Comparative in vitro activities of DU-6859a, levofloxacin, ofloxacin, sparfloxacin, and ciprofloxacin against 387 aerobic and anaerobic bite wound isolates

The activities of DU-6859a, levofloxacin, ofloxacin, sparfloxacin, and ciprofloxacin against bite wound isolates were determined by the agar dilution method. DU-6859a was the most active compound (MICs, < or = 0.125 microg/ml) against all Pasteurella species, Staphylococcus aureus, and streptococci; anaerobes were susceptible to < or = 0.5 microg/ml, except fusobacteria, which were susceptible to < or = 2 microg/ml. Against aerobes, levofloxacin was more active than ofloxacin (MIC at which 90% of isolates are inhibited [MIC90], < or = 1.0 microg/ml for both) and sparfloxacin and ciprofloxacin were also active (MIC90s, < or = 0.25 and < 1 microg/ml, respectively).     

Antistaphylococcal and antistreptococcal killing kinetics of ciprofloxacin, ofloxacin, sparfloxacin, and trovafloxacin

BACKGROUND: Use of blood culture studies for early diagnosis of Mycobacterium avium complex (MAC) infection has become important due to the recent development of effective antibiotic therapy for this condition. This study assessed the abdominal computed tomography (CT) findings in patients with AIDS who presented with bacteraemic MAC infection. METHODS: A retrospective analysis of abdominal CT scans was performed in 24 patients who presented with MAC-positive blood culture. CT images were reviewed specifically to evaluate for lymph node enlargement and attenuation, hepatomegaly, splenomegaly, bowel wall abnormality and for any other pathological changes. Comparison was made to prior reports of the CT findings in this disease process. RESULT: Enlarged intra-abdominal mesenteric and/or retroperitoneal lymph nodes were found in 10 patients (42%). These nodes were characterized by homogeneous, soft-tissue attenuation in eight of the 10 patients. Hepatomegaly, splenomegaly and small bowel wall thickening were noted in 12 (50%), 11 (46%) and four (14%) patients, respectively. CT findings were evaluated as normal in six (25%) patients. CONCLUSIONS: Enlarged mesenteric and/or retroperitoneal lymph nodes in AIDS patients with bacteraemic MAC were observed much less frequently on CT than previously reported in AIDS patient populations. Normal abdominal CT findings do not exclude this diagnosis and may reflect a trend towards earlier detection of MAC disease.     

Comparative antimycobacterial activities of the newly synthesized quinolone AM-1155, sparfloxacin, and ofloxacin

AM-1155 is a newly synthesized 6-fluoro-8-methoxy quinolone. We assessed its in vitro antimycobacterial activity using sparfloxacin (SPFX) and ofloxacin (OFLX) as comparison drugs. The MICs of these agents for various mycobacterial strains were determined by the agar dilution method with 7H11 medium. AM-1155 had lower MICs for 50 and 90% of tested strains of Mycobacterium kansasii, M. marinum, and M. fortuitum-M. chelonae complex than SPFX and OFLX, and the values for M. tuberculosis, M. scrofulaceum, and the M. avium-M. intracellulare complex were similar to those of SPFX and considerably lower than those of OFLX. In addition, the antimicrobial activity of AM-1155 against M. tuberculosis and M. intracellulare phagocytosed into murine peritoneal macrophages was compared with that of OFLX. AM-1155 (1 microgram/ml) inhibited the intracellular growth of both M. tuberculosis and M. intracellulare, whereas OFLX at the same concentration failed to show any such effect. Moreover, AM-1155 (10 micrograms/ml) exhibited a steady bactericidal action against M. tuberculosis, whereas OFLX at the same concentration had only a weak effect. AM-1155 (10 micrograms/ml) also inhibited the growth of M. intracellulare more effectively than OFLX.     

Comparison of the antibacterial activities of the quinolones Bay 12-8039, gatifloxacin (AM 1155), trovafloxacin, clinafloxacin, levofloxacin and ciprofloxacin

The in-vitro activities of the quinolones Bay 12-8039, gatifloxacin (AM 1155), trovafloxacin, clinafloxacin, levofloxacin and ciprofloxacin were compared. Gram-positive cocci were most susceptible to Bay 12-8039, clinafloxacin and trovafloxacin; Enterobacteriaceae and fastidious organisms were most susceptible to clinafloxacin [corrected]; Pseudomonas spp. were most susceptible to clinafloxacin and ciprofloxacin; anaerobes, Helicobacter pylori and Campylobacter jejuni were most susceptible to gatifloxacin, clinafloxacin and trovafloxacin. Against gram-positive cocci, the only agents that were more active than ciprofloxacin were those carrying an azabicyclo (trovafloxacin, Bay 12-8039), 3-amino-pyrrolidinyl (clinafloxacin) or 3-methyl-piperazinyl (gatifloxacin) moiety at position C7.     

Comparative activity of trovafloxacin and Bay 12-8039 against 452 clinical isolates of Streptococcus pneumoniae

BACKGROUND: We compared uptake of hospital and community-based support in elderly people disabled by chronic obstructive pulmonary disease (COPD), normal controls (NCs) and patients with Parkinsons disease, stroke, amputation, or arthritis (disabled controls; DCs). METHODS: There were 65 subjects (35 men) aged 70-93 years (mean 78) with COPD, 55 NCs [23 men; age range 71-90 years (mean 78)] and 53 DCs [27 men; age range 70-92 years (mean 78)]. Patients with COPD and DCs were outpatients with Nottingham extended activities of daily living (NEADL) score < 16. NCs came from a community survey. Subjects with COPD were clinically stable. All were cognitively intact. RESULTS: Mean NEADL scores (and range) were: 10.2 (3-15) for patients with COPD, 9.4 (3-15) for DCs (t=1.14, P=0.26) and 19.0 (11-21) for NCs. There was no difference in meals-on-wheels, district nurse or hospital or physiotherapy provision between patients with COPD and NCs, but those with COPD received more home care (P < 0.01). DCs received more home care (P=0.04), more district nurse input (P < 0.001) and more physiotherapy (P < 0.0001) than those with COPD. CONCLUSIONS: Despite moderate or severe disability, elderly patients with COPD receive little statutory domiciliary support. Reasons for this need further exploration.     

In vitro studies of pharmacodynamic properties of vancomycin against Staphylococcus aureus and Staphylococcus epidermidis

The bactericidal activities of vancomycin against two reference strains and two clinical isolates of Staphylococcus aureus and Staphylococcus epidermidis were studied with five different concentrations ranging from 2x to 64x the MIC. The decrease in the numbers of CFU at 24 h was at least 3 log10 CFU/ml for all strains. No concentration-dependent killing was observed. The postantibiotic effect (PAE) was determined by obtaining viable counts for two of the reference strains, and the viable counts varied markedly: 1.2 h for S. aureus and 6.0 h for S. epidermidis. The determinations of the PAE, the postantibiotic sub-MIC effect (PA SME), and the sub-MIC effect (SME) for all strains were done with BioScreen C, a computerized incubator for bacteria. The PA SMEs were longer than the SMEs for all strains tested. A newly developed in vitro kinetic model was used to expose the bacteria to continuously decreasing concentrations of vancomycin. A filter prevented the loss of bacteria during the experiments. One reference strain each of S. aureus and S. epidermidis and two clinical isolates of S. aureus were exposed to an initial concentration of 10x the MIC of vancomycin with two different half-lives (t1/2s): 1 or 5 h. The post-MIC effect (PME) was calculated as the difference in time for the bacteria to grow 1 log10 CFU/ml from the numbers of CFU obtained at the time when the MIC was reached and the corresponding time for an unexposed control culture. The difference in PME between the strains was not as pronounced as that for the PAE. Furthermore, the PME was shorter when a t1/2 of 5 h (approximate terminal t1/2 in humans) was used. The PMEs at t1/2s of 1 and 5 h were 6.5 and 3.6 h, respectively, for S. aureus. The corresponding figures for S. epidermidis were 10.3 and less than 6 h. The shorter PMEs achieved with a t1/2 of 5 h and the lack of concentration-dependent killing indicate that the time above the MIC is the parameter most important for the efficacy of vancomycin.     

Variation in the susceptibility of strains of Staphylococcus aureus to oxacillin, cephalothin, and gentamicin

Three cases of staphylococcal bacteremia caused by organisms that were inhibited by low concentrations of oxacillin, but were resistant to the killing effects of oxacillin, stimulated us to screen 60 clinical isolates of Staphylococcus aureus for their susceptibility to oxacillin, cephalothin, and gentamicin. All 60 strains were inhibited by low concentrations of the antibiotics. The antibiotics were bactericidal against 27 of the 60 strains and only bacteriostatic against the other 33 after 24 h of incubation. However, after 48 h of incubation, the antibiotics were also bactericidal against the latter group.     

Antibacterial activities of OPC-17116, ofloxacin, and ciprofloxacin against 200 isolates of Neisseria gonorrhoeae

OPC-17116 is a new fluoroquinolone with potent activity against aerobic and anaerobic organisms. We evaluated the susceptibilities of 200 clinical gonococcal isolates including organisms with plasmid and chromosomally mediated resistance to beta-lactams and tetracycline. The antibiotics studied included OPC-17116, ofloxacin, ciprofloxacin, penicillin, tetracycline, erythromycin, azithromycin, and ceftriaxone. All isolates tested were susceptible to the quinolone class of antibiotics. The MICs of ciprofloxacin, ofloxacin, and OPC-17116 for 90% of isolates tested were 0.004, 0.03, and 0.004 micrograms/ml, respectively. For organisms with chromosomally mediated resistance to penicillin and tetracycline, geometric mean MICs of all antibiotics including the quinolones were increased.     

In vitro activities of semisynthetic pneumocandin L-733,560 against fluconazole-resistant and -susceptible Candida albicans isolates

Lipopeptide L-733,560 is a water-soluble derivative of pneumocandin B0 that exhibits enhanced anti-Candida activity. We investigated the in vitro activity of L-733,560 compared with those of amphotericin B, flucytosine, and itraconazole, against fluconazole-resistant (n = 44) and fluconazole-susceptible (n = 46) Candida albicans isolates. Tests were performed with a photometer-read broth microdilution method with RPMI-2% glucose and National Committee for Clinical Laboratory Standards reference strains. Except for those of itraconazole, MICs were not significantly different between the two groups of isolates, as expected for agents with different mechanisms of action. L-733,560 was the most active agent against C.albicans, with MICs for 50 and 90% of the strains tested of 0.01 and 0.06 microgram/ml, respectively.     

Antibacterial activities of combination uses of isepamicin and beta-lactams in vitro against clinically isolated strains. Part 1. Activities against Staphylococcus aureus

In order to evaluate antibacterial activities of combination uses of isepamicin (ISP) and beta-lactams in vitro, minimum inhibitory concentrations (MICs) these drugs were examined singly and in combination against clinically isolated Staphylococcus aureus. The results are summarized as follows; 1. MICs of ISP + cefazolin (CEZ), ISP + cefotiam (CTM) and ISP + flomoxef (FMOX) were low and the activities against methicillin (DMPPC)-susceptible S. aureus (MSSA) were dependent on the concentration of ISP. Combined effects were observed when the concentrations of ISP were at sub-MIC levels (1/2 approximately 1/4 concentrations). 2. MICs of ISP + CEX, ISP + CTM, ISP + FMOX, ISP + imipenem and ISP + panipenem were low and the activities against DMPPC-resistant S. aureus (MRSA) were dependent on the concentration of ISP, and were similar to those against MSSA. Combined effects were observed when the concentrations of ISP were at sub-MIC levels of ISP. Lower MIC50 or MIC90 was observed at ISP concentrations of 4 approximately 16 micrograms/ml. 3. The blood Cmax of ISP exceeded 20 micrograms/ml at one-time administration of ISP 400 mg, and these results suggested that antibacterial activities of combination uses of ISP and beta-lactams was clinically effective against MRSA infections.     

Antipneumococcal activities of RP 59500 (quinupristin-dalfopristin), penicillin G, erythromycin, and sparfloxacin determined by MIC and rapid time-kill methodologies

Previous time-kill studies have shown that RP 59500 is rapidly bactericidal against pneumococci. To extend these findings, the activities of RP 59500, its two components RP 57669 RP 54476, penicillin G, erythromycin and sparfloxacin against 26 penicillin-susceptible, 25 penicillin-intermediate, and 25 penicillin-intermediate, and 25 penicillin-resistant pneumococci were determined by the agar dilution MIC and the time-kill testing methodologies within 10 min (ca. 0.2 h) and at 1 and 2 h. Respective agar dilution MICs at which 90% of isolates are inhibited for penicillin-susceptible, -intermediate, and -resistant strains were as follows: penicillin G, 0.03, 1, and 4 micrograms/ml;RP 59500, 1, 1, and 1 microgram/ml; RP 57669, 8, 32, and 16 micrograms/ml; RP 54476, > 128, > 128, and > 128 micrograms/ml; erythromycin, 0.06, 2, and > 128 micrograms/ml; and sparfloxacin, 1, 0.5, and 0.5 microgram/ml. RP 59500 was equally active (MIC at which 90% of isolates are inhibited, 1.0 microgram/ml) against erythromycin-susceptible and -resistant strains. Time-kill testing results showed that only RP 59500 at one to four times the MIC killed pneumococci at 0.2 h; RP 59500 was also the most active compound at 1 and 2 h. By comparison, penicillin and sparfloxacin at one, two, and four times the MICs reduced the original inoculum by > or = 1 log at 2 h for 46, 80, and 95% and for 50, 72, and 86% of strains, respectively. The killing activity of RP 59500 was the same against erythromycin-susceptible and -resistant strains. RP 57669, RP 54479, and erythromycin were either inactive or bacteriostatic at 2 h. Of all drugs tested, RP 59500 yielded the most rapid killing.     

Variation in postantibiotic effect of clindamycin against clinical isolates of Staphylococcus aureus and implications for dosing of patients with osteomyelitis

Initial measurements of postantibiotic effect (PAE) were made by a standard laboratory method (exposure to 1 mg of clindamycin per liter for 1 h). The range of PAE for 21 strains of Staphylococcus aureus isolated from osteomyelitis patients was 0.4 to 3.9 h, which markedly exceeded the coefficient of variation for the method (6 to 19%). Exposure of S. aureus to three doses of clindamycin at 8-h intervals had no consistent effect on either PAE or MIC. The PAE was dependent on both concentration and duration of exposure to clindamycin: for example, the PAEs for one strain were 1.7 h after exposure to 1 mg/liter for 1 h, 2.4 h after exposure to 4 mg/liter for 1 h, and 5.9 h after exposure to 4 mg/liter for 3 h. Pharmacokinetic simulations showed that the dose required to maintain free serum clindamycin concentrations above the MIC was 300 mg 6 hourly after oral administration (95% confidence interval, 243 to 301 mg) and 1.2 g 6 hourly (95% confidence interval, 305 to 1,145 mg) after intravenous (i.v.) administration. The duration of PAE would have to be at least 2.4 h to allow an increase in the oral dose interval to 8 h or to allow i.v. administration of 300 mg 6 hourly. Additional PAE experiments were performed with the three strains for which PAEs are the shortest after exposure to 1 mg/liter for 1 h (0.4 to 1.2 h). The PAE for these three strains increased markedly to 4.4 to 6.7 h following exposure to 2 mg/liter for 6 h (to mimic the area under the concentration-time curve from 0 to 6 h after a 300-mg dose). These data suggest that oral clindamycin could be administered at 300 mg 8 hourly in the treatment of S. aureus infection, whereas the i.v. dose interval should be 6 h. These suggestions should be confirmed by performing clinical trials.     

Inhibitory activities of quinolones against DNA gyrase and topoisomerase IV purified from Staphylococcus aureus

In order to clarify the mechanism of action of quinolones against Staphylococcus aureus, GrlA and GrlB proteins of topoisomerase IV encoded by genes with or without mutations were purified separately as fusion proteins with maltose-binding protein in Escherichia coli. The reconstituted enzymes showed ATP-dependent decatenation and relaxing activities but had no supercoiling activity. The inhibitory effects of quinolones on the decatenation activity of topoisomerase IV were determined by quantitative electrophoresis with kinetoplast DNA as a substrate. The 50% inhibitory concentrations (IC50s) of levofloxacin, DR-3354, DU-6859a, DV-7751a, ciprofloxacin, sparfloxacin, and tosufloxacin against topoisomerase IV of S. aureus FDA 209-P were 2.3, 97, 0.45, 1.5, 2.5, 7.4, and 1.8 microg/ml, respectively, and were correlated well with their MICs. The IC50s of these drugs were from 2 to 20 times lower than those for the DNA gyrase. These results support genetic evidence that the primary target of new quinolones is topoisomerase IV in quinolone-susceptible strains of S. aureus. Three altered proteins of topoisomerase IV containing Ser-->Phe changes at codon 80 or Glu-->Lys changes at codon 84 of grlA, or both, were also purified. The inhibitory activities of quinolones against the topoisomerase IV which contained a single amino acid change were from 8 to 95 times weaker than those against the nonaltered enzyme. These results suggest that the mutations in the corresponding genes confer quinolone resistance.     

In vitro activities of co-amoxiclav at concentrations achieved in human serum against the resistant subpopulation of heteroresistant Staphylococcus aureus: a controlled study with vancomycin

The effects of concentrations that simulated those in human serum after a single intravenous dose of amoxicillin (2 g), amoxicillin-clavulanic acid (2,000 and 200 mg, respectively), or vancomycin (500 mg), on the viability and beta-lactamase activity of two isogenic (beta-lactamase and non-beta-lactamase producer) heteroresistant Staphylococcus aureus strains were studied in an in vitro pharmacodynamic model. A reduction of > or = 97% of the initial inoculum was obtained with vancomycin and amoxicillin-clavulanic acid against both strains, with respect to the total bacterial population and the oxacillin-resistant subpopulation. The same pattern was observed with amoxicillin and the beta-lactamase-negative strain. beta-Lactamase activity in the beta-lactamase-positive strain changed over time parallel to viability, decreasing with amoxicillin-clavulanic acid or vancomycin and increasing in the amoxicillin and control groups. Clavulanic acid concentrations achievable in serum that changed over time allowed amoxicillin to act against the beta-lactamase-producing methicillin-resistant S. aureus to a similar extent as vancomycin.     

Resistance to gentamicin, tobramycin and amikacin among clinical isolates of bacteria

Susceptibility to the administration of gentamicin, tobramycin and amikacin was determined for all isolates of aerobic and facultative gram-negative bacilli submitted for testing to the clinical bacteriology laboratory of the Massachusetts General Hospital between July 1, 1974, and June 30, 1976. In this 24-month period more than 46,000 isolates of bacteria were tested by the single-disc diffusion (Bauer-Kirby) method. Resistance to one or more of the aforementioned aminoglycosidic aminocyclitol antibiotics was found among 4,114 stains. Correlation with quantitative susceptibility test methods revealed that disc-diffusion methods using 10 microng discs accurately predicted resistance to gentamicin and tobramycin, but overestimated the prevalence of resistance to amikacin by 20 to 60%. Most of the gentamicin-resistant Enterobacteriaceae in this study were also cross-resistant to tobramycin but were susceptible to amikacin. Many gentamicin-resistant strains of Ps. aeruginosa were susceptible to both tobramycin and amikacin. Resistance to amikacin tended to be of relatively low magnitude (most had minimal inhibitory concentrations (MIC's) between 31 and 125 microng/ml), but organisms which were resistant to the administration of amikacin were usually resistant to the other two aminoglycosidic antibiotics as well.     

Comparative in vitro killing activities of meropenem, imipenem, ceftriaxone, and ceftriaxone plus vancomycin at clinically achievable cerebrospinal fluid concentrations against penicillin-resistant Streptococcus pneumoniae isolates from children with meningitis

The activities of meropenem, imipenem, ceftriaxone, and vancomycin were evaluated against 80 penicillin-susceptible and -resistant Streptococcus pneumoniae strains. Meropenem, imipenem, ceftriaxone, and vancomycin MICs at which 90% of the isolates are inhibited were 0.5, 0.25, 1, and 0.25 microg/ml, respectively. Against penicillin-resistant strains, the best killing activity at cerebrospinal fluid concentrations was obtained with imipenem and ceftriaxone-vancomycin. However, while the killing activity of imipenem was significantly greater than that of meropenem, no significant difference was observed between the activities of meropenem and ceftriaxone-vancomycin.