacae was not detectable under the experimental conditions used. It is concluded that phagocytosis may be involved in changes in vaginal biocenosis during the early stages of trichomoniasis.     

Comparative activity of meropenem (SM-7338) against major respiratory pathogens and amikacin-resistant nosocomial isolates

Meropenem, a new broad-spectrum carbapenem antibiotic, demonstrated excellent in vitro activity against major respiratory pathogens includingMoraxella catarrhalis, Haemophilus influenzae andStreptococcus pneumoniae. Minimal inhibitory concentrations of meropenem forMoraxella catarrhalis andHaemophilus influenzae isolates were frequently less than those of imipenem. For nosocomial amikacin-resistant gram-negative bacilli, meropenem had eightfold lower MIC90 values compared to imipenem against strains ofSerratia marcescens, Enterobacter cloacae andEscherichia coli; it was 32-fold more active than imipenem againstProteus mirabilis isolates. Activity was similar to that of imipenem againstPseudomonas aeruginosa isolates. Overall, meropenem showed excellent activity against common community-acquired pathogens as well as amikacin-resistant nosocomial pathogens.     

Synergy of ciprofloxacin and azlocillin in vitro and in a neutropenic mouse model of infection

Combinations of ciprofloxacin with azlocillin, piperacillin and ticarcillin were tested in vitro against clinical isolates. Azlocillin plus ciprofloxacin showed synergy against 30% of Pseudomonas aeruginosa isolates; it was either synergistic or additive against 78% of all isolates tested even those resistant to the beta-lactam. Synergism was rarely noted for Klebsiella pneumoniae, Escherichia coli, Enterobacter spp. or Branhamella spp. isolates. Minimum inhibitory concentrations of ciprofloxacin plus azlocillin, plus piperacillin and plus ticarcillin against Pseudomonas spp. were reduced 4 or 2 fold, respectively. However, the combination azlocillin plus ciprofloxacin showed primarily indifference against gram-positive strains. Neutropenic mice infected with a lethal challenge of Pseudomonas spp. were protected by a combination of azlocillin and ciprofloxacin. Its additive and/or synergistic effects and expanded spectrum of activity against streptococci, methicillin-resistant staphylococci and JK corynebacteria may provide an alternative to traditional therapy.     

Antibacterial activity of the investigational oral and parenteral cephalosporin BK-218

BK-218 is a novel cephalosporin with a dual route of administration and spectrum of activity most similar to that of second-generation cephalosporins. BK-218 was active againstStreptococcus pneumoniae, Haemophilus influenzae andMoraxella catarrhalis but strains resistant to penicillins had higher MICs. BK-218 had greater activity (8-fold) than cefuroxime or cefaclor against oxacillin-susceptibleStaphylococcus spp. Moderate BK-218 activity was observed againstNeisseria gonorrhoeae and commonly isolatedEnterobacteriaceae such asEscherichia coli (MIC90, 1 mg/l),Klebsiella spp. (MIC90, 2 mg/l), andProteus mirabilis (MIC90, 2 mg/l). The following organisms were generally BK-218-resistant (MIC90, >16 mg/l):Bacteroides fragilis, Pseudomonas spp.,Acinetobacter spp.,Xanthomonas maltophilia, Citrobacter spp.,Enterobacter spp., indole-positiveProteus, Serratia spp., enterococci and oxacillin-resistant staphylococci.     

Comparative in vitro activity of the two new oral cephalosporin metabolites RO 19-5247 and RO 15-8074

A total of 629 clinical strains of gram positive and gram negative bacteria were tested for their susceptibility to RO 19-5247, RO 15-8074, and other antimicrobial agents. Both RO 19-5247 and RO 15-8074 had good activity against strains of Enterobacteriaceae;however, resistance was found among some strains of Enterobacter, Citrobacter, Klebsiella and Morganella spp. Both compounds showed moderate to poor active against Acinetobacter spp.,Pseudomonas aeruginosa,staphylococci and Streptococcus faecalis.Against strains of Haemophilus influenzae, Neisseria gonorrhoeae, Gardnerella vaginalis, Streptococcus pneumoniae and streptococci (not enterococci), each compound was highly active in vitro. RO 19-5247 and RO 15-8074 had comparable activity to cotrimoxazole, ceftazidime and ceftizoxime. Each new compound had considerably better activity then did cefaclor and amoxicillin/potassium clavulanate.