Showing papers in "Journal of Antimicrobial Chemotherapy in 1988"
555 citations
TL;DR: The interaction of five anti-pseudomonas antibiotics with both commercial and pseudomonas alginates was studied by investigation of their binding and diffusion characteristics, with strong aminoglycoside binding to alginate reduced, but not eliminated by the presence of physiological concentrations of salts.
Abstract: The interaction of five anti-pseudomonas antibiotics with both commercial and pseudomonas alginates was studied by investigation of their binding and diffusion characteristics. The two sources of alginate were qualitatively but not quantitatively similar in these respects. Unlike the beta-lactams, gentamicin and tobramycin bound avidly to both sources of alginate and, when the alginate gel to antibiotic ratio was high, the aminoglycosides exhibited diffusion coefficients which were approximately 20% of the beta-lactam values. At much lower ratios of alginate to antibiotic the aminoglycosides caused precipitation in the alginate with apparent disruption of the gel structure, and ultimately penetrated the gel at a faster rate than the beta-lactams. The strong aminoglycoside binding to alginate was reduced, but not eliminated by the presence of physiological concentrations of salts.
239 citations
TL;DR: The experience of the Health Authority in South-East London supports the contention that some MRSA are truly epidemic, whilst others do not behave in this manner.
Abstract: We contrast the experiences, in our Health Authority in South-East London, with the particular epidemic methicillin-resistant Staphylococcus aureus (the EMRSA) strain that has recently spread widely around London and South-East England, and with the other MRSA (OMRSA) strains encountered there. Our isolates of the EMRSA were identical by chromosomal restriction enzyme analysis, and the chromosomal and plasmid phenotypes were similar to those described in North London and Eastern Australia. Experimental phage-typing distinguished them from OMRSA encountered in 1984 to 1986. Between 1984 and 1985, the EMRSA caused increased infection and patient colonization compared to the years 1969 to 1983. A change in infection control procedures was usually required to control the EMRSA and in 1986 isolates had returned to their pre-1984 levels. Between 1984 and 1986 OMRSA were still encountered, but did not spread or require changes in infection control procedures. The distribution of other resistant isolates was examined; c 94% of neomycin-resistant isolates were in-patients or clinic patients. Forty-five different phage-type/antibiogram patterns were found in 88 isolates from 66 patients between 1982 and 1985, and patient clusters were uncommon. The ability of the EMRSA to spread is discussed and is probably not purely organism related. Our experience supports the contention that some MRSA are truly epidemic, whilst others do not behave in this manner.
167 citations
TL;DR: The elimination of nasal MRSA by mupirocin, and the introduction of isolation facilities, were associated with the control of the outbreak.
Abstract: During a hospital outbreak of methicillin-resistant Staphylococcus aureus (MRSA), involving more than 200 patients, 40 patients and 32 hospital staff who were stable nasal carriers of MRSA received topical application of 2% mupirocin, formulated in a white soft paraffin and lanolin ointment, to their anterior nares for five days. Nasal carriage was eliminated in all patients and staff, usually within the first 48 h of treatment. Of the 40 patients, 36 remained clear of nasal MRSA for the duration of their follow-up (mean = 2 weeks) and four became re-colonized one to five weeks after their course. Immediately after the course, the number of patients with MRSA isolated from wounds and wrists fell from 16 to 7, and from 16 to 3, respectively. Of the 32 staff, all were negative one week after the course, and of the 22 still available for follow-up at eight weeks, all were consistently negative (mean period of follow-up = 7.8, range = 1-20 weeks). Four patients and five staff were re-colonized with MRSA between one to five, and two to twelve weeks, respectively, after treatment. Overall, in the post-treatment follow-up, 98.6% of the staff-weeks and 90.1% of the patient-weeks were free of nasal MRSA. MICs of mupirocin for both pre and post treatment isolates were all 0.03 or 0.06 mg/l. The elimination of nasal MRSA by mupirocin, and the introduction of isolation facilities, were associated with the control of the outbreak.
161 citations
TL;DR: Clarithromycin was the most active of the new compounds against C. pylori and was as active as ampicillin, and all compounds had MBCs which were the same as or within one two-fold dilution of their MICs.
Abstract: The in-vitro activities of several 14-, 15- and 16-membered macrolides and fluoroquinolones against Campylobacter pylori were determined. In general, 14-membered macrolides, such as clarithromycin and flurithromycin, were more active than the 15-membered macrolide, azithromycin, which was more active than 16-membered macrolides, such as miocamycin and rokitamycin. Fluoroquinolones, except ciprofloxacin and A-61827, were less active than macrolides. Clarithromycin was the most active of the new compounds against C. pylori and was as active as ampicillin. MICs of all compounds at pH 5.5 were increased when compared to MICs determined at pH 7.3. All compounds had MBCs which were the same as or within one two-fold dilution of their MICs. Frequencies of spontaneous resistance development by C. pylori NCTC 11637 at four and eight times the MIC of the compounds were low and ranged from less than 1 x 10(-9) to 1 x 10(-7).
132 citations
TL;DR: There is now convincing evidence that spiramycin, and probably all macrolides, act primarily by stimulating the dissociation of peptidyl-tRNA from ribosomes during translocation.
Abstract: Macrolide antibiotics constitute a group of 12 to 16-membered lactone rings substituted with one or more sugar residues, some of which may be amino sugars. They inhibit bacterial protein synthesis both in vivo and in vitro with varying potencies. Macrolides are generally bacteriostatic, although some of these drugs may be bactericidal at very high concentrations. The mechanism of action of macrolides has been a matter of controversy for some time. Spiramycin, a 16-membered macrolide, inhibits translocation by binding to bacterial 50S ribosomal subunits with an apparent 1:1 stoichiometry. This antibiotic is a potent inhibitor of the binding to the ribosome of both donor and acceptor substrates. Spiramycin induces rapid breakdown of polyribosomes, an effect which has formerly been interpreted as occurring by normal ribosomal run-off followed by an antibiotic-induced block at or shortly after initiation of a new peptide. However, there is now convincing evidence that spiramycin, and probably all macrolides, act primarily by stimulating the dissociation of peptidyl-tRNA from ribosomes during translocation. Although the ribosomes of both Gram-positive and Gram-negative organisms are susceptible to macrolides, these antibiotics are mainly used against Gram-positive bacteria since they are unable to enter the porins of Gram-negative bacteria. Resistance to macrolides in clinical isolates is most frequently due to post-transcriptional methylation of an adenine residue of 23S ribosomal RNA, which leads to co-resistance to macrolides, lincosamides and streptogramins type B (the so-called MLSB phenotype). Other mechanisms of resistance involving cell impermeability or drug inactivation have been detected in Staphylococcus spp. and Escherichia coli. These strains are resistant to 14-membered macrolides (erythromycin and oleandomycin) but remain susceptible to spiramycin.
130 citations
TL;DR: Ciprofloxacin and erythromycin are ineffective in vivo despite these high gastric mucosal concentrations, which will be determined by physicochemical properties of the antimicrobials, such as pKa, stability, activity over a wide range of pH, and lipid solubility.
Abstract: Gastric mucosal concentrations of erythromycin, amoxycillin, ampicillin and ciprofloxacin were determined in patients at upper gastrointestinal endoscopy 38-480 min after a 500 mg dose of erythromycin ethyl succinate, erythromycin stearate, amoxycillin, pivampicillin or ciprofloxacin. All the agents attained concentrations greater than the MIC 90 for Campylobacter pylori. The macrolides attained the lowest concentrations. There was no significant difference between concentrations attained with erythromycin ethyl succinate and stearate. High concentrations were attained by amoxycillin (range 14.6-322 mg/kg) and pivampicillin (range 47.5-209 mg/kg). Ciprofloxacin attained very high concentrations (range 35-1762 mg/kg); inhibitory concentrations 35 mg/kg) were still present at 6 h after the dose. Ciprofloxacin and erythromycin are ineffective in vivo despite these high gastric mucosal concentrations. Penetration into the gastric mucus and crypts where C. pylori is found will be determined by physicochemical properties of the antimicrobials, such as pKa, stability, activity over a wide range of pH, and lipid solubility.
123 citations
TL;DR: The penetration of several antibiotics into human polymorphonuclear leucocytes was measured with a bioassay and the concentration of vancomycin and teicoplanin associated with the neutrophils appeared to be saturable over the range of extracellular concentrations tested.
Abstract: The penetration of several antibiotics into human polymorphonuclear leucocytes was measured with a bioassay. The aminoglycosides (gentamicin, netilmicin), oxacillin and LY146032, a new lipopeptidic antibiotic, had a penetration which was generally less than 60%, whereas new fluoro-quinolones (enoxacin, ciprofloxacin, CI934, Ro236240) and rifamycins (rifampicin, LM427) were concentrated 2.4 to 14.2-fold. The concentration of vancomycin and teicoplanin associated with the neutrophils appeared to be saturable over the range of extracellular concentrations tested (5-20 mg/l). Coumermycin, an inhibitor of DNA-gyrase, was highly concentrated (11.3 to 16.6-fold) within the neutrophils. The penetration of clindamycin and erythromycin was low (0.60- to 1.48-fold).
110 citations
TL;DR: Correlation between spiramycin treatment and negative results of mouse inoculation of placental material suggests that Spiramycin might decrease the risk of materno-fetal transmission of toxoplasma by reducing the severity and duration of toxplasmic placentitis.
Abstract: The results of parasitological investigation of the placenta for toxoplasma in 223 cases with documented congenital toxoplasmosis were analysed according to whether the mother had been treated, or not, with spiramycin during pregnancy. The investigation was negative in 10-11% of the cases when the mother had not been treated or had been inadequately treated; in 25% of the cases with a treatment of 3 g spiramycin day; and in 50% with spiramycin plus the combination of pyrimethamine with sulphonamide. This series is compared with a previous group of 321 women whose placental investigation was negative in 50% of untreated cases and 81% of treated women. The treatment categories are not directly comparable, because it is not possible to have a randomly assigned 'no treatment' group, for ethical reasons. Correlation between spiramycin treatment and negative results of mouse inoculation of placental material suggests that spiramycin might decrease the risk of materno-fetal transmission of toxoplasma by reducing the severity and duration of toxoplasmic placentitis. Current use of spiramycin in infected pregnant women is recommended because of its activity and lack of side effects. The dosage must not be lower than 3 g/day. Additional pyrimethamine plus sulphonamide should be restricted to selected cases with fetal abnormality diagnosed during pregnancy. Some data on pharmacology of spiramycin in mothers, placentas and fetuses are reviewed. They suggest that monitoring of maternal serum antibody titres for a dosage more adapted to individual cases may be desirable.
105 citations
TL;DR: Resistance to teicoplanin and vancomycin is difficult to induce under laboratory conditions and the small increment in resistance that may develop is lost when the organisms are subcultured in the absence of the drugs.
Abstract: Teicoplanin is a glycopeptide antibiotic structurally related to vancomycin. Both agents achieve their effect by binding to acyl-D-alanyl-D-alanine in the bacterial cell wall. The spectrum of activity of teicoplanin, like that of vancomycin, is restricted to Gram-positive aerobic and anaerobic bacteria. However, the activity of the two agents is not identical: teicoplanin is generally more active than vancomycin against streptococci and Gram-positive anaerobes; the two agents exhibit similar activity against Staphylococcus aureus (including methicillin-resistant strains); and vancomycin is more active than teicoplanin against some strains of coagulase-negative staphylococci. Inoculum size influences the activity of teicoplanin, and variations in activity against some strains of coagulase-negative staphylococci have been observed with different culture media. Resistance to teicoplanin and vancomycin is difficult to induce under laboratory conditions and the small increment in resistance that may develop is lost when the organisms are subcultured in the absence of the drugs.
89 citations
TL;DR: Clarithromycin is clearly a potent intraphagocytic antibiotic and potentially superior in this respect to erythromycin, and was found to possess intracellular bioactivity for all three species of bacteria with clarithromyzin being consistently more active than erystromycin.
Abstract: Erythromycin base and its 6-0-methyl derivative clarithromycin were actively accumulated 7.3 +/- 1.2-fold and 9.2 +/- 2-fold respectively by human neutrophils in vitro. The intraphagocytic bioactivities of the antimicrobial agents were investigated using the combination of a radioassay, colony counting method and a fluorescence microassay which facilitates the distinction between intracellular bacteriostatic and bactericidal mechanisms. Staphylococcus aureus, Listeria monocytogenes and Legionella micdadei were used as the test intraphagocytic microbial pathogens. Both agents were found to possess intracellular bioactivity for all three species of bacteria with clarithromycin being consistently more active than erythromycin. Under the assay conditions used both agents were bacteriostatic (intracellularly) for S. aureus and Leg. micdadei and bactericidal for List. monocytogenes. Clarithromycin is clearly a potent intraphagocytic antibiotic and potentially superior in this respect to erythromycin.
TL;DR: Fluconazole was especially effective in patients with candidal infections, and two patients with cryptococcal meningitis were clinically cured; one of the two was also microbiologically cured.
Abstract: Fluconazole (UK-49,858) is a new bis-triazole antifungal drug that can be administered both orally and intravenously. We conducted an open clinical trial on the efficacy of fluconazole (50-100 mg) once daily in 20 non-neutropenic patients with deep-seated fungal infections. Seventeen patients (eight females, nine males, median age 56 years) could be evaluated clinically. All patients had an underlying disease, while eight also received immunosuppressive therapy. The median duration of treatment was 33 days (range 8-194 days). Clinical cure or improvement was achieved in 14 of 17 patients (82%). Nine patients were both clinically and microbiologically cured. Fluconazole was especially effective in patients with candidal infections. Two patients with cryptococcal meningitis were clinically cured; one of the two was also microbiologically cured. No serious side effects of fluconazole were encountered.
TL;DR: The hypothesis that it is the destruction of intestinal bacteria that ultimately results in hypoprothrombinaemia may not be justified and certain antibiotics, which contain thiol-leaving groups, may produce hypop Rothrom binaemia because the thiol group inhibits the vitamin K-dependent step in clotting factor synthesis.
Abstract: Hypoprothrombinaemia is regarded as a serious adverse effect of antimicrobial therapy. This effect has commonly been attributed to the potential of these drugs to kill intestinal bacteria, a possible source of vitamin K, which is a necessary co-factor in the synthesis of four of the clotting factors. This review examines the evidence for and against this hypothesis, first in experimental animals, then in humans, and assesses the reports of antibiotic associated hypoprothrombinaemia in man, with particular attention to information about the mechanism. The hypothesis that it is the destruction of intestinal bacteria that ultimately results in hypoprothrombinaemia may not be justified. Certain antibiotics, which contain thiol-leaving groups, may produce hypoprothrombinaemia because the thiol group inhibits the vitamin K-dependent step in clotting factor synthesis.
TL;DR: The current pattern of antibiotic use by drug store personnel in Bangkok was examined and most antibiotics were dispensed inappropriately with respect to choice of drug and duration of treatment.
Abstract: The current pattern of antibiotic use by drug store personnel in Bangkok was examined. Ten well-trained medical students (simulated patients) presented to 40 randomly selected drug stores with common complaints, namely urethral discharge, acute watery diarrhoea, fever with sore throat, coryza, skin infection and acute dysuria. Analysis of medications obtained revealed that 50-100% of drug stores dispensed antibiotics for each condition. Co-trimoxazole, ampicillin, chloramphenicol, penicillin V and tetracycline were commonly given. Most antibiotics were dispensed inappropriately with respect to choice of drug and duration of treatment. The cost per treatment varied from 20 cents to 6 $US. Strategies to promote rational use are proposed.
TL;DR: The data indicate that there is a need to standardise sputum in antibiotic binding studies and they provide another rationale for favouring the use of ceftazidime over aminoglycosides in infectious exacerbations of cystic fibrosis caused by Pseudomonas aeruginosa.
Abstract: Antibiotics are known to bind to whole cystic fibrosis sputum. However, the composition of sputum varies from one patient to another, making the interpretation of binding studies difficult. This problem has been examined by standardising the macromolecule concentration of sputum from four cystic fibrosis patients and adding tobramycin or ceftazidime directly to the sputum components. Binding to mucin-rich and DNA-rich fractions of sputum was also studied before and after DNase treatment of these fractions. These studies indicated that (i) the degree of tobramycin binding is dependent on the sputum macromolecule concentration, (ii) a significant proportion of tobramycin is bound even at concentrations of 100 mg/l of drug, (iii) tobramycin binds to both the mucin rich fraction and the DNA rich fraction of sputum and (iv) ceftazidime binding to sputum is negligible. Our data indicate that there is a need to standardise sputum in antibiotic binding studies and they provide another rationale for favouring the use of ceftazidime over aminoglycosides in infectious exacerbations of cystic fibrosis caused by Pseudomonas aeruginosa.
TL;DR: The long PAE of aminoglycosides, especially after exposure to high drug concentrations, constitutes an argument in favour of administering aminglycosides in higher-than-usual doses with longer intervals between doses, supported by recent pharmacokinetic, bacteriological and toxicity data.
Abstract: The in-vitro postantibiotic effect (PAE) of amikacin, gentamicin, netilmicin and tobramycin was investigated by a bioluminescent assay of bacterial ATP. Two strains each of Escherichia coli and Pseudomonas aeruginosa were exposed for 1 h to different concentrations of the aminoglycosides. The aminoglycoside was removed by a 10(-3) dilution, and regrowth of bacteria was followed at hourly intervals by monitoring bacterial ATP. This method simplified the PAE studies and made such studies possible at high aminoglycoside concentrations. The length of the PAE was dose-dependent for all the aminoglycosides studied. The PAEs ranged between three and seven hours for all four strains at the aminoglycoside concentrations normally reached in serum during standard dosing. The long PAE of aminoglycosides, especially after exposure to high drug concentrations, constitutes an argument in favour of administering aminoglycosides in higher-than-usual doses with longer intervals between doses. This proposal is also supported by recent pharmacokinetic, bacteriological and toxicity data.
TL;DR: Resistance to antimicrobial agents may result from intrinsic properties of organisms, through mutation and through plasmid- and transposon-specified genes, and from mutants that arise during antimicrobial therapy and are defective in energy-generation systems.
Abstract: Resistance to antimicrobial agents may result from intrinsic properties of organisms, through mutation and through plasmid- and transposon-specified genes. beta-Lactam resistance is most frequently associated with one or more chromosomal- or plasmid-specified beta-lactamases. Recently, mutations modifying penicillin-binding proteins have been detected with increased frequency as a cause of beta-lactam resistance. Mixed mechanisms, reduced permeability and tolerance are other causes of resistance. Aminoglycoside resistance always involves some modification of drug uptake, most often due to a variety of enzymes modifying these compounds. Reduced uptake is a primary cause of resistance in anaerobic bacteria and bacteria growing anaerobically, some strains of Pseudomonas aeruginosa, and mutants that arise during antimicrobial therapy and are defective in energy-generation systems. Resistance to other antimicrobial agents is presented in tabular form.
TL;DR: No correlation between PBP profile and susceptibility was observed with clinical isolates except that PBP-2b exhibited molecular weight changes in moderately susceptible strains, and PBP 2b was the first PBP to show an alteration in penicillin-binding affinity.
Abstract: Penicillin-binding protein (PBP) patterns of penicillin-resistant laboratory-constructed transformants were compared with the PBP profiles of 26 clinical isolates of Streptococcus pneumoniae. For transformation studies DNA from a penicillin-resistant clinical isolate was used to transform a susceptible laboratory strain. Penicillin resistance was achieved in two transformation cycles. The frequency of transformation appeared to be dependent on the genetic status of the recipient used for the second transformation cross. Penicillin resistance was also attained in a single transformation round when time was allowed for full expression of random multiple transformations. PBP 2b was the first PBP to show an alteration in penicillin-binding affinity. This PBP was not easily detected in those transformants for which penicillin MICs exceeded 0.2 mg/l. The PBP profiles of the clinical isolates were complex. In addition to previously-described PBPs, new intermediate classes were demonstrated. No correlation between PBP profile and susceptibility was observed with clinical isolates except that PBP-2b exhibited molecular weight changes in moderately susceptible strains.
TL;DR: The results indicate that administration of amikacin 15 mg/kg in a single daily dose should be a practical and safe principle of administration, however elderly patients often have reduced creatinine clearance and should preferably be given a lower dose of 11mg/kg bw.
Abstract: Forty-five mostly elderly patients with serious infections were treated in a prospective, comparative and randomized pharmacokinetic study with amikacin 11.0 or 15.0 mg/kg administered in a single daily dose as an intravenous, short-term infusion or with amikacin 7.5 mg/kg administered twice daily in the same way. The results indicate that administration of amikacin 15 mg/kg in a single daily dose should be a practical and safe principle of administration. However elderly patients often have reduced creatinine clearance and should preferably be given a lower dose of 11 mg/kg bw. The risk of nephrotoxicity did not increase, but conclusions on ototoxicity and clinical efficacy cannot be drawn from this limited study. This should be considered as an initial part of a future multicentre trial.
TL;DR: A multicentre open trial of teicoplanin in 81 centres in nine European countries included 1431 cases, most of whom had infections caused by Staphylococcus aureus, and 91.7% of the 1333 evaluable cases were clinical cured or improved.
Abstract: A multicentre open trial of teicoplanin in 81 centres in nine European countries included 1431 cases: 531 female, 900 male; mean age 49.4 years, range 1-93 years. These were hospitalized patients most of whom had infections caused by Staphylococcus aureus (816 isolates). Of a total of 1427 Gram-positive pathogens 280 (19.6%) were methicillin resistant. There were 536 skin and soft tissue infections, 263 septicaemias, 135 lower respiratory tract infections, 179 joint and bone infections and 83 endocarditides. More than a third of the infections were severe. Complicating medical factors were present in 69% of cases, including malignant disease in 14% and diabetes mellitus in 11%. Mean teicoplanin dose was 289 mg/day; mean duration of treatment was 14 days. A total of 471 patients received a high dose regimen, 400 mg teicoplanin daily for at least five days. Monotherapy with teicoplanin was used in 1037 cases and combination with other antibiotics in 394. Overall 91.7% of the 1333 evaluable cases were clinical cured or improved. The MIC of teicoplanin was less than or equal to 1 mg/l for 90% of Gram-positive isolates. Adverse events were reported in 189 cases (13.2%). The most common drug-related event was an allergic type skin reaction which occurred in 35 cases (2.4%). Transient hepatic dysfunction was reported in 28 patients (2.0%).
TL;DR: On the basis of in-vitro and animal data, the extracellular slime substance seems to interfere with various host-protective mechanisms and with the action of antistaphylococcal antibiotics.
Abstract: Coagulase-negative staphylococci are the predominant cause of foreign body infections The pathogenesis is related to the ability of these staphylococci to adhere to and grow on polymer surfaces and to produce an extracellular slime substance The exact chemical nature of this extracellular slime substance is still not known, although there is some evidence that it may be a complex glycoconjugate On the basis of in-vitro and animal data, the extracellular slime substance seems to interfere with various host-protective mechanisms and with the action of antistaphylococcal antibiotics These factors can explain several clinical characteristics of coagulase-negative staphylococcal foreign body infections
TL;DR: Drug interactions with the quinolones are of two types: pharmacokinetic and pharmacodynamic; there is evidence that the elderly and patients with liver disease are particularly susceptible to kinetic interactions with ciprofloxacin, and there is no evidence to suggest that ofloxacIn is likely to impair hepatic drug elimination.
Abstract: Drug interactions with the quinolones are of two types: pharmacokinetic and pharmacodynamic. Pharmacokinetic interactions include inhibition of absorption of quinolones by aluminium and magnesium containing antacids and inhibition of metabolism of other drugs by quinolones. Norfloxacin and ofloxacin are not extensively metabolized and do not inhibit drug metabolism; ciprofloxacin and enoxacin reduce theophylline clearance in normal subjects by less than 50% and greater than 50% respectively. Ciprofloxacin inhibits the metabolism of caffeine, theophylline and antipyrine. The latter is a marker of broad substrate specificity and, until proved otherwise, it would be prudent to avoid combination of ciprofloxacin with drugs which are metabolized and have a low therapeutic index. In addition to theophylline, these include cyclosporin, phenytoin and warfarin. There is evidence that the elderly and patients with liver disease are particularly susceptible to kinetic interactions with ciprofloxacin. In contrast, there is no evidence to suggest that ofloxacin is likely to impair hepatic drug elimination. Enoxacin does not impair the metabolism of chlorpropamide or glibenclamide, it is therefore unlikely that any of the quinolones will interact with sulphonylurea hypoglycaemic drugs. A pharmacodynamic interaction has been demonstrated in vitro between quinolones and non-steroidal anti-inflammatory drugs (NSAIDS) or theophylline. All of these drugs inhibit binding of radio-labelled gamma-amino-butyric acid to mouse synaptic membranes and combinations of quinolones with NSAIDS or theophylline are synergistic. Convulsions have been reported in patients who received a combination of enoxacin with either fenbufen, a NSAID, or theophylline. Like theophylline, NSAIDS undergo hepatic metabolism, so the clinical interaction may be the result of combined pharmacokinetic and pharmacodynamic interactions. Drug-interactions with quinolones are a clinically important problem. Drugs, such as ofloxacin, which do not impair hepatic metabolism of other drugs, have a clinically significant advantage over other quinolones. The pharmacodynamic interaction between quinolones and other GABA inhibitors is extremely poorly documented; further in-vitro, animal and clinical studies are urgently required.
TL;DR: Comparison of the methods showed that HPLC gave much lower values of itraconazole concentrations in patient serum samples than did the microbiological method.
Abstract: A reversed-phase high-performance liquid chromatographic (HPLC) method, with internal standard quantification, is described for the analysis of itraconazole in human serum. No interference was encountered from over 60 drugs tested. The standard curve was linear from 10 to 10,000 micrograms/l. The detection limit of the method was 10 micrograms/l, with coefficients of variation from 2.2 to 7.8% over a range of itraconazole concentrations from 20 to 1600 micrograms/l. An agar diffusion method is also described with a lowest reproducible limit of 100 micrograms/l. This method had coefficients of variation from 11.0 to 17.1% over a range of itraconazole concentrations from 100 to 1600 micrograms/l. Comparison of the methods showed that HPLC gave much lower values of itraconazole concentrations in patient serum samples than did the microbiological method.
TL;DR: A single oral dose of ciprofloxacin 500 mg eliminates pharyngeal carriage of N. meningitidis effectively and has few adverse reactions.
Abstract: Single dose oral ciprofloxacin was given to all personnel in a naval training establishment as part of the management of an outbreak of meningococcal meningitis. Two thousand one hundred personnel received the drug and Neisseria meningitidis was eradicated from the pharynx of 97% of 570 who were swabbed two to four days later. In a cohort of 277 personnel who were followed for up to nine weeks, pharyngeal carriage was eliminated from 93% of 104 carriers. The overall prevalence of carriage fell from 19% to less than 1.5% as a result of the use of ciprofloxacin. Few side effects were encountered, compliance was good and meningococci resistant to the antibiotic were not found after therapy. A single oral dose of ciprofloxacin 500 mg eliminates pharyngeal carriage of N. meningitidis effectively and has few adverse reactions.
TL;DR: These synthetic, orally absorbable compounds represent a new series of antibacterial agents unrelated by chemical structure to any other currently available antimicrobial agents.
Abstract: The in-vitro activities of DuP 721 and DuP 105, new oxazolidinone antibacterials, were compared with those of cefazolin, cephalexin, ciprofloxacin, clindamycin, oxacillin, penicillin, and vancomycin against Gram-positive cocci. DuP 721 was approximately four-fold more active than DuP 105 with an MIC of 2.0 mg/l for 90% of the Staphylococcus aureus, beta-haemolytic streptococcus and Streptococcus faecalis strains tested, and an MIC of 4.0 mg/l for 90% of the Str. faecium, penicillin-resistant Str. pneumoniae and viridans streptococcus strains tested. DuP 105 was most active against strains of Staph. epidermidis with an MIC of 4.0 mg/l for 90% of the strains tested. There was no cross resistance between these and the other antibacterial agents that were tested. Both oxazolidinones had bacteriostatic activity in broth against susceptible organisms. Both DuP 721 and DuP 105 inhibited ribosomal protein synthesis in a cell-free system. These synthetic, orally absorbable compounds represent a new series of antibacterial agents unrelated by chemical structure to any other currently available antimicrobial agents.
TL;DR: Evidence indicates that some of these determinants, Pcr, Cdr, Hgr, and Tcr, were plasmid encoded in isolates collected from Australian hospitals prior to 1970, and have since been acquired by the chromosome in more recent Staph.
Abstract: Molecular and genetic analysis of multiresistant isolates of Staphylococcus aureus from widely separated hospitals in Australia has demonstrated that these are clearly related, and that the predominant strains possess up to three different plasmids, which fall into the following classes: (i) small 1.6 kb plasmids, such as pSK3, which are phenotypically cryptic, (ii) 4.5 kb chloramphenicol resistance plasmids, such as pSK2, and (iii) the pSK1 family of multiresistance plasmids, which range in size from 20 to 42 kb and variously encode resistance to antiseptics and disinfectants, trimethoprim (Tpr), penicillin (Pcr) and the aminoglycosides gentamicin, tobramycin and kanamycin (Gmr Tmr Kmr). Gmr Tmr Kmr is encoded on the pSK1 family plasmids by transposon Tn4001, which was also detected on the chromosomes of some clinical isolates. Tn4001 is composed of inverted repeats of the insertion sequence IS256; these repeats flank a Gmr Tmr Kmr sequence encoding for a 57,000 dalton bifunctional protein with aminoglycoside acetyltransferase [AAC(6')] and phosphotransferase [APH(2")] activities. A Tn4001-like structure, which is defective in transposition but encodes for a Gmr Tmr Kmr determinant homologous with that on Tn4001, occurs on conjugative plasmids from strains isolated in North America. Physical studies indicate that Pcr, via a beta-lactamase, and Tpr, via a trimethoprim-insensitive dihydrofolate reductase (DHFR), are also encoded on the pSK1 family by transposons; these transposons have been designated Tn4002 and Tn4003, respectively. Tn4003 is flanked by direct repeats of the insertion sequence IS257. The evolution of the pSK1 family of multiresistance plasmids is traced through the transposition and genetic rearrangement of resistance determinants. Transposition and genetic rearrangement have also contributed to the evolution of a multiresistant chromosome in Staph. aureus. In the majority of contemporary multiply resistant Staph. aureus strains the determinants for resistance to erythromycin (Emr), fusidic acid, methicillin (Mcr), minocycline, rifampicin, spectinomycin, streptomycin, sulphonamides, tetracycline (Tcr), cadmium (Cdr), and mercury (Hgr) are chromosomally encoded; these strains also possess chromosomally encoded Pcr, via a beta-lactamase. Evidence indicates that some of these determinants, Pcr, Cdr, Hgr, and Tcr, were plasmid encoded in isolates collected from Australian hospitals prior to 1970. Through transposition and site-specific integration, they have since been acquired by the chromosome in more recent Staph. aureus strains.(ABSTRACT TRUNCATED AT 400 WORDS)
TL;DR: The resistance of A. calcoaceticus to beta-lactam antibiotics was predominantly due toBeta-lactorases, which were produced by 81% of the strains and observed in 32% ofThe presence of a cephalosporinase type enzyme was detected in acinetobacter strains isolated since 1981 and its incidence increased in 1986.
Abstract: One hundred clinical strains of Acinetobacter calcoaceticus isolated from 1981 to 1986 were screened for enzymatic resistance to beta-lactam antibiotics. Fourteen beta-lactam antibiotics were tested and four phenotypes were defined on the basis of enzymatic resistance and of susceptibility to the following beta-lactams: ticarcillin, piperacillin, cefotaxime, and ceftazidime. The resistance of A. calcoaceticus to beta-lactam antibiotics was predominantly due to beta-lactamases, which were produced by 81% of the strains. In most (71%) of the beta-lactamase producing strains, a penicillinase of the TEM type was observed; in 9% of the strains, all isolated since 1985, a CARB-type penicillinase with a pI 6.3 was observed. The presence of a cephalosporinase type enzyme was detected in acinetobacter strains isolated since 1981 and its incidence increased in 1986. Multiple beta-lactamases (penicillinase plus cephalosporinase) were observed in 32% of the strains.
TL;DR: The bactericidal activity of ciprofloxacin against a coagulase-negative staphylococcus (Staphylitis warneri) was found to be abolished by chloramphenicol so the 4-quinolone does not exert mechanism B against this species, but against S. aureus results similar to those observed in S.warneri were obtained.
Abstract: Ciprofloxacin and ofloxacin are known to exert a second bactericidal mechanism (termed B) against Escherichia coli which functions even when protein synthesis is inhibited by chloramphenicol or when RNA synthesis is inhibited by rifampicin. However, the bactericidal activity of ciprofloxacin against a coagulase-negative staphylococcus (Staphylococcus warneri) was found to be abolished by chloramphenicol so the 4-quinolone does not exert mechanism B against this species. On the other hand, ofloxacin did exhibit mechanism B against S. warneri because the drug remained bactericidal in the presence of chloramphenicol. When S. aureus was investigated results similar to those observed in S. warneri were obtained throughout the range of clinically achievable concentrations of ofloxacin and ciprofloxacin. Ofloxacin seems to exhibit mechanism B against the staphylococci while ciprofloxacin does not. This may explain why ciprofloxacin is more potent than ofloxacin against Gram-negative bacteria but against staphylococci both drugs are equipotent.
TL;DR: Recent studies have confirmed that Gram-negative bacillary bacteraemia may be prevented by oral gut decontamination but not bacter aemia due to Gram-positive bacteria, raising an important question, whether or not a specific anti-Gram-positive antibiotic such as vancomycin should be added to the empirical regimen.
Abstract: Gram-positive pathogens have become a common cause of bacteraemia in granulocytopenic cancer patients. This has been partially attributed to the use of central intravenous devices such as Hickman catheters; mucositis secondary to intensive antineoplastic chemotherapy or herpes infections may also be the source, especially for streptococci, whereas the skin is most probably the source for Staphylococcus epidermidis. Antimicrobial prophylaxis recommended mainly with the aim of reducing the incidence of Gram-negative bacillary infections may also play a significant role. The rate of response of documented infections caused by Gram-positive cocci to 'standard' empirical therapy (which has been mainly directed against Gram-negative bacilli) has been unsatisfactory although the lethality reported has been low. These results raise an important question, whether or not a specific anti-Gram-positive antibiotic such as vancomycin, should be added to the empirical regimen. A recent study suggested that empirical vancomycin provided no benefit since the mortality due to Gram-positive infections was low and a favourable outcome was obtained by adding a specific antibiotic after bacteriological documentation. However, others have shown that empirical use of vancomycin was associated with a more rapid resolution of fever. Vancomycin has been associated with an excess rate of side-effects and is difficult to administer. Another important question is whether or not antimicrobial prophylaxis for gut decontamination should include anti-Gram-positive cover. Recent studies have confirmed that Gram-negative bacillary bacteraemia may be prevented by oral gut decontamination but not bacteraemia due to Gram-positive bacteria.(ABSTRACT TRUNCATED AT 250 WORDS)