In vitro interaction between the penem FCE 22101 and ceftazidime

FCE 22101, a penem antimicrobial agent, was found to resist hydrolysis by bacterial-lactamases and to have a strong affinity for Type Ia enzymes. Like imipenem, FCE 22101 was shown to be capable of inducing resistance to a wide range of-lactam antibiotics. FCE 22101 antagonized the in vitro activity of ceftazidime against enteric bacilli that commonly produce inducible enzymes. This penem should not be combined with other-lactams for chemotherapeutic purposes.     

In vitro activity of PD 117596-2, a broad-spectrum difluoroquinolone

The activity of PD 117596-2, a novel quinolone, was compared to that of other quinolones, ceftazidime, imipenem and gentamicin. PD 117596-2 inhibited mostEnterobacteriaceae at concentrations <0.25 µg/ml, being equal or superior in activity to ciprofloxacin and 2- to 4-fold more active than ofloxacin. It inhibited ceftazidime-resistantEnterobacter spp.,Citrobacter spp. andSerratia marcescens. The MIC90 forPseudomonas aeruginosa, including strains with imipenem MICs of 8 µg/ml and gentamicin MICs > 16 µg/ml, was 0.25 µg/ml. PD 117596-2 was more active than ciprofloxacin againstPseudomonas cepacia andPseudomonas maltophilia, and it inhibitedNeisseria gonorrhoeae andHaemophilus influenzae at < 0.03 µg/ml. PD 117596-2 inhibited staphylococci at 0.5 µg/ml, being 2-fold superior to other quinolones, and with an MIC of 0.25 µg/ml was more active against group A, B, C and G streptococci andStreptococcus pneumoniae. MICs forBacteroides spp. were 2 µg/ml compared to 8–32 µg/ml for other agents. The frequency of spontaneous resistance was low (< 10^–10). Differences in MICs and MBCs were within one dilution, and there was a minimal effect of inoculum size. Although PD 117596-2 was less active at pH 5.5, MICs were < 0.5 µg/ml.     

Multicentre comparative study on the antibacterial activity of FK-037, a new parenteral cephalosporin

The in vitro antibacterial activity of FK-037, a new parenteral cephalosporin structurally related to cefpirome and cefepime, was compared with that of cefotaxime, ceftazidime, aztreonam, cefpirome, cefepime, imipenem and meropenem against 1,837 clinical isolates obtained from three Spanish hospitals. FK-037 inhibited 90 % ofEnterobacteriaceae isolates at 0.25 µg/ml, with the exception ofEnterobacter aerogenes (MIC90 1 µg/ml),Enterobacter cloacae andCitrobacter freundii (MIC90 8 µg/ml). In cefotaxime-and ceftazidime-resistantKlebsiella pneumoniae strains producing SHV-2 and SHV-6 -lactamases, the activity of FK-037, cefpirome and cefepime was similar (MIC range 0.25–32 µg/ml). InEnterobacteriaceae strains hyperproducing chromosomally inducible -lactamases, FK-037 (MIC90 range, 0.25–8 µg/ml) was 8- to 16-fold more active than cefotaxime and ceftazidime but two- to eightfold less active than cefpirome and cefepime. FK-037 and cefpirome were twofold more active than ceftazidime and cefepime againstPseudomonas aeruginosa isolates, with MIC90 values of 16 µg/ml. The activity of FK-037, cefpirome and cefepime was two- to eightfold lower in ceftazidime-resistant derepressedPseudomonas aeruginosa mutants. FK-037 (MIC range, 0.12–2 µg/ml) and the other -lactam agents tested were active against methicillin-susceptible staphylococci; however, only cefpirome and, particularly, FK-037 (MIC90 of 32 µg/ml) displayed some activity against methicillin-resistant strains. In penicillin-susceptible,-intermediate and -resistantStreptococcus pneumoniae isolates, the MIC90s of FK-037 were 0.03, 0.5 and 1 µg/ml, respectively. The corresponding values forStreptococcus viridans isolates were 0.12, 1 and 8 µg/ml, respectively. In bothStreptococcus pneumoniae andStreptococcus viridans isolates, FK-037 displayed activity similar to that of cefotaxime and cefpirome and slightly higher than that of cefepime.     

Interpretive criteria and quality control for antimicrobial susceptibility tests of levofloxacin

To confirm preliminary interpretive breakpoints for prototype 5 µg levofloxacin disks, 490 strains were tested in vitro using commercially manufactured disks. For in vitro susceptibility testing, 5 µg levofloxacin disks can be used with interpretive criteria of 12 mm for resistant (MIC 8.0 µg/ml) and 16 mm for susceptible (MIC 2.0 µg/ml). Proposed quality control limits for tests of levofloxacin are as follows:Escherichia coli ATCC 25922, zones 29–37 mm or MIC 0.008–0.03 µg/ml;Pseudomonas aeruginosa ATCC 27853, zones 19–26 mm or MIC 0.5–2.0 µg/ml;Staphylococcus aureus ATCC 25923, zones 24–31 mm;Staphylococcus aureus ATCC 29213, MIC 0.06–0.25 µg/ml andEnterococcus faecalis ATCC 29212, MIC 0.25–2.0 µg/ml.     

In vitro activity of E-4868, a new trifluoroquinolone,compared to six similar compounds

The compound E-4868 (Laboratorios Dr. Esteve) is a trifluoro, 7-azetidinyl quinolone with properties resembling those of other fluoroquinolones. Its activity in vitro was compared to that of six other similar drugs against more than 700 nosocomial isolates using standard methods. The MIC50s of E-4868 for enteric bacilli ranged from 0.015 to 0.25 µg/ml, being highest forProvidencia spp.Pseudomonas aeruginosa strains were two-fold more susceptible to E-4868 than to ofloxacin. MICs of E-4868 forHaemophilus influenzae, Moraxella catarrhalis and pathogenicNeisseria spp. were all 0.12 µg/ml. E-4868 was equal in activity to or eight-fold more active than ciprofloxacin against gram-positive cocci. The MICs of E-4868 for pneumococci were all 0.5 µg/ml but anaerobes such asBacteroides fragilis were generally less susceptible (MIC90, 4 µg/ml). There was almost complete cross-resistance to several other fluoroquinolones. Resistant mutants were selected by a multiple passage technique but the rate of mutation to resistance was very low (< 10^–8) at an 8 x MIC.     

Post-antibiotic effect of the new streptogramin RP 59500

The post-antibiotic effect (PAE) of RP 59500, a new streptogramin antibiotic, was determined forStaphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Streptococcus pneumoniae, andStreptococcus pyogenes. A 30 min exposure ofStaphylococcus aureus to 5 µg/ml of RP 59500 produced a PAE of 1.9–6.9 h, and a 60 min exposure of 2.5 µg/ml produced a PAE of 3.2–8 h. A 30 min exposure of 5 µg/ml of RP 59500 of coagulase-negative staphylococci produced a PAE of 2.5–7.5 h. PAEs of constitutively erythromycin-resistant staphylococcal isolates were shorter than were the PAEs of highly susceptible isolates. A 30 min exposure to 5 µg/ml of RP 59500 produced a PAE of 7.5–9.5 h forStreptococcus pneumoniae and a PAE of >18 h forStreptococcus pyogenes. RP 59500 produced a longer PAE withStaphylococcus aureus than did vancomycin, oxacillin or erythromycin. These results suggest that RP 59500 may be administered less frequently than would be suggested by its half-life.     

Postantibiotic effect of the penem FCE 22101 against selected gram-positive and gram-negative bacteria in vitro and in vivo by the use of a tissue cage model in rabbits

Isolates of Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae and Klebsiella pneumoniae were tested for their bactericidal activity and postantibiotic effect (PAE) with the new penem FCE 22101. The tissue cage model in rabbits was used to study PAE in vivo. The bactericidal activity against all four species was shown to be in the range of 0.05-4.0 mg/l. A 99.9% killing effect at MBC concentrations was reached within 2 hours with S. pneumoniae and K. pneumoniae and within 6-8 hours with S. aureus and H. influenzae. After in vitro exposure by FCE 22101 a PAE in vitro and in vivo was obtained against S. aureus, S. pneumoniae and H. influenzae strains but no PAE could be demonstrated against K. pneumoniae. FCE 22101 showed a good bactericidal activity and PAE against the strains investigated, except for K. pneumoniae.     

Quality control parameters and interpretive criteria for in vitro susceptibility tests with the macrolide azithromycin

Quality control parameters for broth microdilution and disk diffusion susceptibility tests were defined and the interpretive criteria for disk diffusion tests reviewed. For interpretation of tests with 15 µg azithromycin disks, the following criteria are recommended: 19 mm for the susceptible category (MIC2.0 µg/ml) and 15 mm for the resistant category (MIC8.0 µg/ml). Using these criteria, there was 97 % overall agreement between broth dilution and disk diffusion tests;Haemophilus influenzae isolates were susceptible to azithromycin by both methods. The quality control strainStaphylococcus aureus ATCC 25923 gave zones of 21 to 26 mm in diameter in a six-laboratory collaborative study. In azithromycin broth microdilution tests the following MIC control limits are recommended:Escherichia coli ATCC 25922, 2.0–8.0 µg/ml;Staphylococcus aureus ATCC 29213, 0.25–1.0 µg/ml; andEnterococcus faecalis ATCC 29212, 1.0–4.0 µg/ml.Collaborating investigators contributing data to the quality control studies include P. C. Fuchs, St. Vincent Hospital and Medical Center, Portland, Oregon; S. D. Allen, Indiana University Medical Center, Indianapolis, Indiana; E. H. Gerlach, St. Francis Regional Medical Center, Wichita, Kansas; J. A. Washington, The Cleveland Clinic Foundation, Cleveland, Ohio; L. B. Reller, University of Colorado Medical Center, Denver, Colorado, USA.     

In vitro activity of Ro 09-1428 compared to other cephalosporins

The in vitro activity of Ro 09-1428, a new catechol-type parenteral cephalosporin, was compared to that of ceftazidime, E-1040, cefpirome and cefepime against gram-positive and gramnegative organisms. Ro 09-1428 inhibited group A streptococci at 0.12 µg/ml, and group B, C and G streptococci andStreptococcus pneumoniae at 0.5 µg/ml, whereas forStaphylococcus aureus Ro 09-1428 had MICs of 8–16 µg/ml similar to ceftazidime and E-1040. AgainstPseudomonas aeruginosa Ro 09-1428 was the most active agent, inhibiting isolates at 0.12–2 µg/ml, and inhibited ceftazidime-resistant isolates. The majority ofEscherichia coli, Klebsiella spp.,Proteus mirabilis, Citrobacter diversus, Providencia, Salmonella andShigella were inhibited by 0.5 µg/ml as with the other cephalosporins. For mostCitrobacter freundii andEnterobacter cloacae Ro 09-1428 had higher MICs of 4–16 µg/ml; most ceftazidime-resistant isolates of these species were resistant. Anaerobes, enterococci andListeria monocytogenes were resistant to Ro 09-1428. Ro 09-1428 was not hydrolyzed by TEM-1, TEM-2,Staphylococcus aureus PC-1,Moraxella catarrhalis Bro-1,Enterobacter P-99,Pseudomonas aeruginosa Sabath-Abraham orKlebsiella beta-lactamases, but was hydrolyzed by TEM-3, TEM-7 and TEM-9. Ro 09-1428 was markedly less active at an acid pH.     

In vitro antimicrobial activity of the new antibiotic vermisporin

The antimicrobial activity of vermisporin, a new antibiotic produced by fermentation of the fungusOphiobolus vermisporis, was tested in vitro. Vermisporin inhibited 90 % ofBacteroides fragilis and otherBacteroides spp. at 1 µg/ml (range 0.25–1 µg/ml).Clostridium perfringens were inhibited by 1 µg/ml (range 0.25–2 µg/ml). Vermisporin inhibited 90 % ofStaphylococcus aureus, including methicillin-resistantStaphylococcus aureus, at 0.5 µg/ml (range 0.12–0.5 µg/ml). Vermisporin MICs for group A, B, C, F and G streptococci were < 1 µg/ml when tested in Haemophilus Test Medium but 8 µg/ml in the presence of blood. Vermisporin MICs forEnterobacteriaceae, Pseudomonas aeruginosa andHaemophilus influenzae exceeded 64 µg/ml. Inhibited organisms had MBCs 16- to 32-fold above the MICs.     

Susceptibility ofBacteroides non-fragilis and fusobacteria to amoxicillin,amoxicillin/clavulanate,ticarcillin, ticarcillin/clavulanate,cefoxitin, imipenem and metronidazole

The susceptibility of 234Bacteroides non-fragilis strains and 56 fusobacteria from 12 European centers to amoxicillin, amoxicillin/clavulanate, ticarcillin, ticarcillin/clavulanate, cefoxitin, imipenem and metronidazole was tested and related to -lactamase production. Beta-lactamase production was detected in 42.3 % of theBacteroides strains and 26.8 % of the fusobacteria. The MIC90 of amoxicillin for -lactamase-negative strains was 0.5 µg/ml and the MIC90 of ticarcillin 2.0 µg/ml. In the case of -lactamase-positive strains the MIC90 of amoxicillin (32 µg/ml) and ticarcillin (16 µg/ml) dropped to 1.0 µg/ml upon addition of clavulanate; 65.8 % of these strains were susceptible to amoxicillin and 98.2 % to ticarcillin, but all were susceptible when clavulanate was added. All strains were susceptible to imipenem and metronidazole, and 99.3 % to cefoxitin.     

Interpretive criteria and quality control parameters for determining bacterial susceptibility to fosfomycin tromethamine

Studies with fosfomycin tromethamine disks containing 200 µg of fosfomycin and 50 µg of glucose-6-phosphate confirmed the following zone diameter criteria for the NCCLS method: 12 mm for resistant (MIC256 µg/ml), 13–15 mm for intermediate (MIC 128 µg/ml) and 16 mm for susceptible (MIC64 µg/ml). Additional studies defined acceptable MIC and zone diameter ranges for the following quality control strains:Escherichia coli ATCC 25922, MIC 0.5 to 4.0 µg/ml, zone diameter 23 to 29 mm;Staphylococcus aureus ATCC 25923, zone diameter 26 to 32 mm;Pseudomonas aeruginosa ATCC 27813, MIC 2.0 to 8.0 µg/ml; andEnterococcus faecalis, ATCC 29212, MIC 16 to 64 µg/ml.     

In vitro antimicrobial susceptibility of viridans streptococci isolated from blood cultures

The susceptibility of 211 viridans streptococci isolated from blood cultures to eight antimicrobial agents was determined. All the isolates were susceptible to cefotaxime, ceftriaxone, imipenem and vancomycin. Thirty eight percent of the isolates were resistant to penicillin (MICs 0.25 µg/ml). Tetracycline resistance was found in 41 % of the isolates and in 7 % of these strains tetracycline resistance was combined with erythromycin resistance. FiveStreptococcus mitis isolates exhibited increased (MIC 64 µg/ml and 128 µg/ml) or high-level (MIC 500 µg/ml) resistance to gentamicin, kanamycin and tobramycin. Four of these isolates were also resistant to penicillin (MICs 16–32 µg/m). In vitro synergy was not demonstrated for combinations of penicillin and gentamicin against threeStreptococcus mitis isolates with gentamicin MICs of 1000, 128 and 64 µg/ml. Results of this study indicate the importance of monitoring antibiotic resistance trends in viridans streptococci particularly with respect to penicillin and aminoglycoside resistance.     

Evaluation of plasmid-encoded beta-lactamase resistance inEscherichia coli blood culture isolates

The frequency of beta-lactam resistance was determined among 313 strains ofEscherichia coli, 119 ofEnterobacter/Klebsiella/Proteus spp., and 48 ofPseudomonas spp. isolated from blood cultures (at Turku University Central Hospital and Turku City Hospital) in 1983–1987. During this period the MIC50 of ampicillin forEscherichia coli increased from 8 to 32 µg/ml, the MIC90 of piperacillin from 16 to > 32 µg/ml and the MIC90 of cefuroxime from 4–8 to 16 µg/ml. Among 172 ampicillin-resistant isolates beta-lactamase-mediated resistance was characterized by DNA hybridization with TEM-1, SHV-1, OXA-1, OXA-2, PSE-1, PSE-2 and PSE-4 beta-lactamase probes and by isoelectric focusing. Beta-lactamase types found were TEM-1, TEM-2, SHV-1 and OXA-1. Isoelectric focusing did not show any other plasmid-mediated beta-lactamase varieties. Piperacillin-resistant strains showed mostly TEM-1 activity, but also produced OXA-1 and chromosomal beta-lactamase. Interestingly, a decrease in cefuroxime susceptibility inEscherichia coli occurred in a few OXA-1 producing strains as well as in strains that produced only chromosomal beta-lactamase. TwoEscherichia coli strains that overproduced chromosomal beta-lactamase had increased ceftazidime MIC values (8–16 µg/ml).     

In vitro activity of cefcanel versus other oral cephalosporins

Cefcanel is a new orally absorbed cephalosporin. Its activity was compared with that of cefuroxime, cefaclor, cephalexin, and cefixime against grampositive and negative aerobic and anaerobic bacteria. Cefcanel had excellent activity against methicillin-susceptibleStaphylococcus aureus andStaphylococcus epidermidis, MIC90 1 µg/ml, superior to the other oral cephalosporins. However, methicillin-resistant staphylococci were resistant, MIC 16 µg/ml.Streptococcus pyogenes andStreptococcus pneumoniae were inhibited by 0.015–1 µg/ml, concentrations comparable to other cephalosporins.Clostridium spp. were inhibited by 0.25 µg/ml, 8- to 128-fold lower concentrations than were found for other agents, but the MICs were >64 µg/ml forBacteroides spp. The MIC90 forMoraxella catarrhalis was 1 µg/ml, similar to cefuroxime but 16-fold greater than the MICs of cefixime.Escherichia coli andKlebsiella pneumoniae which were high beta-lactamase producers were resistant, MICs >64 µg/ml, and 50 % ofEnterobacter cloacae andCitrobacter freundii were resistant. Cefcanel was hydrolyzed by TEM-1, TEM-3 and Moraxella Bro-1 beta-lactamases.Escherichia coli containing TEM-1, 2, 3, 5, 7, and 9 had cefcanel MICs of 16 µg/ml. Although cefcanel inhibited gram-positive species as well as or at lower concentrations than other cephalosporins, it lacked activity against gram-negative species that produced common plasmid beta-lactamase although it inhibitedHaemophilus influenzae carrying TEM-1.     

Comparative in vitro activity of the new fluoroquinolone BMY-40062

The results are presented of comparative in vitro susceptibility testing of BMY-40062, a new fluorinated quinolone which contains a tetrabutyl moiety at N-1 and a piperazinyl group at C-7. BMY-40062 inhibited 90 % ofEnterobacteriaceae strains at < 0.5 µg/ml, being either equal in activity to ciprofloxacin or two- to four-fold less active, depending upon the species. BMY-40062 was as active as ciprofloxacin againstPseudomonas aeruginosa (MIC90 0.5 µg/ml) and inhibited most other strains ofPseudomonas species at < 1 µg/ml. It was more active than ciprofloxacin or ofloxacin against hemolytic streptococci andStreptococcus pneumoniae, 90 % of strains being inhibited at < 0.5 µg/ml. MICs increased in the presence of 9 mM Mg²⁺ and at pH 5.5. The frequency of spontaneous mutation was low forEnterobacteriaceae, Pseudomonas aeruginosa andStaphylococcus aureus (10^–10), but repeated exposure to BMY-40062 caused selection of resistant isolates. Clinical isolates ofPseudomonas aeruginosa resistant to ciprofloxacin and ofloxacin were resistant to BMY-40062.     

In vitro activity of biapenem against beta-lactamase producingEnterobacteriaceae

The activity of biapenem was compared with that of imipenem and cefotaxime against 108 strains of -lactamase producingEnterobacteriaceae. Biapenem and imipenem were very active, inhibiting 90 % of the strains at a concentration of 0.5 µg/ml. Both carbapenems were very active against plasmidic -lactamase producers, with MIC90s below 1 µg/ml. However, the MIC90 of biapenem for cephalosporinase producers was 1 µg/ml. Against strains producing extended-spectrum -lactamases, biapenem exhibited better activity against TEM-type producers (MIC90 0.25 µg/ml) than against SHV-type producers (MIC90 0.5 µg/ml). Overall, the in vitro antibacterial activity of biapenem is similar to that of imipenem.     

In vitro activity of OPC-17116 compared to other broad-spectrum fluoroquinolones

The in vitro activity of OPC-17116 was compared to that of five similar fluoroquinolones (ciprofloxacin, enoxacin, norfloxacin, ofloxacin and temafloxacin). A total of 700 isolates from recent cases of clinical bacteremia were tested. Fifty additional stock strains with well-characterized resistance mechanisms were also processed. The minimal concentrations inhibiting 90 % of strains (MIC90) ofEnterobacteriaceae species were for OPC-17116 0.015–0.5 µg/ml and for ciprofloxacin 0.015–0.25 µg/ml.Moraxella catarrhalis, Haemophilus influenzae andNeisseria gonorrhoeae were very susceptible to OPC-17116 (MIC90 0.015 µg/ml) thus being fourfold more active than ciprofloxacin. For all -hemolytic streptococci and pneumococci OPC-17116 MICs were 0.5 µg/ml. The most resistant enteric bacilli were among theCitrobacter freundii andProvidencia rettgeri strains (MIC90 0.5 µg/ml).Pseudomonas aeruginosa strains were comparably susceptible to OPC-17116 (MIC90 0.5 µg/ml). Low pH and CO₂ incubation had an adverse effect on OPC-17116 MICs, and resistance development was documented among current clinical isolates of staphylococci, pseudomonas and someEnterobacteriaceae.     

Comparative in vitro activity of norfloxacin against resistantNeisseria gonorrhoeae

The in vitro activity of seven antibiotics against 52 isolates ofNeisseria gonorrhoeae was determined. Against penicillinase-producingNeisseria gonorrhoeae, ceftriaxone was the most active agent (MIC90 0.015 µg/ml), followed by ceftizoxime and norfloxacin (MIC90 0.03–0.125 µg/ml). Against spectinomycin-resistantNeisseria gonorrhoeae, the most active agents were ceftizoxime, ceftriaxone and norfloxacin (MIC90 0.015–0.125 µg/ml). Ceftizoxime, ceftriaxone and norfloxacin were also the most active agents against tetracycline-resistantNeisseria gonorrhoeae (MIC90 0.06–0.125 µg/ml). Overall, the rank order of activity from the most to the least active agent was as follows: ceftizoxime (MIC90 0.015 µg/ml); ceftriaxone (MIC90 0.06 µg/ml); norfloxacin (MIC90 0.125 µg/ml); cefoxitin (MIC90 2 µg/ml); tetracycline (MIC90 8 µg/ml); penicillin (MIC90 > 8 µg/ml); and spectinomycin (MIC90 > 128 µg/ml).     

Interpretive criteria for disk diffusion susceptibility testing of sparfloxacin

Sparfloxacin disk susceptibility test criteria for the NCCLS and ICS/DIN methods were determined by testing 400 bacterial wild-type isolates. Disks containing 5 µg of the drug could be used satisfactorily in both procedures. The following interpretive zone size breakpoints for the NCCLS and ICS/DIN methods were proposed: 18 and 20 mm respectively for resistance (MIC>1 mg/l), and 23 and 25 mm respectively for susceptibility (MIC0.5 mg/l). These criteria were based on preliminary maximum serum concentrations of approximately 1.5 mg/l after a single oral dose of 400 mg of the drug. Regression equations for both methods correlating MICs and zone sizes based on test results for 361 organisms are presented. The equations allow calculation of breakpoints for higher or lower serum peak levels. Sparfloxacin was two to four times more active than ciprofloxacin against gram-positive cocci, and showed equal activity against gram-negative rods. Zone diameter quality control values forEscherichia coli ATCC 25922 were 26–30 mm (NCCLS) and 30–33 mm (ICS/DIN), and forStaphylococcus aureus ATCC 29213 27–28 mm (NCCLS) and 29–31 mm (ICS/DIN).