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PubMed1978

Differential control of synergistic effect with polyene macrolide antibiotics upon Chinese hamster cells in vitro.

An amphotericin B-resistant cell (AMBR-1), which was isolated from aneuploid Chinese hamster cells (V79), was found to show much higher resistance than the parent V79 cells to other polyene antibiotics, such as pentamycin and filipin. To obtain the 50 to 60% inhibition of the control protein synthesis activity by a synergistic combination of fusidic acid and amphotericin B, 50 microgram fusidic acid per ml were combined with 10 microgram amphotericin B in V79 cells, whereas in AMBR cells 50 microgram fusidic acid per ml were combined with 100 microgram polyene antibiotic per ml. Bleomycin (10 microgram/ml), which alone did not affect cellular DNA synthesis, inhibited DNA synthesis of V79 cells by more than 90% of the control activity when combined with only 1 microgram pentamycin per ml, whereas a similar extent of inhibition in AMBR cells was observed by combination with more than 5 microgram pentamycin per ml.

Amphotericin B↗
PubMed1988

Analysis of drug resistance in the archaebacterium Methanococcus voltae with respect to potential use in genetic engineering.

The sensitivity of the methanogenic archaebacterium Methanococcus voltae to 12 inhibitors was tested in liquid medium. Four compounds appeared to be inhibitors of growth. Their MICs were as follows: pseudomonic acid, 0.1 micrograms/ml (0.19 microM); puromycin, 2 micrograms/ml (3.6 microM); methionine sulfoximine, 30 micrograms/ml (170 microM); and fusidic acid, 100 micrograms/ml (170 microM). On solid medium, the MICs were similar and the frequency of spontaneous resistance was found to be 5 X 10(-5) (methionine sulfoximine), 10(-7) (pseudomonic acid), and less than 10(-7) (puromycin and fusidic acid). Pseudomonic acid was found to inhibit isoleucyl-tRNA synthetase activity as measured by the in vitro aminoacylation of M. voltae tRNA with L-[U-14C]isoleucine. Fusidic acid and puromycin were shown to inhibit poly(U)-dependent polyphenylalanine synthesis in S30 extracts. Acetylpuromycin was inhibitory at much higher concentrations both in vivo and in vitro for M. voltae. Thus, the pac gene of Streptomyces alboniger, which is responsible for acetylation of puromycin and which conferred resistance to puromycin when introduced in eubacteria and eucaryotes, is a potential selective marker in gene transfer experiments with M. voltae. The latter was recently shown to be transformable. The same would be true for the cat gene of Tn9, which encodes resistance to fusidic acid in eubacteria in addition to resistance to chloramphenicol.

Anti-Bacterial Agents↗
PubMed1976

Equilibrium measurements of the interactions of guanine nucleotides with Escherichia coli elongation factor G and the ribosome.

The interactions among Escherichia coli elongation factor G (EF-G), guanine nucleotides, ribosomes, and fusidic acid were investigated by a number of physical techniques. Equilibrium dialysis studies demonstrated the existence of a binary EF-G-GDP complex. This complex forms with a stoichiometry of ca 1:1 and an apparent Ka of 2.5 X 10(5) M-1. While no evidence was obtained for the formation of a ribosome-GDP complex, in the presence of ribosomes, the apparent Ka for guanosine diphosphate (GDP) increased 40-fold over that for binding to EF-G alone. Although the apparent Ka increased, the stoichiometry remained ca. 1 mol of GDP/mol of EF-G. An upper limit of 1.3 X 10(7) M-1 was calculated for the Ka for binding of ribosomes to the EF-G-GDP complex. Fusidic acid had no effect on the apparent Ka's for either the EF-G-GDP or EF-G-beta, gamma-methyleneguanosine triphosphate (GMP-P(CH2)P)=ribosome complexes, but markedly increased the Ka for GDP in the EF-G-GDP-ribosome complex without altering the stoichiometry. The apparent Ka for GDP was shown to be dependent upon the fusidic acid concentration. In addition, the rate of GDP exchange into the quaternary EF-G-GDP-ribosome-fusidic acid complex was inversely related to the fusidic acid concentration. All of the data obtained in these studies suggest that the formation and dissociation of complexes involving EF-G and guanine nucleotides is ordered. GDP is the first component to bind to EF-G, followed by the ribosome, and, finally, fusidic acid. This conclusion is consistent with the kinetic mechanism for the hydrolysis of GTP by EF-G and the ribosome proposed in the preceding paper of this issue (Rohrbach and Bodley (1976b). In addition to these binding studies, guanine nucleotides have also been shown to protect EF-G against both limited trypsinolysis and chemical modification by N-ethylmaleimide. These observations offer additional evidence for the existence of a guanine nucleotide binding site on EF-G.

Binding Sites↗
PubMed1998

Feasibility of measuring lipophilic or protein-bound drugs in the dermis by in vivo microdialysis after topical or systemic drug administration.

Our aim was to assess the microdialysis technique for determining in vivo drug levels of a lipophilic and a protein-bound model drug in the dermis. Forearm skin of healthy volunteers received topical 2% fusidic acid or 0.1% betamethasone-17-valerate formulations twice daily as occluded treatment on irritative dermatitis. Microdialysis sampling in the dermis after 48 h was without measurable drug. Hairless rats received maximized treatment with occluded applications of 10% fusidic acid or 4% betamethasone-17-valerate in ethanol for 72 h followed by microdialysis. Mean levels of betamethasone-17-valerate were 11-45 ng/ml; fusidic acid was not measurable. Systemic administration in clinical doses to rats was without measurable drug levels; increasing doses to 312 mg/kg of fusidic acid and 158 mg/kg of betamethasone-17-valerate yielded betamethasone-17-valerate levels of 25-44 ng/ml and fusidic acid levels of 10-90 ng/ml. This study demonstrates the challenges arising when using microdialysis for measuring in vivo-drug levels. For the drugs chosen it was necessary to administer very high systemic doses or apply a high topical drug concentration to obtain measurable drug levels in the dialysates. Drug levels were in the nanomolar range and demonstrated reproducible and dynamic monitoring of in vivo drug levels in the skin. Using microdialysis for sampling highly protein-bound or lipophilic drugs in the skin requires very sensitive analytical methods, and the sensitivity of the analysis is likely to be the limiting factor.

Administration, Oral↗
PubMed1991

The effect of antistaphylococcal agents used alone and in combinations on the survival of Staphylococcus aureus ingested by human polymorphonuclear leukocytes.

The intracellular activity of a number of drugs used alone and in combinations against Staphylococcus aureus was investigated using an experimental design which imitates the clinical situation and differs from other published methods. Staphylococci were phagocytosed by human polymorphonuclear leukocytes and, after differential centrifugation and washing, the granulocytes were incubated in 90% pooled human serum with clinically relevant drug concentrations. When exposed to antibiotics, more than 40-50% of the bacteria were located intracellularly. Fusidic acid (100 mg/l), erythromycin (20 mg/l), and clindamycin (20 mg/l) all had a bacteriostatic effect during the first 6 h of incubation, whereas rifampicin (1 and 5 mg/l), vancomycin (5 and 20 mg/l), and ciprofloxacin (2 mg/l) all acted bactericidally with decreases in viable counts between 1.3-1.9 log10. The greatest bactericidal effect was achieved with tobramycin (10 mg/l), which produced more than a 4 log10 decrease in viable counts at 6 h. Combinations of fusidic acid with other antibiotics all resulted in killing kinetics different from those achieved with the drugs used individually. The bactericidal effect of ciprofloxacin and dicloxacillin during the first 6 h was abolished when these drugs were combined with fusidic acid. However, at 24 h no significant difference was found between the effect of dicloxacillin alone versus the combination dicloxacillin and fusidic acid. The combination of fusidic acid and rifampicin resulted in a killing identical to that achieved with rifampicin used alone during the first 6 h, but at 24 h the killing by the combination was significantly greater. The bactericidal effect of the combination dicloxacillin (20 mg/l) and tobramycin (10 mg/l) equalled that obtained with tobramycin (10 mg/l) used alone. Rifampicin (5 mg/l) antagonized the bactericidal effect of ciprofloxacin (2 mg/l) during the first 6 h of incubation but at 24 h the combination acted synergistically. The results obtained are partly in agreement and partly in conflict with previous results.

Anti-Bacterial Agents↗
PubMed1972

Technique to improve the rate of healing of incised abscesses.

In a comparative investigation incised skin abscesses were treated by either introducing sterile fusidic acid gel into the cavity on one occasion only or applying daily superficial dressings impregnated with sodium fusidate ointment. In comparison with the dressing group, the intracavity use of fusidic acid gel reduced the mean healing time of incised abscesses by approximately one-half. When abscesses were analysed according to site and size, the reduction in mean healing time was equally striking. No hypersentisivity or irritation to fusidic acid or its sodium salt applied by either method was observed.The procedure of introducing fusidic acid gel into an incised abscess cavity is a promising alternative to superficial antibiotic dressings or wicks in the treatment of incised abscesses.

Abscess↗
PubMed2004

Anti-staphylococcal activity of indolmycin, a potential topical agent for control of staphylococcal infections.

OBJECTIVES: We sought to investigate the anti-staphylococcal activity of indolmycin, with particular emphasis on comparing its activity with fusidic acid and mupirocin. METHODS: Established procedures were used to examine the activity of indolmycin against a range of clinical isolates, including strains resistant to fusidic acid and mupirocin. Indolmycin-resistant mutants were recovered and characterized phenotypically and genotypically. RESULTS: Indolmycin was bacteriostatic and demonstrated good activity against MSSA (methicillin-susceptible Staphylococcus aureus), MRSA (methicillin-resistant S. aureus) and VISA (vancomycin-intermediate S. aureus), including strains resistant to mupirocin or fusidic acid. Spontaneous indolmycin-resistant mutants occurred at a lower frequency than those selected by mupirocin or fusidic acid and exhibited no cross-resistance with the comparative drugs. High-level resistance (indolmycin MIC 128 mg/L) that was associated with an H43N mutation in tryptophanyl-tRNA synthetase (TrpS), the target enzyme of indolmycin, resulted in loss of bacterial fitness. However, the locus responsible for low-level indolmycin resistance (indolmycin MICs 8-32 mg/L) was not identified. CONCLUSIONS: Indolmycin is a potent anti-staphylococcal agent, which exhibits activity against mupirocin- and fusidic acid-resistant strains. Indolmycin might be a candidate for development as a topical agent in the treatment of staphylococcal infections and nasal carriage of MRSA.

Anti-Infective Agents, Local↗
PubMed1986

In vitro and in vivo activity of coumermycin and other antibacterial agents against methicillin-resistant strains of Staphylococcus aureus.

The in vitro activity of coumermycin, fusidic acid, cotrimoxazole, and vancomycin was determined by broth microdilution assay against 33 methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates from the Detroit Receiving Hospital, Detroit, Mich. Coumermycin was the most active drug tested, while fusidic acid, vancomycin, and cotrimoxazole also had good activity. The four antimicrobials were tested in vivo against 7 strains of MRSA employing the mouse protection model. Again, coumermycin was the most active, followed by vancomycin, cotrimoxazole, and fusidic acid. Coumermycin was very active, while vancomycin and fusidic acid were inactive in neutropenic mice infected with an MRSA strain. Coumermycin retained activity when given 18 h before an MRSA infection, while vancomycin activity was lost. Coumermycin was active in a local thigh infection while vancomycin was inactive. The results indicate that coumermycin is potent against MRSA with activity equal or superior to comparable agents in various experimental mouse infections.

Aminocoumarins↗
PubMed1996

A bioavailability comparison in rabbits after a single topical ocular application of prednisolone acetate formulated as a high-viscosity gel and as an aqueous suspension.

To increase contact time between drug and ocular surface and thus improve the bioavailability, we used the high-viscous, water-soluble polymer carbomer Leogel (carbomer 0.5%). The drugs were applied to Copenhagen white rabbits as a single application. We compared the bioavailability of prednisolone acetate 0.5% in Leogel with fusidic acid 1% after 1, 4, 7 and 10 h (n = 3 at each time points) with that obtained when doubling the prednisolone acetate concentration in unchanged Leogel and fusidic acid 1% in 12 rabbits. In addition we compared the bioavailability of prednisolone acetate 0.5% given in 1) Leogel using fusidic acid 1% with that obtained using 2) aqueous sulfacetamide sodium 10% as vehicle after 0.5, 1, 1.5, 2, 3, 6, 8 and 12 h (n = 6 at each time points) in 54 rabbits. When doubling the prednisolone acetate dose an increase in bioavailability was achieved in conjunctiva, cornea and aqueous humour with 1.57, 3.86 and 2.18 times, respectively. Prednisolone concentrations in cornea, conjunctiva and aqueous humour were higher using the Leogel vehicle than using the aqueous suspension. The bioavailability in 0-12 h for prednisolone acetate in Leogel and fusidic acid 1% to conjunctiva was significantly higher (p = 0.003) than for prednisolone acetate in aqueous and sulfacetamide sodium 10%. The bioavailability (0-6 h) for conjunctiva was significantly higher for the Leogel preparation than for the aqueous suspension (p < 0.001). For cornea and aqueous humour, the bioavailability values for the total period (0-12 h) do not differ significantly. However, for the first 6 h the difference is significant (p < 0.001 for cornea and p = 0.003 for aqueous humour).

Administration, Topical↗
PubMed1997

Retrospective study of outcome in patients treated for Staphylococcus aureus bacteremia.

OBJECTIVE: To investigate whether a change in current treatment practice for Staphylococcus aureus bacteremia from flucloxacillin and aminoglycoside to flucloxacillin and fusidic acid was associated with any changes in outcome. METHODS: A retrospective analysis was carried out of 316 episodes of S. aureus bacteremia diagnosed and treated in a tertiary hospital complex between 1983 and 1993. Outcomes considered were (1) death related to the infection and (2) relapse following cessation of antibiotic therapy. RESULTS: Mortality related to infection, which occurred in 24% of patients, was unrelated to treatment with the combination of flucloxacillin and fusidic acid; however, increasing age was a significant risk factor (OR per decade=1.35, 95% CI=1.18-1.55), and increasing duration of treatment (OR per week of treatment=0.63, 95% CI=0.52-0.77), use of flucloxacillin (OR=0.30, 95% CI=0.14-0.64), presence of an intravascular device (OR=0.39, 95% CI=0.20-0.78) and presence of a skin lesion (OR=0.51, 95% CI=0.26-0.99) were significant protective factors. The only factor significantly related to relapse, which occurred in 11% of patients, was treatment with the combination of flucloxacillin and fusidic acid (OR=0.32, 95% CI=0.12-0.85). There was approximately a 70% reduction in the risk of relapse if this combination was used. CONCLUSIONS: This retrospective analysis suggests a clinically important protective effect of fusidic acid against relapse in patients with S. aureus bacteremia. Although the results were adjusted for potential confounding factors, the possibility of bias remains. There is a need for a prospective randomized trial to evaluate the effectiveness of flucloxacillin and fusidic acid for treating S. aureus bacteremia.

Journal Article↗
PubMed1999

Evaluation of bile acids and fusidate derivative as nasal absorption enhancers using an electrophysiological technique.

The present study was carried out to investigate the reversibility of the action of two nasal absorption enhancers, bile acids and fusidate derivative, on nasal membrane resistance. The nasal mucosa was isolated from rabbit nasal septum and mounted in a Ussing-type chamber to allow the monitoring of the membrane resistance and flux of fluorescein isothiocyanate-labeled dextran (FD10, M.W. 9400). Membrane resistance was reduced by 46% following treatment with 0.5% (w/v) sodium taurodihydrofusidate (STDHF) for 10 min and then gradually returned to the control level after being wash. The resistance was restored to 76% of the control level following a 30 min treatment with 0.5% (w/v) STDHF. However, there was no recovery of resistance following treatment with 0.5% (w/v) STDHF for 120 min or 1% (w/v) STDHF for 10in. Concurrently, FD10 transport was enhanced while membrane resistance was reduced. Treatment with 0.5% (w/v) sodium deoxycholate (DC) for more than 10 min showed no reversible action and marked FD10 transport enhancement, whereas a 10-30 min treatment with 0.5% (w/v) sodium glycocholate (GC) or sodium taurocholate (TC) resulted in the rapid recovery of membrane resistance without any enhancement of FD10 permeation. STDHF transport across the nasal mucosa was approximately 2-fold faster than that of DC, GC, and TC. The accumulation of STDHF in the nasal mucosa was 2-fold lower than that of DC and 1.7-fold higher than that of GC and TC after a 30 min treatment. The rank order of hydrophobicity determined by reverse-phase HPLC was: DC>STDHF>GC>TC. These results suggest that the reduction in membrane resistance and its reversibility appear to be due to a balance between the accumulation and clearance of STDHF.

Absorption↗
PubMed2006

Antibacterial resistance and their genetic location in MRSA isolated in Kuwait hospitals, 1994-2004.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a major cause of serious infections in hospitals and in the community worldwide. In this study, MRSA isolated from patients in Kuwait hospitals were analyzed for resistance trends and the genetic location of their resistance determinants. METHODS: Between April 1994 and December 2004, 5644 MRSA isolates obtained from different clinical samples were studied for resistance to antibacterial agents according to guidelines from the National Committee for Clinical Laboratory Standards and the British Society for Antimicrobial Chemotherapy. The genetic location of their resistance determinants was determined by curing and transfer experiments. RESULTS: They were resistant to aminoglycosides, erythromycin, tetracycline, trimethoprim, fusidic acid, ciprofloxacin, chloramphenicol, rifampicin, mupirocin, cadmium acetate, mercuric chloride, propamidine isethionate and ethidium bromide but susceptible to vancomycin, teicoplanin and linezolid. The proportion of the isolates resistant to erythromycin, ciprofloxacin and fusidic acid increased during the study period. In contrast, the proportion of isolates resistant to gentamicin, tetracycline, chloramphenicol and trimethoprim declined. High-level mupirocin resistance increased rapidly from 1996 to 1999 and then declined. They contained plasmids of 1.9, 2.8, 3.0, 4.4, 27 and 38 kilobases. Genetic studies revealed that they carried plasmid-borne resistance to high-level mupirocin resistance (38 kb), chloramphenicol (2.8-4.4 kb), erythromycin (2.8-3.0 kb) and cadmium acetate, mercuric chloride, propamidine isethionate and ethidium bromide (27 kb) and chromosomal location for methicillin, the aminoglycosides, tetracycline, fusidic acid, ciprofloxacin and trimethoprim resistance. Thus, the 27 kb plasmids had resistance phenotypes similar to plasmids reported in MRSA isolates in South East Asia. CONCLUSION: The prevalence of resistance to erythromycin, ciprofloxacin, high-level mupirocin and fusidic acid increased whereas the proportion of isolates resistant to gentamicin, tetracycline, chloramphenicol and trimethoprim declined during the study period. They contained 27-kb plasmids encoding resistance to cadmium acetate, mercuric chloride, propamidine isethionate and ethidium bromide similar to plasmids isolated in MRSA from South East Asia. Molecular typing of these isolates will clarify their relationship to MRSA from South East Asia.

Acetates↗
PubMed2001

Comparative review of topical ophthalmic antibacterial preparations.

The choice of an antibacterial is based on considerations of pharmacodynamic, pharmacokinetic and bacteriological characteristics, risk of selecting resistant mutants, and cost. In this article we review 16 commercially available ophthalmic antibacterial preparations. Fusidic acid and bacitracin are selective for gram-positive bacteria whereas polymyxin B targets gram-negative species. Aminoglycosides and quinolones are broad spectrum antibacterials. The widespread use of an antibacterial increases risks of selecting resistance to it. Acquired resistance is well documented for fusidic acid and rifamycin, and newly described for quinolones. The bioavailability of an antibacterial agent depends on the target bacterial species, the site of infection and the integrity of the haemato-aqueous barrier. Some agents (fusidic acid, quinolones) penetrate the cornea, passing into the anterior chamber of normal eyes at therapeutic concentrations, whereas others (polymixin B, bacitracin) have no penetrating powers and remain at the surface of the eye. Toxicity is mostly manifested by allergic reactions to excipients or active ingredients in topical antibacterial preparations. A few cases of haematological toxicity have brought suspicion on topical chloramphenicol, but the link has yet to be proven. Erythromycin and polymyxin B are probably okay to use as topical applications in pregnant women and nursing mothers. Costs of treatment must be evaluated as a whole (regimen, drug associations). Prices for a bottle of eyedrops may vary 3-fold. The cheapest drugs include chloramphenicol, polymyxin B and gentamicin, the most expensive being fusidic acid and the quinolones.

Administration, Topical↗
PubMed2002

Emergence of vancomycin-intermediate Staphylococcus aureus in a Belgian hospital: microbiological and clinical features.

In 1999, all clinical Staphylococcus aureus isolates from patients admitted to a Belgian University hospital were tested for decreased vancomycin susceptibility. Three vancomycin-intermediate Staphylococcus aureus (VISA) and four hetero-VISA strains were detected among 2145 isolates tested. They emerged from strains that belonged to locally endemic methicillin-resistant S. aureus (MRSA) genotypes in three patients who had received repeated courses of vancomycin therapy. A cystic fibrosis patient with MRSA/VISA-associated broncho-pulmonary exacerbation was successfully treated by continuous vancomycin infusion plus fusidic acid followed by oral minocycline-fusidic acid. Two other patients had VISA recovered from specimens of undetermined clinical significance. Emergence of VISA variants of endemic MRSA strains in Belgium warrants active microbiological surveillance and careful monitoring of vancomycin therapy. Therapy with high-dose vancomycin administered by continuous infusion in combination with other antimicrobials may be a therapeutic option worth investigating for VISA infection.

Adolescent↗
PubMed1980

Purification of Euglena gracilis chloroplast elongation factor G and comparison with other prokaryotic and eukaryotic translocases.

Euglena gracilis chloroplast protein synthesis elongation factor G (EF-Gchl) has been purified to about 80% homogeneity by a two-step procedure which removes all traces of the cytoplasmic and mitochondrial translocases (EF-2 and EF-Gmt). The purification scheme generally results in approximately 130-fold purification with 20% recovery of the total EF-G activity present in whole cell extracts. The Euglena EF-Gchl is a monomeric protein with a molecular weight of approximately 85,000. As observed for all translocases to date, the activity of Euglena EF-Gchl is inhibited by treatment with low concentrations of N-ethylmaleimide, suggesting that a free sulfhydryl group is required for catalytic activity. Treatment with 3 microM fusidic acid results in a 50% inhibition of Euglena EF-Gchl activity and of the EF-G activity present in Chlamydomonas reinhardtii. About 10-fold higher concentrations of this antibiotic are required to inhibit the mitochondrial EF-G of Euglena and Escherichia coli EF-G to the same extent. Yeast mitochondrial EF-G is clearly distinguishable from the other organellar translocases tested, requiring 1 mM fusidic acid for 50% inhibition. Fusidic acid also inhibits the cytoplasmic translocases from yeast, wheat germ, and Euglena, although a wide range of sensitivities is observed. When antiserum raised against highly purified Euglena EF-Gchl is used to inhibit enzymatic translocation, a low degree of cross-reaction of the antiserum with Chlamydomonas EF-G and with E. coli EF-G is observed. The EF-G activity present in spinach is very slightly inhibited by the antiserum, whereas that of yeast is not affected. The mitochondrial and cytoplasmic translocases of Euglena are also unaffected by the antiserum against EF-Gchl. The evolutionary implications of these observations are discussed.

Chlamydomonas↗
PubMed1984

Gentamicin- and methicillin-resistant, clinical isolates of Staphylococcus aureus: comparative in vitro and in vivo efficacy of alternative antimicrobial drugs.

Six representative clinical isolates of gentamicin- and methicillin-resistant (GRMR) Staphylococcus aureus, constituting phage groups II and III, were susceptible only to amikacin, cefamandole, clindamycin, fosfomycin, fusidic acid, netilmicin, nitrofurantoin, trimethoprim-sulfamethoxazole, and vancomycin (Bauer-Kirby test). With few exceptions, the minimal bactericidal concentrations of the beta-lactam and aminoglycoside antibiotics tested, fusidic acid, and irregularly those of vancomycin, but not those of fosfomycin and rifampin, exceeded minimal inhibitory concentrations values by at least 8-fold. In vitro, combinations of rifampin with cefamandole, cefazolin, cefotaxime, erythromycin, fosfomycin, fusidic acid, netilmicin, and vancomycin yielded indifferent effects. The GRMR S. aureus strains were refractory against 50, 65, and 80 vol% of fresh defibrinated blood; following reduction of viable counts at 2 h (greater than or equal to 90%), rebound growth invariably occurred within 4 h after exposure. Combined human blood (55 vol%)-antibiotic assays revealed rifampin as the most effective drug, followed by vancomycin, fusidic acid, and cefamandole, in that order. Blood plus cefotaxime, cefazolin, or netilmicin yielded indifferent effects; fosfomycin failed in vitro. In terms of speed of recovery and survival data (chi 2 test), cyclophosphamide-pretreated, i.e., leukopenic NMRI mice responded best to chemotherapy with rifampin, followed by vancomycin, cefamandole, netilmicin, and fosfomycin, in that order; cefazolin yielded variable results.

Animals↗
PubMedDate not supplied

Antibiotic susceptibility testing (agar disk diffusion and agar dilution) of clinical isolates of Enterococcus faecalis and E. faecium: comparison of Mueller-Hinton, Iso-Sensitest, and Wilkins-Chalgren agar media.

Forty-two isolates of Enterococcus faecalis and 56 isolates of Enterococcus faecium, including 8 vancomycin-resistant strains, were examined for comparative susceptibility to 27 antimicrobial drugs with the agar dilution method, employing Mueller-Hinton (MHA), Iso-Sensitest (ISTA), and Wilkins-Chalgren (WCA) agar. The Bauer-Kirby agar disk diffusion method was used to comparatively test 24 of the agents in parallel. The enterococci yielded better growth on ISTA and WCA. However, WCA completely antagonized co-trimoxazole and, though less, fosfomycin. Importantly, WCA slightly reduced the activities of teicoplanin (minimal inhibitory concentrations, MICs, raised up to twofold) and vancomycin (MICs raised two- to fourfold) against enterococci and staphylococcal quality control strains. Therefore, WCA was judged unsuitable for susceptibility testing of enterococci. For E. faecalis no discrepancies between agar dilution MICs and inhibition zone diameters were encountered with augmentin, ampicillin, ampicillin-sulbactam, chloramphenicol, mupirocin, oxacillin, teicoplanin, and co-trimoxazole. Overall, MHA yielded fewer very major (category I) and major (category II) discrepancies than ISTA. However, numerous minor (category III), slight (category IV), minimal (category V), and/or negligible (category VI) discrepancies were encountered with ciprofloxacin, doxycycline, erythromycin, fosfomycin, fusidic acid, meropenem, ofloxacin and rifampin. With respect to E. faecium, only cefotaxime, mupirocin, oxacillin, and teicoplanin yielded nondiscrepant results. Several very major (I) and major (II) discrepancies were observed with augmentin, ampicillin, ampicillin-sulbactam, doxycycline, fusidic acid, imipenem, and penicillin G. Minor discrepancies (categories III-VI) were particularly numerous with augmentin, chloramphenicol, ciprofloxacin, doxycycline, and piperacillin. The largest numbers of negligible (VI) discrepancies were noted with fosfomycin, fusidic acid, and ofloxacin. It is recommended to test one cephalosporin (cefuroxime or the like) in parallel for educational purposes and to exclude fosfomycin, fusidic acid, and rifampin from test batteries because of the wide scatter of test results. The large number of minimal (V) discrepancies of ciprofloxacin against E. faecalis, the numerous minor (III) and slight (IV) discrepancies of chloramphenicol against E. faecium, and the not insignificant number of very major (I) and minor (III) discrepancies observed with meropenem against isolates of E. faecalis necessitated proposals for new disk intermediate susceptibility criteria.

Agar↗
PubMed1980

Antibiotic-host defence interactions in vitro and in vivo.

A markedly depressed chemotaxis was detected with an agarose gel technique when human leucocytes were incubated with fusidic acid and rifampicin in clinically obtainable concentrations. At high concentrations of newer well absorbed tetracyclines there was a definite depression and a less pronounced inhibition was detected for classical tetracycline. The incorporation of 14C-leucine into a trichloroacetic-acid insoluble form by human neutrophils was markedly depressed by the same antibiotics and it is suggested that some antibiotics acting by inhibition of protein synthesis also affect chemotaxis of human neutrophils. At therapeutic concentrations fusidic acid and rifampicin had a pronounced inhibiting effect on the incorporation of 3H-thymidine by human T-lymphocytes stimulated by PHA and B-lymphocytes by S. aurens, Cowan I. At concentrations above the therapeutic level inhibition was detected for doxycycline, erythromycin, clindamycin and nitrofurantoin. No apparent inhibition of neither chemotaxis by human neutrophils nor thymidine incorporation by lymphocytes could be detected for penicillins, cephalosporins, nalidixic acid, sulfamethoxazole and trimethoprim. Due to high albumin binding for some of the tested antibiotics and other factors involved, experiments were performed to test whether depression also takes place in vivo. The cellular immunity in mice was registered by monitoring the survival of transplanted heart grafts and the humoral immunity by quantitating plaque-forming cells and by titration of antibodies after immunization with sheep erythrocytes. Fusidic acid (500 mg/kg/day) and rifampicin (20 mg/kg/day, human therapeutic dose) had a highly significant effect (P less than 0.001) on the rejection of heart grafts and plaque-forming cells while the effect o serum antibodies was of low significance (P less than 0.02--P less than 0.01). The effect of doxycycline (2.5 mg/kg/day) and fusidic acid (25 mg/kg/day) at human therapeutic dose on immunity in mice was slight but significant (P less than 0.02). The relevance of experiments in mice to the situation in man is discussed. The migration of neutrophils into a skin chamber was shown to be dramatically reduced in eight healthy volunteers during a standard regimen of doxycycline.

Animals↗