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Sub-lethal concentrations of clarithromycin interfere with the expression of Staphylococcus aureus adhesiveness to human cells.

It has been known for some time that some antibiotics, generally at sub-lethal concentrations, are able to alter the morphology and the shape of bacteria. However, more subtle molecular alterations can also be present, such as disorganization of bacterial surface architecture, which leads to changes in the surface electrical charge that can influence the forces of attraction or repulsion responsible for interaction of bacterial surfaces with environmental surfaces. Bacterial adhesion to epithelial cells is a phenomenon regulated by these mechanisms. Clarithromycin, a new macrolide, at sub-inhibitory concentrations from 1/2 to 1/16 of the MIC, that is to say, from 0.12 to 0.015 microgram/ml, significantly reduces adhesion of Staphylococcus aureus to human buccal epithelial cells. Clarithromycin, as other antibiotics that interfere with the bacterial protein synthesis, should also be able to disturb the synthesis of adhesins. These are ligand molecules located on the surface of bacteria, and thus reduce the ability of bacteria to bind specifically to complementary molecules on the surfaces of epithelial cells which is necessary for host colonization.

Bacterial Adhesion↗

Effects of erythromycin, clarithromycin, roxithromycin and azithromycin on murine gut colonization by Candida albicans.

Male Crl:CD1(ICR) BR mice were fed either chow containing Candida albicans or regular chow. The gastrointestinal tract of the C. albicans-fed mice was permanently colonized by the yeast. Groups of C. albicans-colonized mice were subsequently treated either with a macrolide (erythromycin, clarithromycin, roxithromycin or azithromycin) for 10 days or a normal saline solution (controls). Other controls included non-colonized mice receiving the same antibiotics or a saline solution. Our data are as follows: (i) C. albicans-colonized mice treated with each macrolide had highly significant increase in colony counts of C. albicans in their stools compared to C. albicans-colonized mice treated with saline only; (ii) discontinuation of macrolide treatment showed a trend towards lower colony counts, which was not statistically significant (colony counts were sustained even after discontinuation of antibiotic treatment); (iii) dissemination of C. albicans did not occur; (iv) mice fed regular chow treated with the study drugs or saline did not have any yeasts in their stools. In conclusion, oral erythromycin, clarithromycin, roxithromycin and azithromycin cause a modest increase of the C. albicans concentration of the gastrointestinal tract. This increase is not associated with a higher risk of disseminated candidiasis.

Animals↗

Average bioequivalence of clarithromycin immediate released tablet formulations in healthy male volunteers.

The objective of this study was to assess average bioequivalence of two immediate released tablet formulations of 500-mg clarithromycin tablets in 24 healthy Thai male volunteers. In a randomized, single dose, fasting state, two-period, crossover study design with a 1-week washout period, each subject received a 500-mg clarithromycin tablet. Plasma samples were collected over a 24-hour period after oral administration and were analyzed by using a validated method using high performance liquid chromatography with electrochemical detection. Pharmacokinetic parameters were determined by using noncompartmental analysis. The time to reach the maximal concentration (tmax, h), the peak concentration (Cmax, ng/mL), and the area under the curve (AUC0-infinity, ng x h/mL) of the Reference and Test formulations were 2.0 +/- 0.8 vs. 2.2 +/- 0.9, 2793 +/- 1338 vs. 2642 +/- 1344, and 17912 +/- 7360 vs. 17660 +/- 7992, respectively. Relative bioavailability was 0.99. The 90% confidence interval of Cmax and AUC0-infinity were 82.6-112.1% and 84.7-112.0%. Bioequivalence between the Test and Reference formulation can be concluded.

Adult↗

A prospective, randomized trial examining the efficacy and safety of clarithromycin in combination with ethambutol, rifabutin, or both for the treatment of disseminated Mycobacterium avium complex disease in persons with acquired immunodeficiency syndrome.

This multicenter, randomized, open-label phase 3 clinical trial compared the safety and efficacy of 3 clarithromycin-containing combination regimens for the treatment of disseminated Mycobacterium avium complex (MAC) disease in persons with acquired immunodeficiency syndrome. A total of 160 eligible patients with bacteremic MAC disease were randomized to receive clarithromycin with either ethambutol (C+E), rifabutin (C+R), or both (C+E+R) for 48 weeks. After 12 weeks of treatment, the proportion of subjects with a complete microbiologic response was not statistically significantly different among treatment arms: the proportion was 40% in the C+E group, 42% in the C+R group, and 51% in the C+E+R group (P=.454). The proportion of patients with complete or partial responses who experienced a relapse while receiving C+R (24%) was significantly higher than that of patients receiving C+E+R (6%; P=.027) and marginally higher than that of patients receiving C+E (7%; P=.057). Subjects in the C+E+R group had improved survival, compared with the C+E group (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.23-0.83) and the C+R group (HR, 0.49; 95% CI, 0.26-0.92).

AIDS-Related Opportunistic Infections↗

Report on an outbreak of postinjection abscesses due to Mycobacterium abscessus, including management with surgery and clarithromycin therapy and comparison of strains by random amplified polymorphic DNA polymerase chain reaction.

An outbreak of postinjection abscesses occurred in Barranquilla, Colombia, and was associated with local injections of lidocaine given in a single physician's office. Over a 5-month period, 350 (18%) of approximately 2,000 injected patients developed localized cutaneous abscesses or cellulitis; of 210 abscess specimens that were cultured, 205 were positive for rapidly growing mycobacteria, subsequently identified as Mycobacterium abscessus. The source of the outbreak was not identified. M. abscessus could not be characterized by pulsed-field gel electrophoresis, but all isolates were identical in terms of drug and heavy metal resistance patterns and random amplified polymorphic DNA PCR profiles. We believe this is the first report of the use of this latter technique for investigation of an outbreak due to M. abscessus. Therapy with a combination of surgical excision and 3-6 months' administration of clarithromycin was successful for 95% of 148 patients treated in this manner; in contrast, therapy was successful for less than one-third of patients treated with surgery alone or clarithromycin alone. This is the largest of the nine known outbreaks of postinjection abscesses that have occurred due to rapidly growing mycobacteria and is the first in which an effective method of therapy was demonstrated.

Abscess↗

Determinants of rifabutin-associated uveitis in patients treated with rifabutin, clarithromycin, and ethambutol for Mycobacterium avium complex bacteremia: a multivariate analysis. Canadian HIV Trials Network Protocol 010 Study Group.

Uveitis occurred in a substantial proportion of AIDS patients receiving rifabutin, 600 mg daily, together with clarithromycin and ethambutol for treatment of Mycobacterium avium complex bacteremia. A case-control study was undertaken to examine potential risk factors for developing uveitis. Of eight parameters examined, only baseline body weight predicted the development of uveitis by both univariate and multivariate analyses (P = .001). The incidence of uveitis was 14% in patients weighing >65 kg, 45% in patients between 55 and 65 kg, and 64% in patients <55 kg. Concomitant therapy with fluconazole, a drug known to raise serum rifabutin concentrations, was not associated with an increased incidence of uveitis. The risk of uveitis was markedly reduced when rifabutin was given at 300 mg daily in combination with clarithromycin and ethambutol.

AIDS-Related Opportunistic Infections↗

Successful treatment of pulmonary Mycobacterium xenopi infection in a natural killer cell-deficient patient with clarithromycin, rifabutin, and sparfloxacin.

Isolation of Mycobacterium xenopi from the respiratory tract may indicate pneumonia, often clinically indistinguishable from tuberculosis. Resistance to the classic antituberculous drugs renders the treatment of these infections problematic. We report on a case of cavernous pneumonia caused by M. xenopi in a 36-year-old male with natural killer cell deficiency but without severe immunodeficiency. He was successfully treated with a novel triple-drug combination comprising clarithromycin, sparfloxacin, and rifabutin. An impressive subsequent regression of pathological pulmonary changes was observed, and mycobacteria could no longer be detected. The therapeutic potential of clarithromycin and sparfloxacin in the treatment of M. xenopi infections is discussed.

Adult↗

Rapid development of resistance to clarithromycin following monotherapy for disseminated Mycobacterium chelonae infection in a heart transplant patient.

Mycobacterium chelonae (formerly known as M. chelonae subspecies chelonae) is a rapidly growing mycobacterium that can cause disseminated infections, especially in immunocompromised hosts. The bacterium is typically resistant to antimicrobial agents; less than 20% of M. chelonae isolates are susceptible to trimethoprim-sulfamethoxazole, doxycycline, erythromycin, or ciprofloxacin. Findings in a recent study suggested that clarithromycin may be the drug of choice for the treatment of cutaneous (disseminated) disease due to M. chelonae. We describe a 60-year-old heart transplant patient with disseminated M. chelonae infection for whom monotherapy with clarithromycin failed because of the rapid development of resistance to the drug.

Anti-Bacterial Agents↗

Activity of ampicillin/sulbactam, ticarcillin/clavulanate, clarithromycin, and eleven other antimicrobial agents against anaerobic bacteria isolated from infections in children.

The activity of 14 antimicrobial agents against 253 clinical isolates of anaerobic bacteria from pediatric infections was assessed by the agar dilution method. Fifty-eight percent of the isolates were from intraabdominal sites. The drugs tested were ampicillin/sulbactam, ticarcillin/clavulanate, ampicillin, sulbactam, piperacillin, cefoxitin, cefotaxime, cefoperazone/sulbactam, clarithromycin, azithromycin, erythromycin, clindamycin, metronidazole, and chloramphenicol. Ticarcillin/clavulanate was active against all isolates. Clarithromycin was the most active macrolide; combination of this agent with its 14-hydroxy metabolite did not result in synergy. Sixty-two percent of Bacteroides fragilis group isolates, 13% of B. fragilis isolates, and 22% of peptostreptococcal isolates were resistant to clindamycin at a concentration of 4 micrograms/mL. The distribution of these strains in clinical specimens and the patterns of antimicrobial susceptibility documented were different from the findings for isolates from adults in the Los Angeles area.

Ampicillin↗

Skin, soft tissue, and bone infections due to Mycobacterium chelonae chelonae: importance of prior corticosteroid therapy, frequency of disseminated infections, and resistance to oral antimicrobials other than clarithromycin.

Little is known of clinical disease due to Mycobacterium chelonae chelonae. One hundred skin, soft tissue, or bone isolates of this rapidly growing mycobacterium were identified over 10 years. Clinical disease included disseminated cutaneous infection (53%); localized cellulitis, abscess, or osteomyelitis (35%); and catheter infections (12%). Underlying conditions with disseminated infection included organ transplantation, rheumatoid arthritis, and autoimmune disorders; 92% involved corticosteroid use. Trauma and medical procedures were risk factors for localized infections. Corticosteroids and chronic renal failure were risk factors for catheter infections. Overall, 62% of patients were receiving corticosteroids and 72% were immunosuppressed. MICs of six oral antimicrobials were obtained for 180 isolates by broth microdilution. Up to 20% of isolates were susceptible to doxycycline, ciprofloxacin, ofloxacin, and sulfamethoxazole. In contrast, 100% were susceptible to clarithromycin (MICs less than or equal to 1 microgram/mL). Disease due to M. chelonae chelonae usually occurs in the setting of corticosteroid therapy and is often disseminated; the organisms require high MICs of oral antimicrobials other than clarithromycin.

Abscess↗

Molecular mechanisms of clarithromycin resistance in Mycobacterium avium: observation of multiple 23S rDNA mutations in a clonal population.

The peptidyltransferase region of the 23S rRNA gene (the probable target site for the macrolides) was investigated in blood isolates of Mycobacterium avium recovered from 38 patients before and after the development of clarithromycin resistance. Point mutations were identified in 100% of the 74 resistant relapse blood isolates but in none of 69 susceptible pretreatment isolates. Multiple mutations were identified in isolates from 23 (61%) of 38 patients. Of the 63 identified mutations, 95% involved adenine at bp 2058. Single-colony clones from cultures that were mixtures of more than one mutation revealed a single mutation within each clone. Pulsed field gel electrophoresis of genomic DNA restriction fragments revealed that 13 (81%) of 16 multiple mutations identified in the same patient were derived from a single infecting strain. In vitro investigation revealed the same point mutations observed in vivo. This study defines the probable mechanism of clarithromycin resistance in M. avium and provides in vivo evidence that mutational resistance is random and selection-directed.

Base Sequence↗

The development of macrolides: clarithromycin in perspective.

Macrolide antibiotics have been available and used clinically since 1952. The class of drugs originated from a soil sample obtained from the City of Ilo-Ilo on the Island of Paray in the Philippines. Erythromycin has been the most widely used agent of this class called 'macrolides' because they possess the macrocyclic lactone nucleus. Many esters of erythromycin are well established as agents to treat a variety of respiratory and cutaneous infections, particularly in children. There has been a resurgence of interest in macrolides as a result of the recognition of pathogens such as Legionella, Chlamydia and Campylobacter spp. A number of new 14-membered macrolides have been synthesised in recent years with the goal of overcoming some of the problems of the older erythromycin agents. There has been variable activity of erythromycin against Haemophilus influenzae; there has been gastrointestinal irritation, particularly in adults; and the older agents are administered four times a day. Clarithromycin has increased activity against Legionella, and Branhamella spp., and Pasteurella multocida, and, with its 14-OH metabolite, inhibits Haemophilus spp. It is also more active against chlamydia and against anaerobic species while retaining excellent activity against streptococci including Streptococcus pneumoniae. It has increased plasma peak levels and a sufficiently long half-life for twice daily administration. Furthermore, it is well tolerated. Thus clarithromycin offers potential for use in those areas in which a safe, well tolerated macrolide will be used, namely respiratory, skin structure and selected diarrhoeal and genital infections.

Anti-Bacterial Agents↗

The in-vitro activity of clarithromycin and other macrolides against the type strain of Chlamydia pneumoniae (TWAR).

The activity of oxytetracycline and seven macrolide antibiotics was investigated against a prototype strain of Chlamydia pneumoniae in cell culture. Following incubation, inoculated cell monolayers were fixed in methanol and stained with a genus specific immunofluorescent monoclonal antibody before examination for inhibition of inclusion formation. The most active agent was clarithromycin (MIC 0.007 mg/l), followed by erythromycin (0.06 mg/l). Other macrolides were less active; josamycin and roxithromycin (0.25 mg/l), midecamycin acetate and azithromycin (0.5 mg/l) and spiramycin (4.0 mg/l). The MIC of oxytetracycline was 0.25 mg/l. Clinical evaluation of clarithromycin for C. pneumoniae lower respiratory infection is indicated.

Anti-Bacterial Agents↗

Activity of clarithromycin against murine listeriosis.

In-vitro clarithromycin was more active than erythromycin against Listeria monocytogenes. The antibacterial action was bacteristatic. In normal adult mice infected with a virulent strain of L. monocytogenes clarithromycin was also more active than erythromycin. A rapid decrease in viable count was obtained, which was not achieved with erythromycin. Early treatment resulted in a complete abrogation of an immune response to L. monocytogenes. In immunocompromised, congenitally athymic (nude) mice, only a moderate effect on the bacterial numbers was observed, indicating that even in vivo the activity of the macrolides is bacteristatic.

Animals↗

Evaluation of the Etest for rapid susceptibility testing of Mycobacterium avium to clarithromycin.

MICs of clarithromycin were determined by the Etest method for thirty clinical strains of Mycobacterium avium complex (MAC) and compared with MICs results as determined by the reference agar dilution method. Agreement (within +/- 1 log2 dilution) between the Etest and the reference method was 70% for susceptible strains and 100% for resistant strains. No major errors resulting in misclassification in susceptibility or resistance categories were detected for the Etest MIC method. It is suggested that the Etest is easy to perform and is an accurate method for determining susceptibility of MAC strains to clarithromycin.

Anti-Bacterial Agents↗

Activity of azithromycin, clarithromycin, roxithromycin, dirithromycin, quinupristin/dalfopristin and erythromycin against Legionella species by intracellular susceptibility testing in HL-60 cells.

We evaluated a human monocyte cell line (HL-60) as a model for testing the intracellular activity of anti-Legionella antibiotics; 1.5 x 10(6) HL-60 cells/well were differentiated into adherent cells and infected with 1.5 x 10(7) cfu of Legionella pneumophila. The most active agents against L. pneumophila as judged by broth dilution MICs were (in order of activity) azithromycin, clarithromycin, roxithromycin, quinupristin/dalfopristin, erythromycin and dirithromycin. The most active inhibitors of L. pneumophila intracellular multiplication were (in order of activity) azithromycin, erythromycin, quinupristin/dalfopristin, roxithromycin, dirithromycin and clarithromycin. All the agents were highly active against Legionella micdadei and Legionella bozemanii when compared with L. pneumophila.

Anti-Bacterial Agents↗

Anti-anaerobic activity of erythromycin, azithromycin and clarithromycin: effect of pH adjustment of media to compensate for pH shift caused by incubation in CO2.

The activity of erythromycin, azithromycin and clarithromycin against 112 anaerobes was tested by the Oxyrase agar dilution MIC method at pH 7.2 without supplemental CO2 and by an agar dilution MIC method in CO2 with media adjusted to pH 8.0. MICs (mg/L) of erythromycin, azithromycin and clarithomycin against Bacteroides fragilis ATCC 25285 and Bacteroides thetaiotaomicron ATCC 29741 were similar by the two methods. MICs for 94 clinical isolates tested by the two methods were within two dilutions of each other. Eighteen additional isolates required CO2, and did not grow in Oxyrase. With the exception of fusobacteria, with which azithromycin yielded the lowest MICs, clarithromycin had the lowest MICs with both methods. These results show that the pH effect of incubation in CO2 can be avoided by using the Oxyrase method, or by incubating in CO2 with pH adjusted to 8.0. The latter method has the advantage of allowing testing of strains requiring CO2.

Anti-Bacterial Agents↗

Bactericidal activity and postantibiotic effect of clarithromycin and 14-hydroxyclarithromycin, alone and in combination, against Legionella pneumophila.

Time-kill curves using simulated peak and trough serum concentrations, and postantibiotic effect (PAE) were determined for clarithromycin and 14-hydroxyclarithromycin alone and in combination against four strains of Legionella pneumophila. Both compounds were bactericidal at both peak and trough concentrations. The combination at trough concentrations demonstrated lower killing activity than the parent drug in three of the four strains. PAE ranges were 7.28-17.3 h for clarithromycin, 6.78-14.77 h for the metabolite, and 5.15-13.23 h for the combination.

Anti-Bacterial Agents↗