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Susceptibility of anaerobic bacteria to 23 antimicrobial agents.

The antimicrobial susceptibility of 492 anaerobic bacteria, the majority of which were recent clinical isolates, was determined by the agar dilution technique. Penicillin G was active against most of the strains tested at 32 U or less/ml, but only 72% of Bacteroides fragilis strains were susceptible at this level and 9% required 256 U or more/ml. Ampicillin was effective against most of the strains except B. fragilis at 16 mug or less/ml. Amoxicillin was active against only 31% of B. fragilis, 76% of other Bacteroides species, and 67% of Fusobacterium species at 8 mug/ml. Two new penicillins, mezlocillin and azlocillin, were similar to ampicillin in their activity. Carbenicillin and ticarcillin inhibited all but a few strains at 128 mug or less/ml. BLP 1654 was somewhat more active than penicillin G against B. fragilis but had similar activity against other anaerobes. Cephalothin was inactive against B. fragilis, and only 65% of other Bacteroides species were inhibited by 32 mug or less/ml. It was effective against all other anaerobes at that level. Cefamandole showed somewhat greater activity than cephalothin against B. fragilis but generally less activity against gram-positive organisms. Cefazaflur (SKF 59962) was comparable to cephalothin against B. fragilis. Cefoxitin was distinctly more active than cephalothin against B. fragilis. These latter two agents were less active than cephalothin against the gram-positive anaerobes. Chloramphenicol remains active against anaerobic bacteria at 16 mug or less/ml, with rare exceptions. Thiamphenicol was similar to chloramphenicol in its activity. Clindamycin was very active against most of the anaerobes at 8 mug or less/ml. Erythromycin and josamycin were also tested, with josamycin showing greater activity against B. fragilis than either erythromycin or clindamycin. A new oligosaccharide, everninomicin B, was less active than clindamycin against B. fragilis but more active against clostridia and some of the other strains tested. Most of the groups of bacteria tested demonstrated a trend toward resistance to tetracycline. Doxycycline and minocycline were somewhat more active than was tetracycline. Metronidazole was active against the majority of the anaerobes tested; resistance ws demonstrated by some of the gram-positive cocci and gram-positive, non-sporeforming bacilli.

Anaerobiosis↗

PC-904, a new semisynthetic penicillin.

Sodium 6{d(-)-alpha(4-hydroxyl-1,5 naphthyridine-3-carboxamido)phenylacetamido} penicillanate (PC-904) is a new semisynthetic penicillin with broad-spectrum activity against gram-positive cocci and gram-negative bacilli. At a concentration of 1.56 mug/ml, it inhibited 100% of isolates of Proteus mirabilis, 89% of Pseudomonas aeruginosa, 67% of Escherichia coli, and 45% of Enterobacter spp. At a concentration of 12.5 mug/ml, it inhibited 75% of Klebsiella spp. and 67% of Serratia marcescens. PC-904 failed to inhibit the growth of gram-negative bacilli when large inocula were used. Some differences were noted when organisms were tested in different media or at different hydrogen ion concentrations. It is more active than mezlocillin, azlocillin, ticarcillin, carbenicillin, and amoxicillin against E. coli, Klebsiella spp., and P. aeruginosa.

Ampicillin↗

In vitro activity of LY127935, a new 1-oxa cephalosporin, against aerobic gram-negative bacilli.

A total of 434 clinical aerobic gram-negative bacillary isolates were tested against LY127935, a new 1-oxa cephalosporin, and compared with other cephalosporins, penicillins, and aminoglycosides by a broth microdilution technique. Cefotaxime (HR756), a new semisynthetic cephalosporin, and LY127935 were more active, and showed lower minimum inhibitory concentrations (ranges, less than or equal to 0.12 to 2.0 micrograms/ml), than cefamandole, cefoxitin, and cefazolin against Escherichia coli, Klebsiella spp., Enterobacter spp., Proteus mirabilis, indole-positive Proteus spp., Serratia marcescens, Providencia spp., and Citrobacter spp. Against P. aeruginosa, pepercillin, azlocillin, and mezlocillin were the most active beta-lactam agents; 64 micrograms/ml inhibited 99, 93, and 87% of the isolates, respectively. LY127935 and cefotaxime at 16 micrograms/ml inhibited 71% of Pseudomonas isolates, whereas the aminoglycosides gentamicin, tobramycin, and amikacin at a concentration of 4 micrograms/ml inhibited 84, 88, and 93%, respectively. Minimum bactericidal concentrations were determined for all isolates and were generally the same as the minimum inhibitory concentrations.

Aminoglycosides↗

Concentrations of various antibiotics in serum and fluids accumulated in diffusion chambers implanted in various sites in rabbits.

Diffusion chambers with Millipore membranes were implanted in soft tissue, kidneys, and peritoneal and pleural cavities of rabbits. Single doses of azlocillin, cefazolin, and gentamicin were injected intramuscularly and ampicillin was administered orally 2--5 weeks after implantation. The concentrations of the respective drugs in simultaneously collected samples of fluid from each diffusion chamber were measured and compared with concentrations found at the same time in serum. All chambers were tolerated well, and the method proved to be effective for collecting data on the distribution of drugs throughout the body.

Ampicillin↗

GR 20263, a new broad-spectrum cephalosporin with anti-pseudomonal activity.

GR 20263 is a new broad-spectrum injectable cephalosporin which is stable to most beta-lactamases. Its in vitro activities were of the same order as those of cefotaxime against most gram-negative bacteria, were clearly inferior to cefotaxime against Staphylococcus aureus, but were significantly more active against Pseudomonas aeruginosa. Against the 25 strains used, GR 20263 was significantly more active than any of the other agents tested: piperacillin, azlocillin, gentamicin, amikacin, and carbenicillin. GR 20263 protected mice against experimental infections with P. aeruginosa more effectively than other beta-lactam antibiotics; its general effectiveness in this test was comparable with gentamicin. Studies on human volunteers showed that it produces high, long-lasting blood levels, with much of the antibiotic being recovered in the urine. Intramuscular and intravenous injections were well tolerated by the volunteers, and there were no untoward side effects.

Adult↗

In vitro evaluation of Ro 13-9904.

The in vitro activity of a new investigational cephalosporin, Ro 13-9904, was compared with those of four cephalosporins (cephalothin, cefamandole, cefoxitin, and moxalactam), five semisynthetic penicillins (mezlocillin, piperacillin, carbenicillin, ticarcillin, and azlocillin), and the aminoglycoside tobramycin. Ro 13-9904 inhibited 75% of all isolates of Enterobacteriaceae at a concentration of 6.25 micrograms/ml, including Enterobacter spp., Serratia marcescens, and indole-positive Proteus spp. Ro 13-9904 was only minimally active against Pseudomonas aeruginosa and enterococci. There was no significant change (greater than or equal to 2 dilutions) in drug activity when tested in various pH and media. A significant inoculum effect occurred when the size of the inoculum was increased from a concentration of 10(5) to 10(7) organisms per ml.

Bacteria↗

Activities of new beta-lactam antibiotics against isolates of Pseudomonas aeruginosa from patients with cystic fibrosis.

The in vitro activities of gentamicin, tobramycin, amikacin, azlocillin, carbenicillin, mezlocillin, piperacillin, ticarcillin, cefotaxime, ceftizoxime, cefoperazone, cefsulodin, moxalactam, ceftazidime, ceftriaxone, and N-formimidoyl thienamycin were measured against 62 isolates of Pseudomonas aeruginosa obtained from patients with cystic fibrosis. Ceftazidime and N-formimidoyl thienamycin were the most active of these agents.

Anti-Bacterial Agents↗

In vitro activity of apalcillin compared with that of other new penicillins and anti-Pseudomonas cephalosporins.

Apalcillin, a naphthydridine derivative of ampicillin, was compared with ticarcillin, azlocillin, mezlocillin, piperacillin, cefotaxime, and cefoperazone against gram-negative and gram-positive bacterial isolates and with cefsulodin and tobramycin against Pseudomonas aeruginosa. The minimal concentrations of apalcillin at which 50 and 90% of hospital isolates of Escherichia coli were inhibited were similar to those of mezlocillin and piperacillin (1.6 and 100 micrograms/ml, respectively). Apalcillin had minimal inhibitory concentrations similar to those of piperacillin against Citrobacter freundii and Citrobacter diversus. Against Klebsiella, apalcillin inhibited 50% of organisms at a concentration of 6.3 micrograms/ml, similar to piperacillin. The activity of apalcillin against Enterobacter (E. aerogenes, E. cloacae, and E. agglomerans) was similar to that of mezlocillin and piperacillin and greater than that of ticarcillin. The activity of apalcillin against Proteus mirabilis was similar to that of the other agents, as was its activity against indole-positive Proteus and Providencia. Only 40% of Serratia were inhibited at an apalcillin concentration of 25 micrograms/ml. Apalcillin was as active as piperacillin but twofold less active than cefoxitin or moxalactam against Bacteroides fragilis. It was as active as piperacillin, cefoperazone, and cefsulodin against P. aeruginosa (apalcillin inhibited 90% of organisms at a concentration of 25 mg/ml). There was an inoculum effect and a difference in the minimal inhibitory concentration and minimal bactericidal concentration with beta-lactamase strains. Apalcillin was hydrolyzed by plasmid beta-lactamase but not as well by cephalosporinases.

Ampicillin↗

Activities of various beta-lactams and aminoglycosides, alone and in combination, against isolates of Pseudomonas aeruginosa from patients with cystic fibrosis.

The inhibitory and bactericidal activities of carbenicillin, ticarcillin, moxalactam, cefoperazone, azlocillin, piperacillin, ceftazidime, and three aminoglycosides, alone and in various combinations, were determined against 60 isolates of Pseudomonas aeruginosa from the sputum of patients with cystic fibrosis. Ceftazidime was the most active beta-lactam, with minimum inhibitory and bactericidal concentrations for 90% of isolates of 4 micrograms/ml. Moxalactam was the least active of the new beta-lactams, with activity equivalent to that of carbenicillin; each had a minimum inhibitory concentration for 90% of isolates of 64 micrograms/ml and a minimum bactericidal concentration for 90% of isolates of 128 microgram/ml. All combinations of an aminoglycoside plus a beta-lactam showed favorable inhibitory effects. Combinations of beta-lactams showed mostly addition or indifference. Although little antagonism was seen with combinations of beta-lactams or with aminoglycoside-beta-lactam combinations, no consistent advantage of beta-lactam combinations was demonstrated in vitro. These results suggest several single drugs and combinations that merit clinical evaluation in cystic fibrosis patients with Pseudomonas pulmonary infections.

Amikacin↗

In vitro antagonism of beta-lactam antibiotics by cefoxitin.

We assessed the extent and mechanisms of antagonism of beta-lactam antibiotics by cefoxitin. In tests with 41 gram-negative isolates, cefoxitin antagonized cephalothin, cefamandole, cefsulodin, cefotaxime, moxalactam, ampicillin, carbenicillin, piperacillin, mezlocillin, and azlocillin, but not cephalexin, mecillinam, or N-formimidoyl thienamycin. The extent of antagonism varied with the beta-lactam and genus studied. However, antagonism occurred most often with strains possessing inducible cephalosporinases. Antagonism of cephalothin and cefamandole correlated closely with the induction of beta-lactamases capable of inactivating these drugs. Although antagonism of the remaining drugs occurred more often with strains possessing inducible beta-lactamases, these enzymes did not inactivate the drugs. Morphological studies revealed that cefoxitin inhibited filamentation and lysis produced by various beta-lactam drugs. Results of this investigation suggest that cefoxitin antagonizes beta-lactams via (i) induction of drug-inactivating beta-lactamases, and (ii) the induction of beta-lactamases that cannot inactivate the drug but serve as barriers against access to target proteins. This barrier appears most efficient for drugs that bind to penicillin-binding proteins 1 and 3.

Anti-Bacterial Agents↗

Resistance of Pseudomonas aeruginosa PAO to nalidixic acid and low levels of beta-lactam antibiotics: mapping of chromosomal genes.

Resistance to high concentrations of nalidixic acid in Pseudomonas aeruginosa PAO was due to mutations in one locus designated nalA, which was mapped by transduction between hex-9001 and leu-10. The nalA mutants were cross-resistant to pipemidic acid, a nalidixic acid analog, at relatively low concentrations. Replicative DNA synthesis was resistant to both drugs in permeabilized cells of nalA mutants. A locus coding for low-level resistance to nalidixic acid, nalB, was cotransducible with pyrB, proC, and met-28. The nalB mutants were also resistant to low levels of pipemidic acid, novobiocin, and beta-lactam antibiotics (e.g., carbenicillin, azlocillin, and cefsulodin), but not to other drugs, such as gentamicin, rifampin, kanamycin, or tetracycline. In nalB mutants, DNA replication showed wild-type sensitivity to nalidixic acid, whereas carbenicillin-induced filamentation required higher drug levels than in the wild-type strain. Thus, nalB mutations appear to decrease cell permeability to some antibiotics. The sensitivity of replicative DNA synthesis to nalidixic acid and novobiocin was very similar in P. aeruginosa and Escherichia coli; by contrast, the concentrations of these drugs needed to inhibit growth of P. aeruginosa were higher than those reported for E. coli by one or two orders of magnitude.

Anti-Bacterial Agents↗

Susceptibility of Pseudomonas paucimobilis to 24 antimicrobial agents.

Pseudomonas paucimobilis (group IIK, biotype 1) clinical isolates showed in vitro resistance to ampicillin, carbenicillin, cephalothin, cefoxitin, cefamandole, moxalactam, cefotaxime, cefoperazone, mezlocillin, azlocillin, piperacillin, and ticarcillin. Those agents to which the microbes were shown to be susceptible were tetracycline, chloramphenicol, gentamicin, tobramycin, kanamycin, amikacin, netilmicin, sisomicin, trimethoprim-sulfamethoxazole, ceftazidime, ceftriaxone, and ceftizoxime.

Anti-Bacterial Agents↗

Statistical comparison of the antibacterial activities of broad-spectrum penicillins against gram-negative bacilli.

Minimal inhibitory concentrations (MICs) or two alpha-carboxypenicillins (carbenicillin and ticarcillin) and three acylaminopenicillins (azlocillin, mezlocillin, and piperacillin) for 300 aerobic and facultative gram-negative bacilli were determined by a microdilution method and compared by parametric statistical tests. Within each group of penicillins, MICs were highly interrelated; MICs of one antibiotic were readily predictable based on knowledge of MICs of another antibiotic. Ticarcillin was consistently more active than carbenicillin by approximately one dilution step, but the relative activities of the acylaminopenicillins varied by bacterial species. The acylaminopenicillins were generally more active than the alpha-carboxypenicillins, particularly against alpha-carboxypenicillin-resistant organisms. There were exceptions, however, and antibiotic MICs in one group were not readily predictable on the basis of the knowledge of antibiotic MICs in the other group. The enhanced antibacterial potencies and spectra of the acylaminopenicillins against gram-negative bacilli make these antibiotics potentially useful therapeutic agents. It is not necessary for clinical laboratories to routinely perform susceptibility tests with all five antibiotics.

Analysis of Variance↗

Multiply resistant viridans streptococci: susceptibility to beta-lactam antibiotics and comparison of penicillin-binding protein patterns.

A unique group of viridans streptococci has been found in South Africa. These organisms were isolated in close temporal and physical proximity to the isolation of penicillin-resistant pneumococci. The strains were resistant to penicillin, oxacillin, the cephalosporins (all generations), piperacillin, azlocillin, and mezlocillin but were susceptible to vancomycin. Penicillin-binding proteins of two penicillin-resistant South African strains of Streptococcus mitis differed markedly from those of two penicillin-susceptible strains but were identical to those seen in a penicillin-resistant strain isolated in Boston. Although both susceptible strains were identified as S. mitis with identical biochemical profiles, their penicillin-binding protein patterns differed from each other. This finding may have significance with regard to the need for additional taxonomic classification of the viridans streptococci.

Anti-Bacterial Agents↗

In vitro synergistic activities of aminoglycosides and new beta-lactams against multiresistant Pseudomonas aeruginosa.

The in vitro interactions between amikacin, netilmicin, tobramycin, gentamicin, and various antipseudomonal beta-lactams were studied by the agar dilution checkerboard technique against 30 Pseudomonas aeruginosa strains resistant to all tested antibiotics. Amikacin produced more frequent synergy both at the total and clinically applicable level. Among the beta-lactams, clinically relevant synergistic interactions were obtained in the following order: ceftazidime and ceftriaxone greater than moxalactam greater than aztreonam greater than cefotaxime greater than azlocillin greater than cefoperazone greater than cefsulodin greater than carbenicillin.

Aminoglycosides↗

Inoculum effect of new beta-lactam antibiotics on Pseudomonas aeruginosa.

The degree of the inoculum effect shown by the new beta-lactam antibiotics with Pseudomonas aeruginosa was investigated, and the antibiotics were divided into three groups based upon the observations. The group 1 antibiotics (cefotaxime, moxalactam, cefoperazone, azlocillin, piperacillin, and aztreonam) demonstrated a large inoculum effect, were poorly bactericidal, produced aberrant, elongated bacilli, and did not inhibit the increase in turbidity of high inocula during an 18-h incubation. The group 2 antibiotics (ceftazidime and ticarcillin) were slowly bactericidal, caused minimal formation of aberrant, elongated bacilli, and slowly decreased the turbidity of high inocula. The group 3 antibiotics (imipenem and gentamicin) were bactericidal, did not cause the formation of elongated bacilli, and decreased the turbidity of high inocula rapidly. Data are presented which suggest that the inoculum effect seen with the group 1 beta-lactam antibiotics is related to (i) the poor intrinsic antibactericidal activity of these antibiotics for P. aeruginosa at the inocula tested and (ii) failure of these antibiotics to inhibit the formation of aberrant and filamentous bacilli, which can result in increased bacterial mass and turbidity.

Amino Acids↗

Comparison of the activities of penicillin G and new beta-lactam antibiotics against clinical isolates of Bacteroides species.

MICs were determined for 218 clinical isolates of Bacteroides by a broth microdilution method. Imipenem was the most active antibiotic tested. Azlocillin, mezlocillin, and cefoxitin had comparable activities, with resistance among members of the B. fragilis group and B. capillosus. Ceftizoxime was the most active cephalosporin tested. Members of the B. fragilis group showed high levels of resistance to cefotetan and ceftazidime. Resistance to penicillin G varied from 0 to 14%.

Anti-Bacterial Agents↗