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PubMed2005

Topical ocular antibiotics induce bacterial resistance at extraocular sites.

AIM: To compare the prevalence of antibiotic resistance found in nasopharyngeal Streptococcus pneumoniae between villages treated with topical tetracycline or systemic azithromycin as part of a trachoma control programme. METHODS: All children aged 1-10 years were offered either single dose oral azithromycin treatment (20 mg/kg) or a course of topical 1% tetracycline ointment, depending on the area. Treatment was given annually for 3 years. Six months after the third annual treatment in each village, children were surveyed for nasopharyngeal carriage of S pneumoniae and resistance was determined using broth dilution MIC technique. Children in two additional villages, which had not yet been treated, were also surveyed. RESULTS: Nasopharyngeal carriage of S pneumoniae was similar in the tetracycline treated, azithromycin treated, and untreated areas (p=0.57). However, resistance to tetracycline and azithromycin was distributed differently between the three areas (p=0.004). The village treated with topical tetracycline had a higher prevalence of tetracycline resistance than the other villages (p=0.010), while the oral azithromycin treated village had a higher prevalence of macrolide resistance than the other villages (p=0.014). CONCLUSIONS: Annual mass treatment with oral azithromycin may alter the prevalence of drug resistant S pneumoniae in a community. Surprisingly, topical tetracycline may also increase nasopharyngeal pneumococcal resistance. Topical antibiotics may have an effect on extraocular bacterial resistance.

Administration, Oral↗

PubMed2005

An economic and outcomes assessment of first-line monotherapy in the treatment of community-acquired pneumonia within managed care.

OBJECTIVE: To evaluate the resource consumption and outcomes associated with first-line monotherapy for community-acquired pneumonia, focusing specifically on the use of erythromycin, azithromycin, clarithromycin, and levofloxacin. STUDY DESIGN: Retrospective managed care database analysis. PATIENTS AND METHODS: Subjects included patients within a managed care setting over 18 years of age with an initial diagnosis of community-acquired pneumonia from January 1995 to April 2002. Multivariate linear and logistic regression models were used to examine associations with treatment success rates and direct medical costs between antibiotic treatments after controlling for patient demographics and pneumonia risk factors. MAIN RESULTS: Overall, treatment success rates were high (95.8%), the use of second antibiotics was un common (2.3%), and hospitalizations were infrequent (2.0%) among the 1952 subjects studied. After controlling for patient characteristics and risk factors, significantly lower total costs were associated with erythromycin (92.7% lower, p < 0.001), azithromycin (48.7% lower, p < 0.001), and clarithromycin (21.3% lower, p = 0.015) relative to levofloxacin, with no difference in treatment success between groups. Among newer agents, azithromycin (49.2% lower, p < 0.001) and clarithromycin (21.7% lower, p = 0.013) treatment groups were associated with significantly lower total costs than levofloxacin in the full sample. However, in subjects with a chronic disease score above the sample's mean, only azithromycin was associated with significantly lower total costs (47.9% lower, p < 0.001) relative to levofloxacin. CONCLUSION: Erythromycin, azithromycin, and clarithromycin were associated with significantly lower total costs than levofloxacin, although treatment success rates did not differ between groups. Following stratification based upon various subset criteria, erythromycin and azithromycin were observed to have significantly lower total costs than levofloxacin. Although these findings may augment clinical guidelines and evidence-based approaches, health plans should consider evaluating their own patient data to see if similar differences exist in their populations.

Adolescent↗

PubMed1999

Comparative tolerability of erythromycin and newer macrolide antibacterials in paediatric patients.

The macrolides are a well established group of antibacterials frequently used in general practice. The most frequently used macrolides in paediatric patients are erythromycin, a naturally occurring compound, and clarithromycin and azithromycin, recently developed macrolides. Overall adverse effect rates of 7 to 26% for erythromycin, 14 to 26% for clarithromycin, and 6 to 27% for azithromycin have been described in children. Adverse gastrointestinal effects, including nausea, vomiting, diarrhoea and abdominal cramps, are the most common problems in children. Allergic reactions, hepatotoxicity, ototoxicity and adverse effects involving the central and peripheral nervous systems have also been observed in children. Stevens-Johnson, Schonlein-Henoch and Churg-Strauss syndromes have been rarely described in children. Treatment-related laboratory abnormalities have been recorded in 2 to 4% of erythromycin- and in 0 to 1% of both clarithromycin- and azithromycin-treated children. Elevation in liver function tests was the most common abnormality cited. Increased macrolide use in children in recent years has resulted in a growing potential for drug interactions between them and other pharmacologically active agents via the inhibition of cytochrome P450 (CYP) microsomal enzymes. Drug interactions with theophylline, cyclosporin, carbamazepine, terfenadine and warfarin limit erythromycin use. Clarithromycin is a weak inducer of CYP and exhibits fewer drug-drug interactions than erythromycin. However, its use with theophylline, carbamazepine and terfenadine is contraindicated. In contrast, no significant interactions have been reported with azithromycin to date. Macrolides have been proven to be well tolerated in the treatment of upper and lower respiratory tract infections, skin and soft tissue infections, and also in less frequent infections occurring in paediatric patients. In addition, clarithromycin and azithromycin have shown good tolerability profiles in immunocompromised paediatric patients. In conclusion, macrolides antibacterials have proven to be well tolerated in paediatric patients. Although the incidence of adverse effects is similar with the use of erythromycin and the newer macrolides, drug interactions occur significantly less when clarithromycin or azithromycin are administered.

Anti-Bacterial Agents↗

PubMed1999

Pneumococcal macrolide resistance--myth or reality?

There is no doubt that owing to the prolific use of the macrolides and azithromycin over the past several years, resistance has developed and is increasing in incidence. I believe we should re-evaluate the use of these antibiotics for our patients and consider parameters other than the negative in-vitro results. Firstly, microbiology laboratories should return to the habit of providing the clinician with MIC values for pathogenic isolates rather than generic susceptibility reports ((S)usceptible, (I)ntermediate, (R)esistant) that are based on standard disc diffusion testing. Although agar dilution MIC testing is a bulky and labour intensive practice, it provides the best data when conducted in the appropriate environment. Secondly, and more importantly, these MIC values need to be compared with in-vivo antibiotic pharmacokinetics and pharmacodynamics. Although it is possible to compare MIC values directly with serum concentrations of beta-lactams and aminoglycosides, this is not a valid practice for azithromycin or the macrolides. MICs of azithromycin and the macrolides must be compared with the infection site and phagocytic cell concentrations to determine the utility, or lack thereof, of one of these agents. Whereas azithromycin cellular penetration allows maximal pharmacodynamics potentially even against moderately or highly resistant pneumococci, the macrolides do so less optimally. Although there are no reports of widespread clinical failures resulting from macrolide/azalide resistance in pneumococci, it is expected that such reports will appear once the isolates become consistently highly resistant. This is likely to affect the macrolides, erythromycin and clarithromycin, before the azalide, azithromycin owing to the differences in pharmacokinetics of these drugs. Until then, it will be important to determine the MICs of not just one macrolide, but of all macrolides and azalides for the isolates. This will allow the clinician to make a pharmacokinetically and pharmacodynamically sound choice. By choosing clinical MIC breakpoints of 4-8 mg/L for oral macrolides and < or = 32 mg/L for oral azithromycin, rather than the present standard breakpoints, the clinician can make a macrolide/azalide choice that will optimize the pharmacodynamics of the drug against the isolated pathogen and result in the best possible clinical outcome. Once data concerning the cellular penetration of intravenous formulations of these drugs becomes available, it will be possible to develop clinical breakpoints for these formulations as well. Only through utilizing good antibiotic prescribing practices and by using the drugs appropriately when they are used, can resistance trends be stemmed. In this way, not only does a clinician treat the patient more effectively, but they also extend the antibiotic's useful life.

Anti-Bacterial Agents↗

PubMed2026

Prophylactic antibiotics to prevent chest infections in children with neurological impairment: the PARROT RCT.

BACKGROUND: Improvements in neonatal and paediatric care in recent decades have increased the survival of children with non-progressive neurological impairment. Respiratory disease in children with neurological impairment is common, with symptoms difficult to manage and lower respiratory tract infection occurring frequently. To reduce these, prophylactic antibiotics are being increasingly used, but the type, duration and dose of antibiotics can vary considerably, and there is limited evidence about their effectiveness in children and young people. A joint United Kingdom and Australia multicentre, randomised, double-blind, placebo-controlled trial comparing 52 weeks of azithromycin to placebo in children and young people with neurological impairment at risk of lower respiratory tract infection (PARROT) was planned to address this gap. PARROT was a multicentre, parallel group, blinded, pragmatic randomised controlled trial of 52-week duration with a planned sample size of 500 (250 in each arm) participants with neurological impairment. The primary outcome was the proportion of children and young people hospitalised with lower respiratory tract infection over the 52-week period. RESULTS: In total, 90 children and young people (62 in Australia, 28 in the United Kingdom) aged 3-17 years, with a diagnosed non-progressive, non-neuromuscular neurological impairment, who had persistent respiratory symptoms were randomised (1 : 1) to receive azithromycin or placebo. Baseline demographic and clinical characteristics were relatively well balanced across the two treatment groups and countries. Overall, mean (standard deviation) age was 9.2 (4.4) years, with 64% of participants having cerebral palsy, 67% being non-ambulant and 54% being totally tube-fed. At baseline, mean (standard deviation) numbers of hospital admissions with lower respiratory tract infection in the preceding year were 1.8 (2.0)/year, and general practitioner attendances 3.3 (3.0)/year. The PARROT trial was closed early to recruitment due to challenges arising from the COVID-19 pandemic. Sixty-five (72%) participants (azithromycin n = 30, placebo n = 35) completed 52 weeks of treatment and were not withdrawn early from the trial. Regarding the primary outcome, 11 (36.7%) in the azithromycin group were hospitalised with lower respiratory tract infection and 9 (25.7%) in the placebo group [absolute risk reduction 0.11 (95% confidence interval -0.12 to 0.33), relative risk 1.43 (95% confidence interval 0.68 to 2.97)]. Analysis of secondary outcome data was limited by the number of missing data, but parent-reported quality of life for young person and parent, sleep amount/quality for young person and parent, and respiratory symptoms were similar between groups and countries. LIMITATIONS: As PARROT was stopped early and was consequently underpowered, it is not possible to say whether azithromycin prophylaxis is any more effective than placebo in reducing the proportion of children admitted to hospital with lower respiratory tract infection after a 52-week period. CONCLUSIONS AND FUTURE WORK: Although we cannot comment on the effectiveness of prophylactic antibiotics in this context, we can draw some useful conclusions from this trial. Thus, the importance placed by families on hospitalisation and its prevalence in both treatment groups, even during the pandemic, would suggest that this is an appropriate primary outcome measure for future trials in this high-risk group of children and young people. Furthermore, the high attrition rate and large numbers of missing data, specifically for questionnaire-based outcomes at later follow-up points, should encourage researchers to be mindful of minimising trial burden to families for any future trials wherever possible. FUNDING: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/17/01.

Humans↗

PubMed2000

Potential of macrolide antibiotics to inhibit protein synthesis of Pseudomonas aeruginosa: suppression of virulence factors and stress response.

Recently we have reported that sub-minimum inhibitory concentrations (MICs) of macrolide antibiotics, such as erythromycin, clarithromycin, and azithromycin, induce loss of viability of Pseudomonas aeruginosa with longer incubation periods. In the present study we examined the effects of sub-MICs of macrolide antibiotics on protein synthesis and the expression of heat shock proteins (Gro-EL) in P. aeruginosa and the association of these factors with the viability of P. aeruginosa. In seven strains of P. aeruginosa clinical isolates, inhibition of protein synthesis was generally observed in bacteria grown on agar with sub-MIC azithromycin (8 microg/ml) at 24 h, and this was followed by loss of viability after an additional 24-h incubation. The inhibition of protein synthesis was shown in bacteria treated with sub-MICs of erythromycin and clarithromycin, but not with sub-MICs of other antibiotics examined (josamycin, tobramycin, ofloxacin, clindamycin, and ceftazidime) even at relatively high sub-MICs. In the heat shock condition (45 degrees C), strong expression of the heat shock protein Gro-EL was induced in bacteria grown on antibiotic-free medium, whereas there was a delay of such a response in bacteria exposed to 4 microg/ml of azithromycin. Reflecting these results, an abrupt reduction of viability in azithromycin-treated bacteria was observed within 3 h in the heat shock condition. Western blot analysis, using specific antibody for Gro-EL, demonstrated that erythromycin, clarithromycin, and azithromycin, at concentrations of 0.5-2 microg/ml, inhibited the expression of lower-molecular weight Gro-EL bands in the constitutive state. These results indicated that macrolides, at concentrations far below the MICs, suppressed protein synthesis in P. aeruginosa, an effect which may be associated with the inhibition of P. aeruginosa virulence and its loss of viability with longer incubation. Moreover, it is likely that the macrolides may sensitize bacteria to stresses, as these antibiotics induced alterations in a major stress protein, Gro-EL, in constitutive and inducible states.

Anti-Bacterial Agents↗

PubMed2004

Bactericidal activity of moxifloxacin against multidrug-resistant Streptoccocus pneumoniae at clinically achievable serum and epithelial lining fluid concentrations compared with three other antimicrobials.

Time-kill studies compared the activities of moxifloxacin with those of levofloxacin, azithromycin and amoxicillin-clavulanate against 10 pneumococcal strains with various drug susceptibilities. Three Streptococcus pneumoniae strains were resistant to moxifloxacin: 6, 7 and 2 strains were resistant to levofloxacin, azithromycin and amoxicillin-clavulanate, respectively. Of these, 1 strain was resistant to all antimicrobial agents studied. Moxifloxacin and amoxicillin-clavulanate were bactericidal after 24h at serum Cmax levels against 9 and 8 strains, respectively, while levofloxacin and azithromycin were bactericidal against 3 and 2 strains, respectively. A higher activity was only observed for amoxicillin-clavulanate for logarithmic phase cultures at 1, 4 and 8h compared with stationary phase organisms. Amoxicillin-clavulanate and moxifloxacin were bactericidal at free serum levels (protein unbound) after 24h against 8 and 3 strains, respectively. Moxifloxacin was bactericidal at epithelial lining fluid levels against all strains at 24h, including one moxifloxacin, amoxicillin-clavulanate and azithromycin-resistant strain; lower levels of bactericidal activity was observed for levofloxacin, azithromycin and amoxicillin-clavulanate against 7, 2 and 4 strains, respectively. This demonstrated the importance of moxifloxacin tissue levels.

Anti-Bacterial Agents↗

PubMed2026

Microbiological analysis and whole-genome sequencing of Neisseria gonorrhoeae from the microbiological failures in the international, zoliflodacin, phase 3, clinical trial for treatment of uncomplicated urogenital gonorrhoea: a retrospective, genomic, observational study.

BACKGROUND: Zoliflodacin, a first-in-class oral bacterial, DNA gyrase (GyrB) inhibitor, showed non-inferiority to ceftriaxone combined with azithromycin in a recent large international, phase 3, randomised controlled trial for treatment of uncomplicated urogenital gonorrhoea. The aim of this study was to describe the microbiological and whole-genome sequencing (WGS) analyses of paired baseline (pre-treatment) and test-of-cure (TOC) gonococcal isolates from the zoliflodacin phase 3, randomised controlled trial to further characterise and evaluate the protocol-specified microbiological failures with zoliflodacin (n=22) or ceftriaxone and azithromycin (n=1). METHODS: In this retrospective, genomic, observational study, results from antimicrobial susceptibility testing (agar dilution method) of isolates (n=960; 936 baseline isolates from 763 participants and 24 TOC isolates [23 with a paired baseline isolate in the same anatomical site] from 20 participants) collected during the zoliflodacin phase 3, randomised controlled trial done in 16 outpatient clinics in Belgium, the Netherlands, South Africa, Thailand, and the USA (Nov 6, 2019-March 16, 2023) are described. WGS analysis was performed on paired baseline and TOC isolates from participants with microbiological failures (zoliflodacin 44 isolates [19 participants]; ceftriaxone and azithromycin two isolates [one participant]), and the three baseline isolates with highest zoliflodacin minimum inhibitory concentration (MIC 0·5 mg/L). FINDINGS: All isolates were inhibited by the same zoliflodacin concentrations (MICs ≤0·008 to 0·5 mg/L) as wild-type strains cultured internationally in 2013-23. In participants with a microbiological failure after zoliflodacin treatment (n=22, 19 participants), zoliflodacin MIC values for baseline and TOC isolates were similar, and resistance selection was lacking. WGS showed that five (23%) of 22 infections (95% CI 10-43 [in four participants]) of zoliflodacin microbiological failures had different strains at TOC versus baseline. In 17 zoliflodacin microbiological failures (15 participants), isolates at baseline and TOC were indistinguishable. 13 of these 17 microbiological failures, corresponding to 59% (95% CI 39-77; 13 of 22) of all zoliflodacin microbiological failures, were in urogenital or rectal sites in 11 participants and the isolates had zoliflodacin MICs less than or equal to 0·008 to 0·25 mg/L. The single microbiological failure after ceftriaxone and azithromycin treatment had different strains at TOC versus at baseline. No sequenced isolates had mutations associated with elevated zoliflodacin MICs. INTERPRETATION: In the zoliflodacin phase 3, randomised controlled trial, 23% of the zoliflodacin microbiological failures and the single ceftriaxone and azithromycin microbiological failure had different gonococcal strains at TOC versus baseline, which suggests reinfections and not treatment failures. In addition, 59% of the zoliflodacin microbiological failures, all in anogenital sites, had no obvious microbiological explanation based on the low zoliflodacin MICs, previous pharmacodynamic studies, and no evidence of resistance selection after zoliflodacin therapy. A reinfection as the cause for these microbiological failures could not be excluded. We recommend that WGS is implemented in future randomised controlled trials for gonorrhoea treatment to further evaluate possible microbiological failures, exclude reinfections (to avoid underestimating the cure rates), and characterise antimicrobial resistance determinants. FUNDING: GARDP through grants from Germany BMFTR (03KA1831), UK DHSC as part of GAMRIF, Japan MHLW, the Netherlands' Ministry of Health, Welfare and Sport and Directorate-General for International Cooperation, the Federal Office of Public Health of Switzerland, the Canton of Geneva, Switzerland, and Örebro University Hospital, Sweden.

Humans↗

PubMed1998

Inhibition of triazolam clearance by macrolide antimicrobial agents: in vitro correlates and dynamic consequences.

BACKGROUND: Macrolide antimicrobial agents may impair hepatic clearance of drugs metabolized by cytochrome P4503A isoforms. Potential interactions of triazolam, a substrate metabolized almost entirely by cytochrome P4503A in humans, with 3 commonly prescribed macrolides were identified using an in vitro metabolic model. The actual interactions, and their pharmacodynamic consequences, were verified in a controlled clinical study. METHODS: In an in vitro model using human liver microsomes, 250 mumol/L triazolam was incubated with ascending concentrations (0 to 250 mumol/L of troleandomycin, azithromycin, erythromycin, and clarithromycin. In a randomized, double-blind, 5-trial clinical pharmacokinetic-pharmacodynamic study, 12 volunteers received 0.125 mg triazolam orally, together with placebo, azithromycin, erythromycin, or clarithromycin. In a fifth trial they received placebo plus placebo. RESULTS: Mean 50% inhibitory concentrations versus 4-hydroxytriazolam formation in vitro were as follows: 3.3 mumol/L troleandomycin, 27.3 mumol/L erythromycin, 25.2 mumol/L clarithromycin, and greater than 250 mumol/L azithromycin. Apparent oral clearance of triazolam when given with placebo or azithromycin was nearly identical (413 and 416 mL/min), as were peak plasma concentrations (1.25 and 1.32 ng/mL) and elimination half-life (2.7 and 2.6 hours). Apparent oral clearance was significantly reduced (P < .05) during erythromycin and clarithromycin trials (146 and 95 mL/min). Peak plasma concentration was correspondingly increased, and elimination half-life was prolonged. The effects of triazolam on dynamic measures were nearly identical when triazolam was given with placebo or azithromycin, but benzodiazepine agonist effects were enhanced during erythromycin and clarithromycin trials. CONCLUSION: The in vitro model identifies macrolides that may impair triazolam clearance. Anticipated interactions, and their pharmacodynamic consequences in volunteer subjects, were verified in vivo.

Administration, Oral↗

PubMed1999

Susceptibility and resistance emergence studies with macrolides.

An extended elimination half-life and good tissue penetration enable oral azithromycin to attain high and prolonged concentrations in infected tissues, yielding high antibacterial activity in vivo. It has been suggested, however, that prolonged subinhibitory concentrations of azithromycin from 2 to 4 weeks after therapy may lead to the emergence of azithromycin resistance in vivo, compared with other macrolide antibiotics. Data from two types of in vitro susceptibility studies, an animal tissue infection model, and a clinical pediatric study demonstrate that prolonged tissue concentrations of azithromycin are unlikely to lead to the emergence of resistance in the clinical setting. Further, data from in vitro susceptibility studies indicate that resistance to macrolides, and azithromycin in particular, is significantly over-estimated for bacterial strains incubated in the presence of CO2.

Animals↗

PubMed2000

Discontinuation of prophylaxis against Mycobacterium avium complex disease in HIV-infected patients who have a response to antiretroviral therapy. Terry Beirn Community Programs for Clinical Research on AIDS.

BACKGROUND: Several agents are effective in preventing Mycobacterium avium complex disease in patients with advanced human immunodeficiency virus (HIV) infection. However, there is uncertainty about whether prophylaxis should be continued in patients whose CD4+ cell counts have increased substantially with antiviral therapy. METHODS: We conducted a multicenter, double-blind, randomized trial of treatment with azithromycin (1200 mg weekly) as compared with placebo in HIV-infected patients whose CD4+ cell counts had increased from less than 50 to more than 100 per cubic millimeter in response to antiretroviral therapy. The primary end point was M. avium complex disease or bacterial pneumonia. RESULTS: A total of 520 patients entered the study; the median CD4+ cell count at entry was 230 per cubic millimeter. In 48 percent of the patients, the HIV RNA value was below the level of quantification. The median prior nadir CD4+ cell count was 23 per cubic millimeter, and 65 percent of the patients had had an acquired immunodeficiency syndrome-defining illness. During follow-up over a median period of 12 months, there were no episodes of confirmed M. avium complex disease in either group (95 percent confidence interval for the rate of disease in each group, 0 to 1.5 episodes per 100 person-years). Three patients in the azithromycin group (1.2 percent) and five in the placebo group (1.9 percent) had bacterial pneumonia (relative risk in the azithromycin group, 0.60; 95 percent confidence interval, 0.14 to 2.50; P=0.48). Neither the rate of progression of HIV disease nor the mortality rate differed significantly between the two groups. Adverse effects led to discontinuation of the study drug in 19 patients assigned to receive azithromycin (7.4 percent) and in 3 assigned to receive placebo (1.1 percent; relative risk, 6.6; P=0.002). CONCLUSIONS: Azithromycin prophylaxis can safely be withheld in HIV-infected patients whose CD4+ cell counts have increased to more than 100 cells per cubic millimeter in response to antiretroviral therapy.

AIDS-Related Opportunistic Infections↗

PubMed1997

Microbiologic activity of the newer macrolide antibiotics.

In vitro susceptibility testing has demonstrated good activity of the azalide azithromycin and the macrolide clarithromycin against Gram-positive and -negative pathogens as well as atypical organisms involved in the etiology of upper and lower respiratory tract infections. One difference between these drugs in terms of their antimicrobial spectrum is the activity of azithromycin against Haemophilus influenzae. This organism is 2 to 8 times more susceptible in vitro to azithromycin than to clarithromycin or to erythromycin, the prototypical macrolide antibiotic. A principal concern in the management of respiratory tract infections today is the emergence of penicillin-resistant strains of Streptococcus pneumoniae. Both azithromycin and clarithromycin are active against penicillin-susceptible S. pneumoniae, although the activity of azithromycin is somewhat less than that of erythromycin and clarithromycin. Results of susceptibility testing of resistant organisms have varied among centers; in some areas all of the intermediately and some of the highly penicillin-resistant S. pneumoniae isolates are susceptible to the newer macrolides, whereas in other areas they are not. High tissue antibiotic concentrations achieved with these drugs may contribute to their effectiveness against some of the resistant S. pneumoniae isolates.

Adolescent↗

PubMed2005

The risk of overanticoagulation with antibiotic use in outpatients on stable warfarin regimens.

BACKGROUND: Medication interactions account for a significant proportion of overanticoagulation in warfarin users. However, little is known about the incidence or degree of interaction with commonly used oral antibiotics. OBJECTIVE: To investigate the incidence and degree of overanticoagulation associated with commonly used oral antibiotics. DESIGN: Retrospective cohort study of patients using warfarin who initiated an antibiotic (azithromycin, levofloxacin, or trimethoprim/sulfamethoxazole (TMP/SMX)) or terazosin for clinical indications between January 1998 and December 2002. The incidence of international normalized ratio (INR) elevation and the degree of change and bleeding events after institution of either medication type was recorded. SUBJECTS: Patients at a university-affiliated Veteran's Affairs Medical Center. RESULTS: The mean change in INR was -0.15 for terazosin, 0.51 for azithromycin, 0.85 for levofloxacin, and 1.76 for TMP/SMX. These mean INR changes in the antibiotic groups were all statistically different from the terazosin group. The incidence of supratherapeutic INR was 5% for terazosin, 31% for azithromycin, 33% for levofloxacin, and 69% for TMP/SMX. The incidence of absolute INR >4.0 was 0% for terazosin, 16% for azithromycin, 19% for levofloxacin, and 44% for TMP/SMX. CONCLUSIONS: Among acutely ill outpatients, oral antibiotics (azithromycin, levofloxacin, and TMP/SMX) increase the incidence and degree of overanticoagulation.

Administration, Oral↗

PubMedDate not supplied

Efficacy of novel antimicrobials against clinical isolates of opportunistic amebas.

We examined the effects of the macrolide antimicrobial agent azithromycin and phenothiazine compounds against clinical isolates of Acanthamoeba spp. and Balamuthia mandrillaris, opportunistic pathogens of human beings and other animals. Acanthamoeba growth was inhibited in vitro at 1, 5, and 10 micrograms/ml of azithromycin, but not the macrolides, erythromycin, and clarithromycin. In experiments attempting to simulate in vivo conditions, azithromycin protected monolayers of rat glioma cells from destruction by Acanthamoeba at a concentration of 0.1 microgram/ml, and delayed destruction at concentrations of 0.001 and 0.01 microgram/ml. We concluded that the minimal inhibitory concentration of azithromycin was 0.1 microgram/ml. Our results, however, suggested that the drug was amebastatic but not amebicidal, since ameba growth eventually resumed after drug removal. The phenothiazines (chlorpromazine, chlorprothixene, and triflupromazine) inhibited Acanthamoeba growth by 70-90% at 5 and 10 micrograms/ml, but some of these compounds were toxic for rat glioma cells at 10 micrograms/ml. Azithromycin was not very effective against B. mandrillaris in an in vitro setting, but was amebastatic in tissue culture monolayers at concentrations of 0.1 microgram/ml and higher. Balamuthia amebas showed in vitro sensitivity to phenothiazines. Ameba growth was inhibited 30-45% at 5 micrograms/ml in vitro, but completely at 5 micrograms/ml in the rat glioma model. In spite of their potential as antiamebic drugs in Balamuthia infections, toxicity of phenothiazines limits their use in clinical settings.

Acanthamoeba↗

PubMed1999

Pharmacokinetics of azithromycinin rabbit lacrimal glands and conjunctiv a.

PURPOSE AND BACKGROUND: To measure azithromycin levels in rabbit lacrimal and Harder glands, conjunctiva and plasma after a single oral dose of 20 mg/kg. Drug levels in lacrimal gland tissue are significant in trachoma because the gland may be involved in the disease process and it is the source of tears by which the drug is carried to the external eye. METHODS: Lacrimal and Harder glands, conjunctiva and plasma were collected from New Zealand white female rabbits at 24, 48, 72, 96 and 144 h following a single oral dose of azithromycin (20 mg/kg). Azithromycin levels in tissue and plasma were measured using high-performance liquid chromatography (HPLC) electrochemical detection. RESULTS: Azithromycin levels peaked within the first 24 h in all tissues and plasma assayed. The highest concentration was in the lacrimal gland (6.2 microg/g, SD +/- 0.8), followed by Harder gland (4.4 microg/g, SD +/- 0.8), conjunctiva (0. 9 microg/g, SD +/- 0.5) and plasma (0.06 microg/g, SD +/- 0.03). These concentrations reached their lowest measured levels at 120 and 144 h. CONCLUSION: Azithromycin levels measured throughout the 144 h after dosing were consistently above the minimum inhibitory range (MIC) for Chlamydia trachomatis (0.03-0.25 microg/ml) in the lacrimal glands, while the conjunctiva maintained a concentration above the MIC for 96 h and stayed within MIC levels for 144 h.

Administration, Oral↗

PubMed2000

Discontinuation of Mycobacterium avium complex prophylaxis in patients with antiretroviral therapy-induced increases in CD4+ cell count. A randomized, double-blind, placebo-controlled trial. AIDS Clinical Trials Group 362 Study Team.

BACKGROUND: Patients infected with HIV who experience increases in CD4(+) cell counts are at reduced risk for opportunistic infections. However, the safety of discontinuing prophylaxis against Mycobacterium avium complex has been uncertain. OBJECTIVE: To compare the rate of M. avium complex infection in patients with increased CD4(+) cell counts who receive azithromycin and those receiving placebo. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: 29 university-based clinical centers in the United States. PARTICIPANTS: 643 HIV-1-infected patients with a previous CD4(+) cell count less than 0.05 x 10(9) cells/L and a sustained increase to greater than 0.10 x 10(9) cells/L during antiretroviral therapy. INTERVENTION: Azithromycin, 1200 mg once weekly (n = 321), or matching placebo (n = 322). MEASUREMENTS: Mycobacterium avium complex cultures, CD4(+) cell counts, and clinical evaluations for AIDS-defining illnesses and bacterial infections were done every 8 weeks. Plasma HIV-1 RNA levels were measured at 16-week intervals. RESULTS: During follow-up (median, 16 months), 2 cases of M. avium complex infection were reported among the 321 patients assigned to placebo (incidence rate, 0.5 event per 100 person-years [95% CI, 0.06 to 1.83 events per 100 person-years]) compared with no cases among the 322 patients assigned to azithromycin (CI, 0 to 0.92 events per 100 person-years), resulting in a treatment difference of 0.5 event per 100 person-years (CI, -0.20 to 1.21 events per 100 person-years) for placebo versus azithromycin. Both cases were atypical in that M. avium complex was localized to the vertebral spine. Patients receiving azithromycin were more likely than those receiving placebo to discontinue treatment with the study drug permanently because of adverse events (8% vs. 2%; hazard ratio, 0.24 [CI, 0.10 to 0.57]). CONCLUSIONS: Prophylaxis against Mycobacterium avium complex can safely be withdrawn or withheld in adults with HIV infection who experience increases in CD4(+) cell count while receiving antiretroviral therapy.

AIDS-Related Opportunistic Infections↗

PubMed2004

Macrolide antibiotics for cystic fibrosis.

BACKGROUND: Chronic severe infection with Pseudomonas aeruginosa, affects many people with cystic fibrosis (CF). There is evidence from the laboratory and from other disease processes that macrolide antibiotics, whilst not directly active against Pseudomonas aeruginosa, may have indirect actions against this organism. OBJECTIVES: We aimed to test the hypotheses that, in people with CF, macrolide antibiotics:(1) improve clinical status compared to placebo or another antibiotic;(2) do not have unacceptable adverse effects. If benefit was demonstrated, we aimed to assess the optimal type, dose and duration of macrolide therapy. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group trials register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings. We contacted principal investigators known to work in the field, previous authors and pharmaceutical companies who manufacture macrolide antibiotics for unpublished or follow-up data (December 2003). Most recent search of the Group's register: January 2004 SELECTION CRITERIA: Published or unpublished randomised controlled trials of macrolide antibiotics compared to placebo, another class of antibiotic or another macrolide antibiotic. Studies comparing regimens of the same macrolide antibiotic at different doses will also be included. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed study quality. Three groups were contacted for missing data and we hope to include these in future reviews. MAIN RESULTS: Searches identified 14 studies, four were included in this review (296 participants). Two studies enrolled adults, one children (a significant number of whom were not colonised with Pseudomonas aeruginosa) and one both adults and children. All the clinical studies reported small but significant improvements in respiratory function with azithromycin versus placebo. Meta-analysis at the one-month and six-month time points demonstrates a significant benefit with respect to relative change in FEV1 (at six months, for n = 104, azithromycin and n = 114, placebo; WMD 5.82% (95% CI 2.45 to 9.20)). The largest study reported a significant increase in mild adverse events (nausea, diarrhoea and wheezing). REVIEWERS' CONCLUSIONS: There is clear evidence from these studies of a small but significant improvement in respiratory function following treatment with azithromycin. The largest study employed a three times a week dose and, in this study, treatment with azithromycin was associated with a significant increase in mild adverse events. Further studies are needed to clarify the precise role of azithromycin in the treatment of CF lung disease.

Anti-Bacterial Agents↗

PubMed1993

Correlation between macrolide lung pharmacokinetics and therapeutic efficacy in a mouse model of pneumococcal pneumonia.

The correlation between the pharmacokinetics of erythromycin, roxithromycin, clarithromycin, spiramycin and azithromycin and their efficacy was investigated in two pneumococcal pneumonia models. Female Swiss and C57B1/6 mice were infected with Streptococcus pneumoniae strain P4241 by the intratracheal per oral route. This virulent strain produces acute pneumonia with death within 3-4 days (Swiss mice), or subacute pneumonia with death within 10 days (C57B1/6 mice) in untreated mice and the outcome of the disease is closely related to progressive weight loss. Swiss mice received three doses of each macrolide 50 mg/kg bd beginning 18 h post-infection. C57B1/6 mice received three doses of each macrolide 25 mg/kg, bd (except azithromycin was 12.5 mg/kg bd) beginning 48 h post-infection. Cure rates were evaluated on the basis of body weight variations recorded daily after the end of treatment. Pharmacokinetic parameters were determined in infected and non-infected mice after a single dose of each macrolide 50 mg/kg sc. The pharmacokinetics of azithromycin was also determined in leucopenic Swiss mice. We observed a hierarchy of in-vivo efficacy as follows: azithromycin > spiramycin = clarithromycin > roxithromycin = erythromycin which did not correlate with in-vitro MIC or MBC. The same hierarchy was found in terms of the lung T1/2. Lung T1/2s of macrolides could thus be predictive of their efficacy in respiratory tract infections. A reduced tissue AUC of azithromycin was seen in leucopenic mice suggesting leucocytes may help transport macrolides to sites of infection.

Animals↗