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PubMed1997

A prospective study of the impact of community-based azithromycin treatment of trachoma on carriage and resistance of Streptococcus pneumoniae.

In February 1995, single-dose azithromycin was given to children with trachoma and their household contacts who were children. For children with trachoma, rates of carriage of pneumococci immediately before treatment with azithromycin and 2-3 weeks, 2 months, and 6 months after treatment were 68% (54 of 79), 29% (11 of 38), 78% (29 of 37), and 87% (34 of 39), respectively. The proportion of carriage-positive children with azithromycin-resistant Streptococcus pneumoniae strains was 1 of 54 (1.9%) before treatment and then 6 of 11 (54.5%), 10 of 29 (34.5%), and 2 of 34 (5.9%) at follow-up visits. The profile of pneumococcal serotypes changed after azithromycin treatment. Azithromycin-resistant strains (serotypes 10F, 23A, and 45) were isolated from 1 (1.3%) of 79 pretreatment swab specimens, from 16 (21.3%) of 75 swab specimens collected up to 2 months after treatment, and from 2 (6%) of 32 obtained 6 months after treatment. Mathematical modeling showed a more rapid appearance of azithromycin-resistant pneumococcal strains in previously colonized children than in previously noncolonized children. Thus, it appears that the selective effect of azithromycin allowed the growth and transmission of preexisting azithromycin-resistant strains. More research is needed to clarify the clinical relevance and implications of azithromycin use.

Adolescent↗
PubMed1990

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

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.

Animals↗
PubMed1993

Comparison of azithromycin versus clarithromycin in the treatment of patients with upper respiratory tract infections.

The efficacy and safety of azithromycin and clarithromycin were compared in an open multicentre study involving 380 adult patients with acute otitis media, acute sinusitis, or acute streptococcal pharyngitis or tonsillitis. Patients were assigned randomly to receive azithromycin as a single dose of 500 mg daily for three days, or clarithromycin 250 mg bid for ten days. Overall clinical efficacy was found to be similar in each treatment group at day 10-14, with a satisfactory outcome (cured or improved) in 95% of azithromycin and 96% of clarithromycin patients. Bacteriological efficacy was also similar, with eradication of the pathogen in 94% and 95% of isolates, respectively, in the azithromycin and clarithromycin groups. In otitis media, a satisfactory clinical response was seen in 97% of patients in each treatment group. Azithromycin therapy resulted in a clinical response rate of 93% in sinusitis patients, with bacteriological eradication in 93% of patients. Two patients (who were cured clinically) had persistent pathogens. Similarly, clarithromycin achieved clinical response and bacteriological eradication in 95% and 92% of sinusitis patients, respectively. Pathogens persisted in two patients with clinical cure, and in one case of clinical failure. In pharyngitis or tonsillitis, Streptococcus pyogenes was eradicated successfully in 95% of patients in both groups, and the clinical success rates were 96% and 97% for azithromycin and clarithromycin, respectively. No case of clinical failure was associated with persistence of S. pyogenes infection. At the follow-up assessment of this diagnosis group, reinfection had occurred in three (8%) azithromycin patients and one (3%) clarithromycin patient, and all but one patient remained asymptomatic. Both drugs were well-tolerated, with 8.4% of patients on azithromycin and 7.4% on clarithromycin reporting adverse events, mainly gastrointestinal. It was concluded that a three-day course of azithromycin was as effective and well-tolerated as a ten-day course of clarithromycin in adults with acute upper respiratory tract infections.

Acute Disease↗
PubMed1993

Multicentre evaluation of azithromycin in comparison with co-amoxiclav for the treatment of acute otitis media in children.

A total of 389 children (age 0.6-10.2 years) with typical signs and symptoms of acute otitis media were randomized (1:1) to treatment with either azithromycin or co-amoxiclav. The dosage schedule for azithromycin was 10 mg/kg/day, in a single daily dose, administered for three days. Co-amoxiclav was given at a dose of 13.3 mg/kg (amoxycillin equivalent) tid for ten days. Patients were evaluated 4-6 days and 12-16 days after the start of therapy. A satisfactory clinical response was reported for 93.2% of the 192 evaluable azithromycin-treated patients (144 cured, 35 improved), and for 97.3% of the 189 evaluable co-amoxiclav-treated patients (148 cured, 36 improved). Six (3.0%) relapses occurred in the azithromycin group, and four (2.1%) in the co-amoxiclav treatment group, respectively. Side-effects were recorded in a significantly fewer number of the azithromycin patients (23 of 197; 11.7%) compared with the co-amoxiclav patients (43 of 192; 22.4%, P < 0.02). Adverse events were mainly gastrointestinal in nature, with diarrhoea the most frequent complaint (32 cases with co-amoxiclav; five with azithromycin; P < 0.001). One patient from each group discontinued therapy because of treatment-related adverse events. Laboratory analyses (mainly haematological in nature) showed abnormalities in six of 100 azithromycin patients and ten of 101 co-amoxiclav patients. It was concluded that three-day, single-dose azithromycin and ten-day tid co-amoxiclav therapy have comparable clinical efficacy in paediatric patients with acute otitis media; however, there was a lower incidence of side effects in the azithromycin group.

Acute Disease↗
PubMed1996

An open comparative study of azithromycin and roxithromycin in the treatment of acute upper respiratory tract infections.

An open, multicentre study was undertaken in order to evaluate the efficacies and safety profiles of azithromycin and roxithromycin in 440 adults with acute otitis media, sinusitis or acute beta-haemiolytic streptococcal pharyngitis/tonsillitis. Treatment with 500 mg azithromycin, administered orally once daily for 3 days, produced a satisfactory clinical outcome (cure or improvement) in 51/52 (98%) patients with otitis media, 91/91 (100%) patients with pharyngitis/tonsillitis and 64/68 (94%) patients with sinusitis. Treatment with 150 mg roxithromycin, given orally twice daily for 10 days, produced satisfactory clinical responses in 54/55 (98%), 91/92 (99%) and 69/73 (94%) patients with otitis media, pharyngitis/tonsillitis and sinusitis respectively. Of the 17 azithromycin-treated patients with sinusitis who were clinically and bacteriologically evaluable, Staphylococcus aureus persisted in two and Streptococcus pneumoniae in one. S. aureus also persisted in 1/12 clinically and bacteriologically-evaluable patient treated with roxithromycin. Of the 58 and 64 patients with pharyngitis/tonsillitis treated with azithromycin and roxithromycin, respectively, who were clinically and bacteriologically evaluable, Streptococcus pyogenes persisted at the end of treatment in 7/58 (12%) in the azithromycin group and in 13/64 (20%) in the roxithromycin group. At follow-up, there was no evidence of S. pyogenes reinfection in patients treated with azithromycin. Three episodes of reinfection occurred in the roxithromycin treatment group. Also, three patients showed evidence of clinical relapse at follow-up, although no pathogens were isolated. Azithromycin was associated with a lower incidence of adverse events. No azithromycin-treated patient was withdrawn prematurely because of a treatment-related event. Three roxithromycin-treated patients were withdrawn from treatment because of severe headache, thyroiditis or fatigue. In conclusion, for adults with acute upper respiratory tract infections, a 3-day course of once-daily azithromycin was found to be as effective and as well tolerated as a 10-day course of twice-daily roxithromycin.

Acute Disease↗
PubMed1996

Correlation of increased azithromycin concentrations with phagocyte infiltration into sites of localized infection.

Azithromycin reaches high concentrations in phagocytic and other host cells, suggesting that they may transport this agent to specific sites of infection. Models of localized infection (Haemophilus influenzae middle ear infection in gerbils, Streptococcus pyogenes implanted contaminated paper disc and Streptococcus pneumoniae pneumonia in mice) that induced severe inflammatory response after challenge were used to explore this hypothesis. Animals were given a single 100 or 50 mg/kg po dose of azithromycin at various times from 2 to 120 h following introduction of a pathogen or sterile medium. When azithromycin was given during a period of little or no inflammation, there was marginal difference between concentrations found in infected or non-infected sites (bulla, disc, lung). However, when the compound was given during a period of inflammation, considerably higher drug concentrations were found in infected sites than in non-infected sites at 5-24 h after dosing (0.38-0.44 mg/c compared with 0.07-0.14 mg/L of bulla wash; 1.01-1.75 micrograms compared with < or = 0.01-0.03 microgram at the disc site; 1.72-5.28 mg/kg compared with 0.7-1.53 mg/kg of lung). When the observation periods were extended to include 48, 56 or 96 h after dosing, the ratio of azithromycin infection site concentration: serum concentration steadily increased with time in all model systems (middle ear, implanted disc and pneumonia), reflecting the maintenance of concentrations at the sites of infection, while serum concentrations declined. Bioassay of cell pellets and supernatants, obtained from pooled bulla washes of gerbils treated with azithromycin during a period of inflammation, revealed that cellular components accounted for about 75% of the azithromycin detected. These data show that increased azithromycin concentrations occur at sites of localized infection. This correlates with the presence of inflammation and is associated with the cellular components of the inflammatory response. Therefore, phagocytes may be important vehicles for delivering azithromycin to and sustaining azithromycin concentrations at sites of infection.

Animals↗
PubMed2002

Azithromycin versus penicillin V for treatment of acute group A streptococcal pharyngitis.

OBJECTIVE: To compare a 3-day azithromycin vs. a 10-day penicillin V regimen for treatment of acute group A streptococcal (GAS) pharyngitis in children and to determine whether viral infection and/or pharyngeal GAS carriage in patients and adult contacts affect clinical and bacteriologic efficacy. METHODS: This multicenter, randomized, comparative, open label study compared 3-day, once daily 10 mg/kg azithromycin oral suspension with a 10-day regimen of 100,000 IU/kg/day penicillin V oral suspension in three divided doses in children with acute GAS pharyngitis. Clinical and bacteriologic efficacy and tolerability of the antibiotics were evaluated. Recurrence of symptoms and infection was monitored for 6 months. RESULTS: In total, 292 children (age range, 2 to 12 years) received at least one dose of study medication. Clinical success (cure/improvement) with either antibiotic was similar at the end of therapy (Day 14; azithromycin, 95%; penicillin V, 97%) and at Day 28 (azithromycin, 94%; penicillin V, 95%). Bacteriologic eradication was significantly less with azithromycin than with penicillin V at Day 14 (azithromycin, 38%; penicillin V, 81%; P < 0.001) and at Day 28 (azithromycin, 31%; penicillin V, 68%; P < 0.001). There was no associated increase in GAS-related sequelae. The lower incidence of bacteriologic eradication with azithromycin was not the result of possible concomitant viral infections in the patients, GAS carriage in one parent/guardian or any reduced susceptibility in pretreatment GAS isolates. Both antibiotics were equally well-tolerated. CONCLUSIONS: Treatment with 3-day, once daily 10 mg/kg azithromycin for GAS pharyngitis is associated with similar high levels of clinical efficacy, but lower levels of bacteriologic eradication, than with 10-day 100,000 IU/kg/day penicillin V.

Administration, Oral↗
PubMedDate not supplied

Single dose azithromycin treatment of gonorrhea and infections caused by C. trachomatis and U. urealyticum in men.

BACKGROUND AND OBJECTIVES: Single dose regimens have advantages in the treatment of STD. Azithromycin has unique pharmacokinetics that may make single dose regimens feasible. Treatment with a single 1 g dose of azithromycin was compared to 100 mg doxycycline twice daily for seven days. STUDY DESIGN: This was a randomized third-party blinded study on 183 male patients, 176 of whom could be evaluated for efficacy. RESULTS: Chlamydia trachomatis was cultured from 148 patients, 79 receiving azithromycin and 69 receiving doxycycline. Six patients receiving azithromycin had positive cultures on follow-up, four were known to have had sexual intercourse with infected partners. Fifty-one patients had gonorrhea; 28 were treated with azithromycin and 23 with doxycycline. Neisseria gonorrhoeae was eradicated from all patients except one receiving azithromycin. He denied sexual exposure during follow-up. Sixty patients were infected with Ureaplasma urealyticum, 35 were treated with azithromycin and 25 with doxycycline. Five patients in each group had positive cultures on follow up. Three patients receiving azithromycin and two receiving doxycycline were known to have had sexual exposure during follow-up. CONCLUSION: A single dose of azithromycin showed similar effectiveness as a 7-day regimen of doxycycline.

Adolescent↗
PubMed1997

Comparison of E-test with agar dilution methods in testing susceptibility of N. gonorrhoeae to azithromycin.

BACKGROUND AND OBJECTIVES: The antimicrobial susceptibility pattern of Neisseria gonorrhoeae varies from one country to another and may also change with time. To monitor these variations and changes, it is desirable to have a method that is simple and reproducible. This study was undertaken to determine the in vitro susceptibility of N. gonorrhoeae to azithromycin and to assess the reliability of results obtained using E-test methodology for determination of the minimum inhibitory concentration (MIC) of azithromycin. STUDY DESIGN: The MICs for 135 clinical isolates of N. gonorrhoeae were determined by a modified Kirby-Bauer method recommended by the National Committee for Clinical Laboratory Standards against penicillin, cefuroxime, ceftriaxone, norfloxacin, tetracycline, kanamycin, spectinomycin, and azithromycin. The MIC of azithromycin was determined by both the E-test and agar dilution method. All tests were done simultaneously. RESULTS: The MIC of azithromycin to all 135 isolates ranged from 0.078 to 0.25 microgram/ml with the agar dilution method and from 0.016 to 0.50 microgram/ml with the E-test. The MIC50 and MIC90 of azithromycin were 0.064 microgram/ml and 0.125 microgram/ml, respectively, by the agar dilution method, whereas they are slightly higher by the E-test method. Seventy-six of the isolates were beta-lactamase producers and 69 were high-level tetracycline-resistant N. gonorrhoeae. There was no difference in the MIC50 and MIC90 of azithromycin in these groups of isolates. The percentage agreement within the acceptable +/-1 log2 dilution difference between MICs obtained by E-test and those obtained by the agar dilution method was 97.8%. CONCLUSIONS: Azithromycin has a very good in vitro antigonococcal activity, and the E-test is a reliable method to determine the MIC of azithromycin against N. gonorrhoeae.

Anti-Bacterial Agents↗
PubMed1998

Failure of azithromycin therapy in gonorrhea and discorrelation with laboratory test parameters.

BACKGROUND: Azithromycin is efficacious in the treatment of chlamydial genital tract infection but less so in gonorrhea. However, MICs of azithromycin for gonococci from previously reported azithromycin treatment failures were consistently below the 'susceptible' MIC level of 2 mg/L. GOAL OF THIS STUDY: To examine gonococci not eliminated with 1 g azithromycin therapy to establish treatment outcome/MIC correlates in gonorrhea. STUDY DESIGN: The MICs and phenotypes of gonococci isolated from five cases of treatment failure after 1 g azithromycin therapy were determined and compared with the MICs of a systematic sample of routine isolates. RESULTS: Azithromycin MICs of gonococci from five cases of failed 1 g azithromycin treatment were 0.125 or 0.25 mg/L, well within the current 'susceptible' MIC range. None of the isolates were of the mtr phenotype. The MIC90 of a systematic sample of 219 gonococcal isolates was 0.25 mg/L. CONCLUSION: The antibiotic MIC/treatment outcome correlates that are usually found in gonorrhea do not apply for azithromycin. Current MIC criteria do not accurately define susceptibility or resistance of gonococci to azithromycin and by themselves do not predict the likely outcome of therapy. Pharmacokinetic factors may decrease the predictive value of MIC data.

Adult↗
PubMed2001

Insights into the mechanism of azithromycin interaction with an Escherichia coli functional ribosomal complex.

Azithromycin, a derivative of erythromycin with improved activity against Gram-negative bacteria, exhibits a marginal inhibition effect in a model system derived from Escherichia coli, in which a peptide bond is formed between puromycin and AcPhe-tRNA bound at the P-site of poly(U)-programmed ribosomes. This renders the study of azithromycin interaction with Ac[(3)H]Phe-tRNA. poly(U). 70S ribosome complex (complex C) impossible, if we analyze its effect on peptide bond formation. To overcome this problem, we have used an alternative approach to investigate kinetically the azithromycin interaction with complex C and to compare the azithromycin binding properties with those of erythromycin. This approach was based on the ability of azithromycin to compete with tylosin, a macrolide antibiotic strongly inhibiting the puromycin reaction. Detailed kinetic analysis revealed that the encounter complex CA between complex C and azithromycin (A) undergoes a slow isomerization to a tighter complex C*A, which remains active toward puromycin. The determination of inhibition and isomerization rate constants enabled us to classify azithromycin as a slow-binding ligand of ribosomes. Compared with erythromycin, azithromycin is a better inducer and stabilizer of the C*A complex. This finding may explain the superiority of azithromycin as inhibitor of translation in E. coli cells and many other Gram-negative bacteria.

Anti-Bacterial Agents↗
PubMed1990

Intracellular accumulation of azithromycin by cultured human fibroblasts.

Azithromycin was shown to achieve high concentrations in human skin fibroblasts. Intracellular penetration occurred rapidly (10 micrograms/mg of cellular protein after 3 h) and then increased progressively over a 3-day period; azithromycin accumulated up to 21 times more than erythromycin (61.1 versus 2.9 micrograms/mg of protein). Uptake was dependent on the extracellular concentration, was inhibited at 4 degrees C, did not occur in nonviable cells, and was reduced by a low pH. Intracellular accumulation was not affected by the metabolic inhibitor 2,4-dinitrophenol or sodium fluoride or by the nucleoside transport inhibitor 2-chloradenosine. Once concentrated in cells, azithromycin remained intracellular and was released slowly in the absence of extracellular drug, compared with erythromycin (17 versus 78% released after 1 h). After 48 h of incubation in drug-free medium, 27% of the initial amount of azithromycin remained cell associated. The release of azithromycin was not affected by various monokines reported to stimulate fibroblasts (interleukin-1 or tumor necrosis factor) or by exposure to bacteria. Incubation of azithromycin-loaded fibroblasts with human polymorphonuclear leukocytes resulted in a higher intracellular accumulation of azithromycin in polymorphonuclear leukocytes than in cells incubated with free nonintracellular azithromycin for the same time (8.3 versus 2.2 micrograms/ml after 2 h), suggesting a more efficient or rapid uptake through cell-to-cell interaction. The widespread distribution of fibroblasts in tissues suggests a potential for these cells, and possibly other lysosome-containing tissue cells, to serve as a reservoir for azithromycin, slowly releasing it for activity against extracellular organisms at sites of infection and passing it to phagocytes for activity against intracellular pathogens and potential transport to sites of infection.

2,4-Dinitrophenol↗
PubMed1992

Activity of azithromycin against Mycobacterium avium infection in beige mice.

The comparative activities of azithromycin and clarithromycin and the activities of azithromycin alone and in combination with other antimycobacterial agents were evaluated in the beige mouse model of disseminated Mycobacterium avium complex infection. Azithromycin was similar in activity to clarithromycin. Azithromycin plus clofazimine plus ethambutol reduced the number of splenic organisms more than azithromycin alone, while the combination was less active than azithromycin alone for bacteria in lungs. Rifabutin had activity similar to that of azithromycin for organisms in spleens and lungs. Rifabutin plus azithromycin was more active than either agent alone for organisms in spleens, but the combination's activity was not significantly different from that of rifabutin for organisms in lungs. The activity of azithromycin against several M. avium complex isolates was evaluated. The reduction of viable cell counts in spleens ranged from 1.7 to 0.8 log units. For the three isolates studied, there was little correlation between the in vitro MIC and the in vivo activity.

Animals↗
PubMed1994

Azithromycin pharmacokinetics and intracellular concentrations in Legionella pneumophila-infected and uninfected guinea pigs and their alveolar macrophages.

Azithromycin pharmacokinetics in Legionella pneumophila-infected and uninfected guinea pigs were assessed by measuring the drug concentration in whole lungs or the drug content in bronchoalveolar lavage (BAL) fluid in separate experiments. Azithromycin concentrations were measured by using a bioassay. The mean azithromycin content in the BAL fluid of infected guinea pigs was higher than that in controls at 10 h (0.87 versus 0.39 microgram; P = 0.05), 24 h (1.10 versus 0.37 microgram; P = 0.003), and 48 h (1.21 versus 0.28 microgram; P = 0.05) after a single intraperitoneal injection of drug (15 mg/kg). The mean peak lung azithromycin concentration was higher in control animals than in infected animals (15.8 versus 13.4 micrograms/ml). The mean lung azithromycin concentration in infected animals was significantly higher than that in controls 48 h after dosing (12.7 versus 10.4 micrograms/g; P = 0.04). There were no significant differences between infected and uninfected animals in serum azithromycin levels. Complementary experiments assessed intracellular/extracellular concentration ratios of azithromycin and erythromycin in L. pneumophila-infected and control guinea pig alveolar macrophages. Azithromycin was highly concentrated in alveolar macrophages, and the intracellular/extracellular concentration ratios for infected cells were significantly higher (P < 0.0001) than those observed in controls after 4 h (127 versus 119), 24 h (481 versus 361), and 48 h (582 versus 520) of incubation. Erythromycin was also preferentially concentrated in infected cells (P < 0.0001). AZ intracellular concentrations were at least fivefold higher than those measured for erythromycin, and this differential increased with incubation time. Thus, azithromycin recovery from BAL fluid, and from guinea pig lungs at the 48-h time point, was higher in the presence of experimental Legionnaires' disease. This likely results from recruitment of phagocytes, including macrophages, that have an enhanced capacity to highly concentrate the drug.

Animals↗
PubMed1994

Localization of azithromycin in Toxoplasma gondii-infected cells.

Agents effective against intracellular pathogens must enter infected cells, crossing vacuolar membranes surrounding the organisms and then penetrating into the microbe and localizing to the microbial target site. We have characterized these parameters for azithromycin entry into Toxoplasma gondii-infected Chinese hamster ovary cells and murine macrophage-like J774 cells. Azithromycin uptake into infected host cells was concentrative and was dependent upon proton gradients. Subcellular fractionation of azithromycin-loaded infected CHO cells demonstrated > 95% intracellular drug in host cell lysosomes and cytosol, with < 5% associated with the parasite. Uptake of azithromycin into the T. gondii vacuole increased if parasites were coated with antibody prior to internalization by murine J774 cells, conditions which result in the formation of acidified phagolysosomes. No redistribution or retention of azithromycin in the parasite was observed when drug efflux from antibiotic-loaded infected CHO cells was monitored. Azithromycin entry into extracellular T. gondii was concentrative, was temperature and pH dependent, and was not different when azithromycin-sensitive and -resistant parasites were compared. These results demonstrate that azithromycin concentrates primarily in acidified compartments in parasites and host cells. The high concentration of azithromycin within these compartments may not be biologically relevant to inhibition of intracellular parasite growth by this agent.

Animals↗
PubMed1998

In vitro selection of resistance to four beta-lactams and azithromycin in Streptococcus pneumoniae.

Selection of resistance to amoxicillin (with or without clavulanate), cefaclor, cefuroxime, and azithromycin among six penicillin G- and azithromycin-susceptible pneumococcal strains and among four strains with intermediate penicillin sensitivities (azithromycin MICs, 0.125 to 4 microg/ml) was studied by performing 50 sequential subcultures in medium with sub-MICs of these antimicrobial agents. For only one of the six penicillin-susceptible strains did subculturing in medium with amoxicillin (with or without clavulanate) lead to an increased MIC, with the MIC rising from 0.008 to 0.125 microg/ml. Five of the six penicillin-susceptible strains showed increased azithromycin MICs (0.5 to >256.0 microg/ml) after 17 to 45 subcultures. Subculturing in medium with cefaclor did not affect the cefaclor MICs of three strains but and led to increased cefaclor MICs (from 0.5 to 2.0 to 4.0 microg/ml) for three of the six strains, with MICs of other beta-lactams rising 1 to 3 twofold dilutions. Subculturing in cefuroxime led to increased cefuroxime MICs (from 0.03 to 0.06 microg/ml to 0.125 to 0.5 microg/ml) for all six strains without significantly altering the MICs of other beta-lactams, except for one strain, which developed an increased cefaclor MIC. Subculturing in azithromycin did not affect beta-lactam MICs. Subculturing of the four strains with decreased penicillin susceptibility in amoxicillin (with or without clavulanate) or cefuroxime did not select for beta-lactam resistance. Subculturing of one strain in cefaclor led to an increase in MIC from 0.5 to 2.0 microg/ml after 19 passages. In contrast to strains that were initially azithromycin susceptible, which required >10 subcultures for resistance selection, three of four strains with azithromycin MICs of 0.125 to 4.0 microg/ml showed increased MICs after 7 to 13 passages, with the MICs increasing to 16 to 32 microg/ml. All azithromycin-resistant strains were clarithromycin resistant. With the exception of strains that contained mefE at the onset, no strains that developed resistance to azithromycin contained ermB or mefE, genes that have been found in macrolide-resistant pneumococci obtained from clinic patients.

Anti-Bacterial Agents↗
PubMed1999

Decreased azithromycin susceptibility of Neisseria gonorrhoeae due to mtrR mutations.

Single-dose azithromycin therapy has recently been used in Uruguay for the treatment of uncomplicated gonococcal infections. As part of an active surveillance study to monitor the emergence of antibiotic resistance in gonococcal isolates, we examined the levels of azithromycin susceptibility in 51 consecutive isolates obtained from males with uncomplicated gonococcal urethritis. Isolates with decreased susceptibility to azithromycin (MICs, 0.25 to 0.5 microg/ml) were common, and these isolates often displayed cross-resistance to hydrophobic antimicrobial agents (erythromycin and Triton X-100). Resistance to erythromycin and Triton X-100 is frequently due to overexpression of the mtrCDE-encoded efflux pump mediated by mutations in the mtrR gene, which encodes a transcriptional repressor that modulates expression of the mtrCDE operon. Accordingly, we questioned whether clinical isolates that express decreased azithromycin susceptibility harbor mtrR mutations. Promoter mutations that would decrease the level of expression of mtrR as well as a missense mutation at codon 45 in the mtrR-coding region that would result in a radical amino acid replacement within the DNA-binding motif of MtrR were found in these strains. When these mutations were transferred into azithromycin-susceptible strain FA19 by transformation, the susceptibility of gonococci to azithromycin was decreased by nearly 10-fold. The mtrCDE-encoded efflux pump system was responsible for this property since insertional inactivation of the mtrC gene resulted in enhanced susceptibility of gonococci to azithromycin. We conclude that the mtrCDE-encoded efflux pump can recognize azithromycin and that the emergence of gonococcal strains with decreased susceptibility to azithromycin can, in part, be explained by mtrR mutations.

Anti-Bacterial Agents↗
PubMed2001

Effects of azithromycin and rifampin on Chlamydia trachomatis infection in vitro.

An in vitro cell culture model was used to investigate the long-term effects of azithromycin, rifampin, and the combination of azithromycin and rifampin on Chlamydia trachomatis infection. Although standard in vitro susceptibility testing indicated efficient inhibition by azithromycin, prolonged treatment did not reveal a clear elimination of chlamydia from host cells. Chlamydia were temporarily arrested in a persistent state, characterized by culture-negative, but viable, metabolically active chlamydia, as demonstrated by the presence of short-lived rRNA transcripts. Additionally, azithromycin induced generation of aberrant inclusions and an altered steady-state level of chlamydial antigens, with the predominance of Hsp60 protein compared to the level of the major outer membrane protein. Treatment with azithromycin finally resulted in suppression of rRNA synthesis. Chlamydial lipopolysaccharide and processed, functional rRNA were detectable throughout the entire incubation period. These in vitro data show a good correlation to those from some recent clinical investigations that have reported on the persistence of chlamydia, despite appropriate antibiotic treatment with azithromycin. Rifampin was highly active by in vitro susceptibility testing, but prolonged exposure to rifampin alone for up to 20 days resulted in the emergence of resistance. No development of resistance to rifampin was observed when chlamydia-infected cells were incubated with a combination of azithromycin and rifampin. This combination was shown to be more efficient than azithromycin alone, in that suppression of rRNA synthesis occurred earlier. Thus, such a combination may prove more useful than azithromycin alone.

Anti-Bacterial Agents↗