Showing papers in "Journal of Antimicrobial Chemotherapy in 1990"

The pharmacokinetics of azithromycin in human serum and tissues

Abstract: The pharmacokinetics of azithromycin, a new azalide antibiotic, were examined in man. Approximately 37% of a single oral dose of 500 mg was bioavailable and produced a peak serum concentration of 0.4 mg/l. Multiple dose regimens (two doses of 500 mg separated by 12 h and followed by 500 mg qds for five days, or two doses of 250 mg separated by 12 h and followed by 250 mg qds for nine days) produced only slight increases in peak serum concentrations. The serum protein binding of azithromycin declined from about 50% at 0.02 mg/l to 12% at 0.5 mg/l. Tissue concentrations of azithromycin were much higher than serum concentrations. After two 250 mg doses 12 h apart, peak azithromycin concentrations exceeded 3 mg/kg in prostate, tonsil and many other tissues. Concentrations in tissues declined with apparent half-lives of 2.3 days in prostate and 3.2 days in tonsil. The high tissue concentrations suggest that proposed standard dosage regimens of 500 mg qds on day 1 followed by 250 mg qds for four days, or three daily dosages of 500 mg, will produce tissue concentrations above 3 mg/kg in a variety of tissues. Since these tissue concentrations exceed the MICs of relevant pathogens, these dosage regimens should be effective against respiratory tract and soft-tissue infections. A single 1 g dose may be effective in the treatment of many sexually transmitted diseases.

Nephrotoxicity of vancomycin, alone and with an aminoglycoside

Abstract: The incidence of nephrotoxicity in patients receiving vancomycin alone or in combination with an aminoglycoside was prospectively evaluated. A total of 231 courses of antibiotic therapy in 224 patients were consecutively monitored over 28-month period. One hundred and sixty-eight patients received vancomycin alone, 63 patients received vancomycin with an aminoglycoside, and 103 patients received gentamicin. Nephrotoxicity was defined as an increase in serum creatinine of 0.5 mg/dl or a 50% increase above baseline, whichever was greater. Eight patients (5%) receiving vancomycin alone, 14 patients (22%) receiving vancomycin with an aminoglycoside, and 11 patients (11%) receiving gentamicin alone were found to have nephrotoxicity. Factors found to be associated with increased risk of nephrotoxicity in patients receiving vancomycin were concurrent therapy with an aminoglycoside, length of treatment with vancomycin (greater than 21 days), and vancomycin trough serum concentration (greater than 10 mg/l). Although the incidence of vancomycin nephrotoxicity is low, patients receiving vancomycin therapy with the above risk factors should be closely monitored.

Comparison of the acid stability of azithromycin and erythromycin A

Abstract: In acidic aqueous media, erythromycin A is rapidly degraded via intramolecular dehydration to form erythromycin-6.9-hemiketal and then anhydroerythromycin, both of which possess little antimicrobial activity. Azithromycin, a new azalide antibiotic, has a methyl-substituted nitrogen in place of the carbonyl at the 9a position of the aglycone ring, thus blocking the internal dehydration pathway. As a result, azithromycin decomposition occurs primarily via acid-catalysed hydrolysis of the ether bond to the neutral cladinose sugar. Rate constants and the time for 10% decay (T1/10) were determined for both azithromycin and erythromycin A at pH2 using various levels of acetonitrile cosolvent and constant ionic strength. Semi-log plots of the decay rate constants versus the reciprocal of the solution dielectric constants were used to extrapolate to totally aqueous conditions. In solution at 37 degrees C and pH2 with ionic strength mu = 0.02, azithromycin was degraded with a T1/10 of 20.1 min while erythromycin underwent 10% decay in only 3.7 sec. The activation energy for hydrolysis of the ether bond connecting cladinose to azithromycin was 25.3 kcal/mol while the internal dehydration reaction of erythromycin had an activation energy of 15.6 kcal/mol. A solution stability profile was generated for azithromycin over the pH range of 1.0 to 4.1 at 30 degrees C. Stability was found to improve ten-fold for each unit increase in pH.

Adverse events associated with itraconazole in 189 patients on chronic therapy

Abstract: Itraconazole was administered at doses of 50-400 mg/day to 189 patients with a variety of systemic mycoses for a median of five months. Adverse reactions possibly due to itraconazole were seen in 74 patients (39%). Mild gastrointestinal reactions were most common; other reactions including hypertriglyceridaemia, hypokalaemia and liver enzyme elevations occurred less frequently. No fatal reactions have been noted and toxicity has rarely led to a discontinuation of therapy. Chronic therapy with itraconazole appears well tolerated by the majority of patients.

A comparative study on the inhibitory actions of chloramphenicol, thiamphenicol and some fluorinated derivatives

Abstract: Chloramphenicol, thiamphenicol and three fluorinated derivatives, Sch 24893, Sch 25298 and Sch 25393, were studied with respect to inhibition of the growth of selected bacterial strains and cell-free translation systems. Thiamphenicol was the least potent inhibitor in the former experiments, but behaved similarly to chloramphenicol and Sch 25298 in the latter, thereby displaying selective inhibition of prokaryotic protein synthesis. Thiamphenicol and Sch 25298 were shown to be like chloramphenicol in inhibiting peptidyl transferase activity specifically on 70 S ribosomes, but the antibiotics bound to their common ribosomal-receptor site with different efficiencies in the order chloramphenicol greater than thiamphenicol greater than Sch 25298. Selected bacterial strains highly resistant to chloramphenicol and thiamphenicol because of chloramphenicol acetyltransferase production were, in contrast, highly sensitive to inhibition by the fluorinated antibiotics. Thus Sch 24893, Sch 25298 and Sch 25393 may have important uses in veterinary and clinical medicine.

The antimicrobial activity of fusidic acid.

Abstract: Fusidic acid, a fusidane that interferes with protein synthesis via the translocase enzyme, is mainly notable for its activity against staphylococci, coagulase-positive and negative, whether or not they are resistant to methicillin and related penicillins. It is also active against corynebacteria and against many genera of strict anaerobes and microaerophiles. Mutants showing resistance, by more than one mechanism, may readily be selected in vitro. Combination of fusidic acid with other antibiotics generally gives addition or indifference, but also delays emergence of resistant mutants.

Pharmacokinetics of azithromycin in rats and dogs.

Abstract: After intravenous or oral administration to rats and dogs, azithromycin was rapidly distributed into the tissues, where concentrations frequently exceeded those in serum by 100-fold or more within 24 h of a single dose. Tissue concentrations were proportional to the dose following single administrations of 10 to 40 mg/kg in rats and dogs. Tissue concentrations were higher after multiple dosing and became greater as the dose was increased from 10 to 40 mg/kg. Elimination half-lives were similar in most tissues and were about 40 h in rats after seven doses of 20 mg/kg and about 90 h in dogs after five doses of 30 mg/kg. Serum concentrations declined in a multi-exponential manner, reflecting initial rapid distribution into tissues and then slow return to serum from tissues. Azithromycin had good oral bioavailability in rats and dogs (46% and 97%, respectively). Rapid uptake of azithromycin by tissues from serum and slow redistribution from tissues to serum are apparently factors governing the pharmacokinetics of azithromycin in rats and dogs. Serum concentrations do not reflect the availability of azithromycin in tissues.

Azithromycin in the treatment of sexually transmitted disease

Abstract: One hundred and eighty-two patients were enrolled in a randomized third-party blinded study to assess the efficacy and safety of azithromycin in the treatment of sexually transmitted diseases. Three regimens of azithromycin, including a single oral dose, were compared with a standard treatment with doxycycline. The patients were followed for four weeks. Efficacy was evaluated in 168 patients (113 azithromycin, 55 doxycycline). Fourteen patients had negative cultures or did not come for all follow-up visits. Of the 168, 138 were infected with Chlamydia trachomatis, 43 with Neisseria gonorrhoeae, and 45 with Ureaplasma urealyticum. Ninety-six per cent of patients with chlamydial infections and 92% of those with gonorrhoea were cured with azithromycin. Two patients infected with N. gonorrhoeae, four with C. trachomatis and six with U. urealyticum had positive cultures on follow-up visits after receiving azithromycin. Of these 11 patients with positive cultures on follow-up visits, seven (five with U. urealyticum and two with C. trachomatis) violated the protocol by having intercourse with infected individuals during the study. Azithromycin was very well tolerated; one patient complained of mild abdominal pain shortly after receiving the drug, seven patients complained of mild nausea and two patients had mild diarrhoea.

Central nervous system toxicity of quinolones: human and animal findings.

Abstract: Quinolones have been reported to induce CNS reactions in 0.9-2.1% of cases, but severe reactions occur in less than 0.5%. Flumequine and fleroxacin, but not other quinolones, have produced convulsions in animals after systemic administration; by interventricular injection convulsions could be produced by some quinolones, but by pefloxacin only when a dose of 400 micrograms was reached. A possible mechanism for CNS excitation may be the displacement of GABA from receptors. Quinolones may interact with other drugs--theophylline, caffeine, non-steroidal anti-inflammatory drugs--in producing CNS effects.

Susceptibility of bacterial biofilms to tobramycin: role of specific growth rate and phase in the division cycle

Abstract: A novel method of cell culture, enabling growth rate control of sessile Gram-negative populations, has been employed to assess the sensitivity of Escherichia coli towards the aminoglycoside antibiotic, tobramycin. Changes in sensitivity, dependent on the growth rate, were compared with those for suspended populations grown in a chemostat and also those for newly-formed daughter cells shed from the biofilm during its growth and development. At specific growth rates up to 0.3 h-1 the susceptibility both of the resuspended biofilm cells and of their planktonic, chemostat grown controls increased in proportion to the growth rate. As the growth rate was increased further (up to 0.7h-1), the susceptibility of the resuspended biofilm cells remained high, whilst that of the planktonic controls decreased. Newly-formed daughter cells, dislodged from the biofilm, demonstrated a uniformly high sensitivity to the antibiotic at all growth rates. This sensitivity corresponded to that of the fastest-growing cells resuspended from biofilms. Lack of growth rate dependency of killing for the newly-formed daughter cells and their high sensitivity to tobramycin suggested that tobramycin activity might vary during the cellular division cycle. Indeed, when synchronous populations were exposed to tobramycin at various times during their division cycle, sensitivity decreased markedly 20 min before the onset of septation, and increased as septation began. Regulation of the cellular division cycle might therefore account, at least partly, for the observed effects of growth rate on susceptibility.

Rapid emergence of resistance in Pseudomonas aeruginosa in cystic fibrosis patients due to in-vivo selection of stable partially derepressed β-lactamase producing strains

Abstract: The development of significant mechanisms of resistance to beta-lactam antibiotics in Pseudomonas aeruginosa in cystic fibrosis (CF) patients have been studied in ten CF patients during a two week course of anti-pseudomonal beta-lactam antibiotic therapy. Sputum samples were collected on days 1, 7 and 15. Entire homogenized sputum samples were examined directly for the number of bacteria resistant to different levels of antibiotics. This allowed the detection of pre-existing resistant subpopulations of bacteria as well as following the changes in beta-lactam antibiotic susceptibility during treatment. P. aeruginosa isolates were characterized by means of sero-grouping, phage- and pyocin-typing. Outer membrane proteins of paired sensitive and resistant strains were characterized. Sonicated extracts of cells were assayed for basal and induced beta-lactamase activity. Beta-lactamase activity was further characterized by isoelectric focusing and inhibition profiles. Our observations were in accordance with the hypothesis that the sensitive inducible population was overrun by the pre-existing resistant subpopulation, during treatment. The resistant in-vivo selected P. aeruginosa population exhibited stable partially derepression but the beta-lactamase inhibitor tazobactam restored beta-lactam antibiotic activity.

Drug interactions with quinolones.

Abstract: The pharmacodynamic and pharmacokinetic drug interactions and pharmaceutical compatibilities of fluoroquinolones are reviewed. Incompatibilities are observed between quinolones and penicillins such as flucloxacillin and amoxicillin and with clindamycin when mixed in an administration set. Fluoroquinolones, especially enoxacin, and to a lesser extent ciprofloxacin and pefloxacin, inhibit the metabolic clearance of theophylline and caffeine. It is advisable to use non-interacting quinolones such as ofloxacin or norfloxacin or to measure theophylline levels and reduce caffeine intake where appropriate. A potential interaction with midazolam needs further study. The absorption of fluoroquinolones is markedly reduced by antacids, calcium carbonate, ferrous sulphate and sucralfate. Although quantitative differences between fluoroquinolones exist, these combinations should be avoided whenever possible. Cimetidine reduces the metabolic clearance of pefloxacin. More studies are needed on the possible reduction of absorption of fluoroquinolones by opiates. Several case reports of a pharmacodynamic interaction between fluoroquinolones and cyclosporin or oral anticoagulants exist. No pharmacokinetic interaction has been observed and more, controlled studies are needed to assess the significance of the pharmacodynamic interaction. A high incidence of convulsions has been observed in patients receiving the combination enoxacin and fenbufen, an NSAID. A synergistic inhibitory effect of fluoroquinolones and several NSAIDs has been observed on the binding of the neurotransmitter GABA. Although the relevance of this interaction is probably not great, except with fenbufen, a possible epileptogenic effect of the combination cannot be excluded.

Cellular uptake, localization and activity of fluoroquinolones in uninfected and infected macrophages

Abstract: Pefloxacin, like other fluoroquinolones, accumulates in macrophages and several other types of nucleated cells (but not in erythrocytes). Upon fractionation of macrophage homogenates by isopycnic centrifugation in sucrose gradients, fluoroquinolones are not found associated with any specific cellular structure. We have compared the activities of pefloxacin and roxithromycin against intracellular Staphylococcus aureus in mouse J774 macrophages. Pefloxacin was significantly more active for equivalent intracellular drug concentrations (i.e. expressed by reference to the respective MICs of the drugs as determined in broth), suggesting differences in intracellular availability and/or capacity of the drugs to express their activity in the intracellular environment. The difference was enhanced by incubating the cells in acidic medium. We have also examined the cellular pharmacokinetics and intracellular distribution of pefloxacin in uninfected and Legionella pneumophila infected guinea pig macrophages. In contrast to uninfected cells from which pefloxacin was quickly released, macrophages infected with legionella retained approximately 20-30% of the accumulated pefloxacin after a 60-min wash-out. Cell fractionation studies indicated that the drug remaining in cells was associated with components of high buoyant density. These fractions also contained [3H] if cells had been incubated with [3H] labelled legionella (by in-vitro exposure to [3H]-thymidine, before phagocytosis). These results suggest that part of the intracellular pefloxacin becomes associated with legionella, or with legionella-containing cytoplasmic structures.

Induction of β-lactamase and methicillin resistance in unusual strains of methicillin-resistant Staphylococcus aureus

Abstract: Two unusual, heterogeneously-resistant, strains of Staphylococcus aureus appeared resistant to oxacillin, but susceptible to methicillin by disc diffusion methods. In agar dilution tests, both strains were oxacillin-resistant. One was susceptible to methicillin, and the other gave a paradoxical reaction, with growth only on plates containing low (0.5, 1 and 2 mg/l) and high (32 and 64 mg/l) concentrations of antibiotic. Induction of methicillin resistance was tested by inoculating each strain on to agar plates containing an inhibitory concentration of methicillin (8 mg/l), and then placing discs containing inducers (oxacillin, nafcillin, methicillin and CBAP [2-(2'-carboxyphenyl) benzoyl-6-aminopenicillanic acid]) on the agar surface. Colonies grew only around discs containing effective inducers. Oxacillin and CBAP were much more potent inducers of methicillin resistance and beta-lactamase than was nafcillin or methicillin. These data suggest that the mechanism that regulates induction of the low-affinity penicillin binding protein (PBP-2') may be altered in these strains. Similar mechanisms appear to induce both beta-lactamase and methicillin resistance.

Does administration of an aminoglycoside in a single daily dose affect its efficacy and toxicity

Abstract: Treatment efficacy, oto- and nephrotoxicity, and aminoglycoside pharmacokinetics were evaluated in a prospective, comparative, randomized clinical study of aminoglycosides given once a day or three times a day for severe infections. Sixty patients were treated with netilmicin or gentamicin 4.5 mg/kg bodyweight/day, either once a day or divided into three doses a day. The patients were allocated randomly to the different groups. The clinical effect was difficult to compare in the different groups, because of the small numbers of patients. Therapeutic failures were seen in seven patients (three after one and four after three doses per day). Two patients, one with Staphylococcus aureus endocarditis and one with streptococcal endocarditis, on netilmicin once daily and conventional high-dose therapy with a penicillin had positive blood cultures after five and seven days of treatment, respectively. Vestibular function and hearing acuity were examined by serial audiograms and electronystagmograms. In spite of extensive diagnostic evaluation, only two cases of ototoxicity were detected. One patient treated with gentamicin three times a day developed vertigo and a severe abnormality of her electronystagmogram. One young patient treated with gentamicin once daily had a slight bilateral reduction of hearing. Nephrotoxicity was mild and did not differ in the four treatment groups. This was the first investigation of a once-daily dosing regimen conducted in seriously ill patients with systemic infections. We could not demonstrate any evidence that aminoglycoside treatment once daily has greater oto- or nephrotoxicity than the traditional three times daily regimen.

Effect of growth-rate on resistance of Gram-negative biofilms to cetrimide

Abstract: A method of cell culture, which allows control of growth rate for sessile Gram-negative populations, has been employed to assess the sensitivity of Escherichia coli biofilms to the antiseptic compound, cetrimide. Growth-rate-dependent changes in sensitivity were compared for chemostat-grown, planktonic cells, for cells resuspended from the biofilm and also for newly formed daughter cells shed from the biofilm during its growth and development. Susceptibility to cetrimide decreased in all instances with increases in growth-rate up to mu = 0.15 h-1. As growth rate was increased beyond this value then sensitivity increased in proportion to the rate of division. At rates of growth less than mu = 0.15 h-1 the susceptibility of the biofilm-derived cells and their offspring was significantly less than that of cells of planktonic origin.

Safety profile of the quinolones

Abstract: The most important finding from preclinical evaluation of fluoroquinolones has been their arthropathogenic potential in young animals. This toxic effect is found with all quinolones known so far and has led to the decision not to use them in children and adolescents, despite the fact that the significance of the effect for humans is still unclear. The mutagenic potential of the drugs seems to be low although bacterial DNA-metabolism is a major target of their action. Newer in-vitro methods to study topoisomerases from bacterial and mammalian cells are suitable to detect differences in the derivatives with regard to their mutagenic potential. The major adverse effects observed clinically with the four most often used fluoroquinolones norfloxacin, ciprofloxacin, ofloxacin and enoxacin are gastrointestinal disturbances (1.8-5%), reactions of the central nervous system (0.9-1.6%) and skin reactions (0.6-1.4%). Higher incidences have been noticed during the clinical evaluation of fleroxacin at doses of 400 mg or more. A comparison of the adverse reaction frequencies of fluoroquinolones with those of other antimicrobial agents can most closely be made with the results from double-blind studies. Such results show that in most cases fluoroquinolones have been tolerated as well as or better than conventional drugs. Clinically relevant drug interactions have been observed with some quinolones that are metabolized primarily in the liver: enoxacin and ciprofloxacin reduce the theophylline clearance. Also, interactions of quinolones with Mg2(+)-containing antacids, which result in tremendous loss of bioavailability, are of therapeutic importance. Overall, fluoroquinolones are well tolerated and the incidences of side effects are similar to those of other antibacterials.

Interactions of tazobactam and clavulanate with inducibly- and constitutively-expressed Class I β-lactamases

Abstract: Clavulanate and tazobactam (YTR 830) were tested as inhibitors and inducers of the AmpC-type Class I beta-lactamases of Pseudomonas aeruginosa, Enterobacter cloacae, Citrobacter freundii, Serratia marcescens, Morganella morganii and the Ic beta-lactamase of Proteus vulgaris. Both clavulanate and tazobactam inhibited the Pr. vulgaris Class Ic beta-lactamase and potentiated ticarcillin and piperacillin against beta-lactamase derepressed variants of this species. Tazobactam, but not clavulanate, also had some ability to inhibit the AmpC Class I enzymes of M. morganii, C. freundii, Ps. aeruginosa, E. cloacae and S. marcescens. The piperacillin + tazobactam combination, unlike ticarcillin + clavulanate, showed some degree of synergy against most derepressed strains of these species. This behaviour partly depended upon the greater inhibitory activity of tazobactam for the enzymes, but also on piperacillin being easier to potentiate than ticarcillin. The synergy between piperacillin and tazobactam was greatest for M. morganii and C. freundii, least for Ps. aeruginosa and E. cloacae. Unfortunately, it is in the last two species that these enzymes pose the greatest resistance threat. Tazobactam caused little or no antagonism of piperacillin against beta-lactamase inducible species, whereas clavulanate antagonized ticarcillin against beta-lactamase inducible strains of E. cloacae and M. morganii (not other species). The antagonism of ticarcillin was attributable to beta-lactamase induction. The lack of antagonism with the tazobactam+piperacillin combination was related to tazobactam being a weaker inducer than clavulanate, not to piperacillin being less susceptible to antagonism than ticarcillin.

Prevalence of a transferable SHV-5 type beta-lactamase in clinical isolates of Klebsiella pneumoniae and Escherichia coli in Greece.

Abstract: Analysis with a double-disc synergy test (DDST) of clinical isolates of Klebsiella pneumoniae and Escherichia coli during the period October 1988-September 1989 revealed that 24% of the former and 4% of the latter, mainly isolated from urine, possessed an extended-spectrum beta-lactamase. During this period no DDST was positive for isolates of other enterobacterial species. Transfer of ceftazidime resistance was demonstrated from six K. pneumoniae and two E. coli isolates resistant to third generation cephalosporins and aztreonam. Apart from one strain of K. pneumoniae, these strains harboured self-transferable multiresistance plasmids (c. 91 kb) with closely related EcoRI, HindIII, AvaII and PstI restriction patterns. These plasmids encoded an extended-spectrum beta-lactamase that conferred an unusually high level of resistance to ceftazidime and aztreonam (MIC greater than or equal to 64 mg/l). This enzyme had a pI of 8.2 and a substrate profile similar to that of the SHV-5 enzyme isolated initially in Chile, and later in France (CAZ-4). The remaining K. pneumoniae isolate harboured a transmissible multiresistance plasmid (c. 182 kb) that encoded the widely distributed SHV-2 enzyme. The resistance to cefoxitin that was observed in some of these strains was associated with outer membrane protein alterations.

Comparison of azithromycin and erythromycin in the treatment of atypical pneumonias

Abstract: An open, randomized, multicentre study compared the efficacy and safety of the prototype, azalide, azithromycin, and erythromycin in the treatment of atypical pneumonias. Azithromycin was administered for five days at a dosage of 250 mg bd on day 1 and 250 mg once daily on days 2 to 5. Erythromycin was given for ten days at 500 mg qid. Causative pathogens were identified by serological methods. Of 57 patients treated with azithromycin, Mycoplasma pneumoniae and Chlamydia psittaci were identified in 31 and eight patients, respectively. Of 44 patients treated with erythromycin, M. pneumoniae and C. psittaci were identified in 24 and eight patients, respectively. There were no therapeutic failures in either treatment group. Side effects were observed in one of 57 patients on azithromycin and in six of 44 patients on erythromycin. Azithromycin appears to be as effective as erythromycin in the treatment of atypical pneumonias and better tolerated.

The causative organisms of septicaemia and their epidemiology.

Abstract: During the 20 years, 1969-88, nearly 4000 episodes of septicaemia were studied prospectively at St. Thomas' Hospital. Forty percent were community-acquired and 60% hospital-acquired. Overall the commonest isolate was Escherichia coli (22%). In community-acquired bacteraemias, Esch. coli, Streptococcus pneumoniae and Staphylococcus aureus accounted for almost 60% of episodes, and the commonest foci of infection were the urinary tract (Esch. coli) and the respiratory tract (Str. pneumoniae). Esch. coli was particularly common in diabetic patients and Str. pneumoniae in alcoholics. In hospital-acquired septicaemia, Esch. coli and Staph. aureus accounted for 40% of episodes, but a further 30% were caused by enterobacteria other than Esch. coli, and Pseudomonas aeruginosa. The commonest foci of infection were the urinary tract, often with catheterization or instrumentation, and intravascular access sites, from which episodes of septicaemia were increasingly caused by coagulase-negative staphylococci.

Emergent resistance to ciprofloxacin amongst Pseudomonas aeruginosa and Staphylococcus aureus :clinical significance and therapeutic approaches

Abstract: Sporadic emergence of resistance during therapy with ciprofloxacin has been noted since its use in clinical trials began. It has occurred particularly, although not exclusively, with Pseudomonas aeruginosa and Staphylococcus aureus, both of which have MICs in the range 0.5-2.0 mg/l. Although not invariably associated with clinical failure of therapy, emergence of resistance has usually occurred in infections either where large numbers of organisms are present or in tissues where ciprofloxacin concentrations may not be optimal, or where both factors apply. Care in selection of patients, attention to optimal duration of therapy and adequate dosage may help to prevent emergence of resistance but combination therapy has not proven effective. Resistance may in some bacterial strains be permanent but in others frequently reverts to normal sensitivity. In some situations, spread to other patients is a significant problem and treatment in isolation (or at home) may be advisable. Emergence of resistance to ciprofloxacin in these species usually occurs in recognizable situations and, in such circumstances, the availability of alternative therapy and the quantitative risk of the emergence of resistance must be balanced against potential benefit. Ciprofloxacin should never be used for trivial infections caused by staphylococci or P. aeruginosa.

Comparative studies of azithromycin in skin and soft-tissue infections and sexually transmitted infections by Neisseria and Chlamydia species

Abstract: Two open, randomized, single centre studies have investigated the efficacy and safety of azithromycin (CP-62,993) in the treatment of infections by azithromycin-sensitive pathogens: (A) acute bacterial infections of skin or soft tissue (compared with erythromycin; n = 82); and (B) urethritis and/or cervicitis caused by Neisseria gonorrhoeae and/or Chlamydia trachomatis (compared with doxycycline; n = 108). In study A, azithromycin was administered to 42 patients for five days at a dosage of 250 mg bd on day 1 and 250 mg once daily on days 2-5; erythromycin was given to 40 patients for seven days at a dosage of 500 mg every 6 h. In study B, azithromycin was administered either as a single 1 g dose or as a single 500 mg dose on day 1 and 250 mg once daily on days 2 and 3; doxycycline was given at a dose of 100 mg every 12 h for seven days. In study A, 68 patients were clinically assessed: clinical cure or improvement in patients receiving azithromycin or erythromycin was achieved in 86% and 82%, respectively. The principal causative pathogen was Staphylococcus aureus; there was eradication of 15/25 pathogens (60%) with azithromycin and 13/23 (57%) with erythromycin. In study B, 94 and 93 patients were clinically assessed at weeks 1 and 2, respectively: clinical cure was achieved with all treatment regimens at week 1; at week 2 there was reappearance of symptoms in one patient with a mixed infection who had received 3-day azithromycin.(ABSTRACT TRUNCATED AT 250 WORDS)

In-vitro activity of ofloxacin against Mycobacterium tuberculosis and its clinical efficacy in multiply resistant pulmonary tuberculosis

Abstract: The in-vitro susceptibilities to ofloxacin of 159 clinical sputum isolates of Mycobacterium tuberculosis, comprising 95 isolates sensitive to all drugs, 31 isolates resistant to streptomycin or isoniazid or both, 27 isolates resistant to streptomycin, isoniazid and rifampicin and six isolates resistant to rifampicin (and in three cases to other drugs) were determined. Favourable MICs of ofloxacin (0.63-1.25 mg/l) were demonstrated for 147 isolates (92%). Twenty-two patients with resistant strains (including one patient with rifampicin intolerance) were studied: ten were given 300 mg ofloxacin and ten were given 800 mg ofloxacin, once daily in both cases, together with second-line accompanying drugs, for nine months to one year. Two received 800 mg of ofloxacin once daily alone for similar periods. In the 300 mg-ofloxacin group and the 800 mg-ofloxacin group, five and eight patients, respectively, achieved culture conversion; the rest failed. In the former group, the peak serum ofloxacin concentrations were 3.71-8.08 mg/l and the mean sputum/serum ratio was 0.85. In the latter group, the corresponding values were 10-18.7 mg/l, and 0.76, respectively. All patients tolerated the drugs well. Analysing only patients with accompanying drugs, those on ofloxacin 800 mg once daily had more rapid sputum culture conversion than those on ofloxacin 300 mg once daily (Mann-Whitney Wilcoxon Rank Sum Test: P less than 0.05), indicating more rapid bacteriolysis and implying the definite efficacy of ofloxacin when used together with second-line accompanying drugs in the management of resistant tuberculosis.

In-vitro activity of azithromycin, erythromycin, ciprofloxacin and norfloxacin against Neisseria gonorrhoeae, Haemophilus ducreyi, and Chlamydia trachomatis.

Abstract: The minimum inhibitory concentrations (MICs) of azithromycin, erythromycin, ciprofloxacin and norfloxacin for 300 strains of Neisseria gonorrhoeae, 100 strains of Haemophilus ducreyi and six strains of Chlamydia trachomatis were determined. The two quinolones were more active against gonococcal strains than were the two macrolides. Azithromycin was approximately eight-fold more active against N. gonorrhoeae than was erythromycin (MIC90: 0.25 mg/l azithromycin, 2.0 mg/l erythromycin). The Mtr phenotype of gonococci increased azithromycin MICs approximately four fold. Azithromycin was less active than erythromycin against C. trachomatis. Azithromycin had considerable activity against H. ducreyi and was ten-fold more active than was erythromycin (MIC90: 0.004 mg/l azithromycin, 0.03 mg/l erythromycin). Clinical trials of azithromycin in the treatment of chlamydial infection and genital ulcer disease are indicated.

Correlation of the extravascular pharmacokinetics of azithromycin with in-vivo efficacy in models of localized infection

Abstract: Infection models were used to clarify the roles of serum and extravascular concentrations in the in-vivo efficacy observed with azithromycin. In-vivo experiments were designed to give serum concentrations well below the MIC and tissue levels generally above the MIC at time of challenge and during the course of infection. The efficacy of azithromycin against a Salmonella enteritidis oral challenge (a tissue-associated infection model) in mice correlated directly with azithromycin liver levels, but not serum concentrations. The significance of extravascular pharmacokinetics was observed in a comparative study of azithromycin and ciprofloxacin against the salmonella challenge. Ciprofloxacin has a greater than 100-fold in-vitro potency advantage over azithromycin against this organism, but azithromycin (5 mg/kg) produced a greater reduction in cfu than ciprofloxacin (100 mg/kg) at the primary site of infection (liver). In another model, extravascular fluid levels, measured by bioassay of implanted paper discs, were compared with plasma levels in relation to control of a localized Staphylococcus aureus infection in rats. Extravascular fluid levels of azithromycin were greater than the MIC of the strain used for five days after a 100 mg/kg dose, while erythromycin levels were less than 20% of the MIC at 30 h after a 200 mg/kg dose. Serum concentrations of both compounds were less than 20% of the MIC at the time of challenge. The antibiotic levels at the site of infection correlated with the reduction of Staph. aureus cfu (99% with azithromycin compared with controls, P less than 0.01; 0% with erythromycin) recovered from inoculated discs. The significance of extravascular concentrations of azithromycin was further supported in other models of localized infections induced with Escherichia coli or a mixture of Staph. aureus and Bacteroides fragilis.

Relationship of high tissue concentrations of azithromycin to bactericidal activity and efficacy in vivo

Abstract: Measurement of killing kinetics of azithromycin against strains of Streptococcus pneumoniae and Klebsiella pneumoniae in vitro showed that it had a limited bactericidal activity (greater than 90% kill) for the first eight hours of incubation, but developed complete bactericidal activity (greater than 99.9% kill) by 24 h incubation. Since high and sustained tissue levels of azithromycin occur in animals and humans, it was proposed that it might produce a bactericidal effect in vivo. This was demonstrated in a lung infection model in mice, designed to mimic the in-vitro killing studies. A 25 mg/kg dose of azithromycin given 24 h before intranasal challenge reduced the recoverable Str. pneumoniae population by greater than 99.9%, in comparison with untreated controls. Erythromycin did not produce a bactericidal effect at 100 mg/kg, and roxithromycin only reduced the viable count by 96%, at a dose of 50 mg/kg. Against a K. pneumoniae lung infection, a 50 mg/kg dose of azithromycin reduced the bacterial count by 99%. The bactericidal effect was correlated with lung tissue concentrations of azithromycin. In a proliferating Escherichia coli paper disc infection model, extravascular fluid concentrations of azithromycin were correlated with a 99.9% reduction in bacterial count, while corresponding serum concentrations were always less than the MIC. Dosing with azithromycin eradicated Haemophilus influenzae from the bulla (middle ear) of gerbils, as was not the case with erythromycin and roxithromycin. This effect was correlated with the antibiotic concentration in bulla lavage.

Efficacy of azithromycin for therapy of active syphilis in the rabbit model

Abstract: Azithromycin was shown to be as effective as standard benzathine penicillin and erythromycin in the therapy of active syphilis in the rabbit model. Following production of primary chancres by intradermal inoculation of 10(6) Treponema pallidum, groups of six rabbits were treated with benzathine penicillin (200,000 units im weekly for two weeks), erythromycin base (30 mg/kg/day orally four times daily for 15 days) or azithromycin (30 mg/kg/day given orally once or twice daily for 15 days); one group was untreated. Daily darkfield (DF) microscopic examinations of chancre aspirates were conducted to identify motile organisms. Although all treated animals became DF negative prior to completion of therapy, the median time to DF negativity was longer in animals given azithromycin once daily, compared with animals receiving benzathine penicillin (P less than 0.01); no difference was seen in comparison with animals receiving erythromycin. Untreated animals remained DF positive for greater than 15 days. The mean maximum lesion diameters for all treated animals were similar and were significantly smaller than in untreated rabbits; fewer lesions ulcerated in treated than in untreated animals. Subsequent dose-ranging studies indicated that administration of lower doses of azithromycin (15 mg/kg/day given orally either once or twice daily, or 7.5 mg/kg/day given once daily) was as effective as benzathine penicillin for therapy of active syphilis in this model, though the median time to darkfield negativity was significantly longer in the azithromycin-treated animals (P less than 0.01). Persistent infection was demonstrable in lymph nodes of untreated animals, but no evidence of virulent T. pallidum was found three months following transfer of tissue from any animal treated with penicillin, erythromycin, or azithromycin.