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PubMed1995

Postantibiotic effects and postantibiotic sub-MIC effects of roxithromycin, clarithromycin, and azithromycin on respiratory tract pathogens.

Pharmacodynamic parameters have become increasingly important for the determination of the optimal dosing schedules of antibiotics. In this study, the postantibiotic effects (PAEs), the postantibiotic sub-MIC effects (PA SMEs), and the sub-MIC effects (SMEs) of roxithromycin, clarithromycin, and azithromycin on reference strains of Streptococcus pyogenes group A, Streptococcus pneumoniae, and Haemophilus influenzae were investigated. The PAE was induced by 2x MICs (S. pneumoniae) or 10x MICs of the different drugs for 2 h, and the antibiotics were eliminated by washing and dilution. The PA SMEs were studied by addition of 0.1, 0.2, and 0.3x MICs during the postantibiotic phase of the bacteria, and the SMEs were studied by exposition of the bacteria to the drugs at the sub-MICs only. Growth curves were followed by viable counts for 24 h. The SMEs were generally very short. A PAE of 2.9 to 8 h was noted for all antibiotics against all strains. Clarithromycin induced a statistically significantly shorter PAE on S. pneumoniae than did roxithromycin and azithromycin and did so also against H. influenzae in comparison with azithromycin. The PA SMEs were long and varied at 0.3x MIC between 6.4 19.6 h. This pronounced suppression of regrowth of bacteria which are first treated with a suprainhibitory concentration of antibiotics and then reexposed to sub-MIC levels indicates that long dosing intervals for macrolides and azalides can be allowed.

Azithromycin↗
PubMed1995

Synergistic activities of clarithromycin and antituberculous drugs against multidrug-resistant Mycobacterium tuberculosis.

The rise of multidrug-resistant Mycobacterium tuberculosis has complicated therapy for tuberculosis and led us to search for a potentially active combination of drugs against these strains. The susceptibilities of 12 strains of multidrug-resistant M. tuberculosis to standard antituberculous drugs (isoniazid, rifampin, ethambutol, and pyrazinamide), clarithromycin, and its metabolite, 14-hydroxyclarithromycin, were determined by use of the BACTEC radiometric method. All strains were resistant to at least two of the antituberculous drugs. Clarithromycin and 14-hydroxyclarithromycin MICs were in the range indicating resistance at > or = 8.0 micrograms/ml for all strains. Combination testing by the BACTEC method was performed with various concentrations of isoniazid, rifampin, and ethambutol, and with clarithromycin/14-hydroxyclarithromycin at fixed concentrations of 2.0/0.5 micrograms/ml, respectively. Addition of clarithromycin/14-hydroxyclarithromycin to these antituberculous drug mixtures resulted in a 4- to 32-fold reduction in MICs of isoniazid, rifampin, and ethambutol and made resistant strains susceptible. Fractional inhibitory concentrations ranged from 0.23 to 0.50 for all strains, suggesting a synergistic interaction between standard antituberculous drugs and clarithromycin/14-hydroxyclarithromycin. The ability of clarithromycin/14-hydroxyclarithromycin to enhance the activities of isoniazid, ethambutol, and rifampin in vitro suggests that this combination may be efficacious in the treatment of multidrug-resistant M. tuberculosis infections.

Antitubercular Agents↗
PubMed1996

Activity of KRM-1648 alone or in combination with both ethambutol and kanamycin or clarithromycin against Mycobacterium intracellulare infections in beige mice.

The in vivo activities of KRM-1648 alone or in combination with both ethambutol (EB) and kanamycin (KM) or clarithromycin (CAM) were tested against Mycobacterium intracellulare infections in beige mice. KRM-1648 was more active than rifampin (RFP) when each drug was used alone, and the efficacy of KRM-1648 was similar to those of both kanamycin and clarithromycin. The combination KRM-1648-KM-EB was strongly active and rapidly reduced the numbers of bacilli both in lungs and in spleens compared with RFP-KM-EB. The combination KRM-1648-CAM had greater therapeutic effects than RFP-CAM; this difference in efficacy was more pronounced for lungs than for spleens. These findings suggest that KRM-1648 is a promising candidate for combination therapy with other potent antimycobacterial drugs.

Animals↗
PubMed1996

Clarithromycin in treatment of early Lyme disease: a pilot study.

Forty-one patients with erythema migrans were enrolled in an open-labelled pilot study of oral clarithromycin, 500 mg twice daily for 21 days, for the treatment of early Lyme disease. Immediately posttherapy, pretreatment signs and symptoms resolved among 91% of the 33 evaluable patients. At 6 months, all 28 of the evaluable patients were well. Clarithromycin shows promise as an effective agent for the treatment of early Lyme disease and warrants further study.

Adolescent↗
PubMed1996

Mutations in 23S rRNA are associated with clarithromycin resistance in Helicobacter pylori.

Twelve clarithromycin-resistant Helicobacter pylori isolates (100% of resistant isolates examined) from seven different patients each contained an A-->G transition mutation within a conserved loop of 23S rRNA. A-->G transition mutations at positions cognate with Escherichia coli 23S rRNA positions 2058 and 2059 were identified. Clarithromycin-susceptible H. pylori isolates from 14 different patients displayed no polymorphisms in a conserved loop within domain V of 23S rRNA. The study is the first to report mutations in H. pylori associated with resistance to an antimicrobial agent used in established peptic ulcer treatment regimens.

Anti-Bacterial Agents↗
PubMed1997

Macrolide resistance in Helicobacter pylori: mechanism and stability in strains from clarithromycin-treated patients.

Helicobacter pylori strains from seven patients treated with clarithromycin were investigated for development, mechanism, and stability of resistance. Genetic relatedness between pre- and posttreatment isolates was shown by arbitrary primed PCR. Clarithromycin resistance was associated with A-to-G transitions at either position 2143 or 2144 or at both positions 2116 and 2142. In four cases, the mutations were homozygous. The Cla(r) phenotype was stable after 50 subcultivations in vitro. No erythromycin-modifying enzymes or rRNA methylases were found by biological assays, PCR and sequencing, or cloning methods.

Anti-Bacterial Agents↗
PubMed1998

Bacteriostatic and bactericidal in vitro activities of clarithromycin and erythromycin against periodontopathic Actinobacillus actinomycetemcomitans.

The susceptibilities of 87 periodontitis-associated strains of Actinobacillus actinomycetemcomitans to clarithromycin and erythromycin were determined by standard methodology recommended for Haemophilus influenzae. For clarithromycin the MIC at which 90% of the isolates were inhibited was </=2.0 microg/ml and the minimal bactericidal concentration at which 90% of the strains were killed was </=4.0 microg/ml, suggesting that it would be a candidate for therapeutic trials in patients with periodontitis.

Aggregatibacter actinomycetemcomitans↗
PubMed1998

Activities of HMR 3004 (RU 64004) and HMR 3647 (RU 66647) compared to those of erythromycin, azithromycin, clarithromycin, roxithromycin, and eight other antimicrobial agents against unusual aerobic and anaerobic human and animal bite pathogens isolated from skin and soft tissue infections in humans.

The activities of HMR 3004 and HMR 3647 and comparator agents, especially macrolides, were determined by the agar dilution method against 262 aerobic and 120 anaerobic strains isolated from skin and soft tissue infections associated with human and animal bite wounds. HMR 3004 and HMR 3647 were active against almost all aerobic and fastidious facultative isolates (MIC at which 90% of the isolates are inhibited [MIC90], < or = 0.5 and 1 microg/ml, respectively) and against all anaerobes [Bacteroides tectum, Porphyromonas macacae (salivosa), Prevotella heparinolytica, Porphyromonas sp., Prevotella sp., and peptostreptococci] at < or = 0.25 and < or = 0.5 microg/ml, respectively, except Fusobacterium nucleatum (HMR 3004, MIC90 = 16 microg/ml; HMR 3647, MIC90 = 8 microg/ml) and other Fusobacterium species (MIC90, 1 and 2 microg/ml, respectively). In general, HMR 3004 and HMR 3647 were more active than any of the macrolides tested. Azithromycin was more active than clarithromycin against all Pasteurella species, including Pasteurella multocida subsp. multocida, Eikenella corrodens, and Fusobacterium species, while clarithromycin was more active than azithromycin against Corynebacterium species, Weeksella zoohelcum, B. tectum, and P. heparinolytica.

Animals↗
PubMed1999

Multiplex sequence analysis demonstrates the competitive growth advantage of the A-to-G mutants of clarithromycin-resistant Helicobacter pylori.

Clarithromycin resistance in Helicobacter pylori is due to point mutation within the 23S rRNA. We examined the growth rates of different types of site-directed mutants and demonstrated quantitatively the competitive growth advantage of A-to-G mutants over other types of mutants by a multiplex sequencing assay. The results provide a rational explanation of why A-to-G mutants are predominantly observed among clarithromycin-resistant clinical isolates.

Alanine↗
PubMed1999

Mononuclear and polymorphonuclear leukocyte dispositions of clarithromycin and azithromycin in AIDS patients requiring Mycobacterium avium complex prophylaxis.

The intracellular dispositions of clarithromycin and azithromycin in AIDS patients requiring Mycobacterium avium complex (MAC) prophylaxis were studied. The dispositions of both drugs in mononuclear and polymorphonuclear leukocytes were markedly different. Our data support the proven efficacy of these agents for MAC prophylaxis since clarithromycin and azithromycin displayed sustained intracellular concentrations which exceeded their MICs for MAC throughout the dosing periods.

Acquired Immunodeficiency Syndrome↗
PubMed2001

In vitro susceptibility of Coxiella burnetii to linezolid in comparison with its susceptibilities to quinolones, doxycycline, and clarithromycin.

The in vitro susceptibility to linezolid shown by nine Greek isolates of Coxiella burnetii derived from patients with acute Q fever was investigated. MICs of linezolid were compared with those of pefloxacin, ciprofloxacin, ofloxacin, trovafloxacin, doxycycline, and clarithromycin using the shell vial assay. MICs of linezolid and clarithromycin ranged from 2 to 4 microg/ml; those of doxycycline, trovafloxacin, and ofloxacin ranged from 1 to 2 microg/ml; those of pefloxacin ranged from 1 to 4 microg/ml; and those of ciprofloxacin ranged from 4 to 8 microg/ml. Linezolid was effective in controlling intracellular parasites in cultures of Vero cells infected by C. burnetii. No bactericidal activity by linezolid was obtained against C. burnetii at 8 microg/ml.

Acetamides↗
PubMed2001

In vitro activity of clarithromycin against intracellular Helicobacter pylori.

The in vitro intracellular effect of clarithromycin, amoxicillin, metronidazole, lansoprazole, and rifabutin, tested at concentrations corresponding to one times the MIC, two times the MIC, and four times the MIC, was evaluated against an invasive Helicobacter pylori strain. At four times the MIC, clarithromycin showed an early bactericidal effect within 4 h of incubation and, in determining the complete killing within a 16 h-incubation period, lansoprazole and rifabutin showed comparable activity, yielding bactericidal activities within 4 and 8 h of incubation, respectively. Amoxicillin and metronidazole showed bacteriostatic activity only.

Amoxicillin↗
PubMed2002

Randomized controlled trial of sequential intravenous (i.v.) and oral moxifloxacin compared with sequential i.v. and oral co-amoxiclav with or without clarithromycin in patients with community-acquired pneumonia requiring initial parenteral treatment.

The objective of the present trial was to compare the efficacy, safety, and tolerability of moxifloxacin (400 mg) given intravenously (i.v.) once daily followed by oral moxifloxacin (400 mg) for 7 to 14 days with the efficacy, safety, and tolerability of co-amoxiclav (1.2 g) administered by i.v. infusion three times a day followed by oral co-amoxiclav (625 mg) three times a day, with or without clarithromycin (500 mg) twice daily (i.v. or orally), for 7 to 14 days in adult patients with community-acquired pneumonia requiring initial parenteral therapy. A total of 628 patients were enrolled and assessed by evaluation of their clinical and bacteriological responses 5 to 7 days and 21 to 28 days after administration of the last dose of study medication. Although the trial was designed, on the basis of predefined outcomes, to demonstrate the equivalence of the two regimens, the results showed statistically significant higher clinical success rates (for moxifloxacin, 93.4%, and for comparator regimen, 85.4%; difference [Delta], 8.05%; 95% confidence interval [CI], 2.91 to 13.19%; P = 0.004) and bacteriological success rates (for moxifloxacin, 93.7%, and for comparator regimen, 81.7%; Delta, 12.06%; 95% CI, 1.21 to 22.91%) for patients treated with moxifloxacin. This superiority was seen irrespective of the severity of the pneumonia and whether or not the combination therapy included a macrolide. The time to resolution of fever was also statistically significantly faster for patients who received moxifloxacin (median time, 2 versus 3 days), and the duration of hospital admission was approximately 1 day less for patients who received moxifloxacin. The treatment was converted to oral therapy immediately after the initial mandatory 3-day period of i.v. administration for a larger proportion of patients in the moxifloxacin group than patients in the comparator group (151 [50.2%] versus 57 [17.8%] patients). There were fewer deaths (9 [3.0%] versus 17 [5.3%]) and fewer serious adverse events (38 [12.6%] versus 53 [16.5%]) in the moxifloxacin group than in the comparator group. The rates of drug-related adverse events were comparable in both groups (38.9% in each treatment group). The overall incidence of laboratory abnormalities was similar in both groups. Thus, it is concluded that monotherapy with moxifloxacin is superior to that with a standard combination regimen of a beta-lactam and a beta-lactamase inhibitor, co-amoxiclav, with or without a macrolide, clarithromycin, in the treatment of patients with community-acquired pneumonia admitted to a hospital.

Administration, Oral↗
PubMed2004

T2182C mutation in 23S rRNA is associated with clarithromycin resistance in Helicobacter pylori isolates obtained in Bangladesh.

Twelve clarithromycin-resistant (MIC, > or = 1 microg/ml) Helicobacter pylori isolates were analyzed for point mutations in the 23S rRNA gene. Sequence analysis of all of the resistant isolates revealed a T-to-C transition mutation at position 2182. Transformation experiments confirmed that a single T-to-C transition mutation at position 2182 is associated with clarithromycin resistance.

Anti-Bacterial Agents↗
PubMed2005

Mitochondrial ribosome as the target for the macrolide antibiotic clarithromycin in the helminth Echinococcus multilocularis.

The mitochondrial rRNA of the tapeworm species Echinococcus multilocularis carries an adenine at sequence position 2058 (numbering according to that for Escherichia coli) of the large-subunit rRNA (lsrRNA), while the nucleus-encoded rRNA, as determined in this study, is characterized by 2058G. This indicates a dichotomy in the drug susceptibilities of ribosomes: cytoplasmic ribosomes are predicted to be resistant to macrolide antibiotics, while mitochondrial ribosomes lack the most common chromosomal resistance determinant, lsrRNA 2058G. Upon incubation with the macrolide clarithromycin, the formation of vesicles from metacestode tissue was reduced in a dose-dependent manner. Electron microscopy revealed distinct morphological alterations both of the mitochondria and of the vesicle wall (e.g., loss of microtriches) in drug-treated vesicles. Adult worms lost their motility and displayed morphological changes (shortening and constriction of proglottids and the presence of vacuoles) upon incubation with clarithromycin. Our findings demonstrate that macrolides have distinct in vitro effects on E. multilocularis, endorsing the use of sequence-based in silico approaches for exploitation of available ribosomal drugs as anthelmintic agents.

Animals↗
PubMed2006

Pulsatile delivery of clarithromycin alone or in combination with amoxicillin against Streptococcus pneumoniae.

We evaluated pulsatile dosing of clarithromycin and amoxicillin alone or combined against Streptococcus pneumoniae with various susceptibilities. When combined, pulsatile amoxicillin with clarithromycin was superior to either 8- or 12-h dosing against the intermediate strain and was identical for the susceptible strain. Pulse dosing of antimicrobials warrants further investigation.

Amoxicillin↗
PubMed1992

MIC quality control guidelines for Haemophilus susceptibility tests using cefdinir (FK482), cefepime, cefetamet, cefpirome, ceftibuten, fleroxacin, temafloxacin, clarithromycin, RP59500, and trospectomycin.

A multilaboratory study was performed to establish broth microdilution MIC quality control (QC) guidelines for 10 investigational drugs which previously demonstrated significant activity against Haemophilus influenzae. MIC QC ranges for H. influenzae ATCC 49247 with Haemophilus test medium were determined by using multiple contemporary lots of Haemophilus test medium and the National Committee for Clinical Laboratory Standards' recommended numbers of replicate tests. On the basis of these results, QC ranges (generally modal MIC +/- one log2 dilution) are proposed for cefdinir, cefepime, cefetamet, cefpirome, ceftibuten, fleroxacin, temafloxacin, clarithromycin, RP59500, and trospectomycin. The proposed QC guidelines for clarithromycin and temafloxacin were recently accepted by the National Committee for Clinical Laboratory Standards.

Anti-Bacterial Agents↗