Developmental toxicity of 4-substituted amphetamines in mice

Until recently, therapy for most Nontuberculous Mycobacterial (NTM) disease, especially disease caused by Mycobacterium avium-complex (MAC), has been difficult and frustrating. The introduction of the newer macrolides (clarithromycin and azithromycin) has significantly added to the efficacy of regimens for both disseminated and pulmonary MAC disease. Clinical activity of these agents is lost when a MAC isolate develops in-vitro resistance that is facilitated by use of the macrolides as single agents. These valuable drugs should, therefore, never be used as single agents for the treatment of disseminated or pulmonary MAC disease. The newer macrolides also show promise for the treatment of other NTM infections such as those caused by M. abscessus, M. fortuitum, M. chelonae, M. xenopi, M. marinum, M. haemophilum, and M. genavense. Rifabutin, a derivative of rifamycin S, is an effective agent for prophylaxis against disseminated MAC and may have utility for treatment of pulmonary and disseminated MAC disease. Interactions between clarithromycin and rifamycin may alter efficacy of the macrolide and enhance toxicity of rifabutin. Although therapy of many NTM infections remains difficult with somewhat unpredictable results, the introduction of newer drugs, particularly the macrolides, has appreciably improved a previously dismal outlook for successful therapy.     

Macrolide antibiotics

The macrolides remain excellent antibiotics for many infections particularly those involving intracellular and/or respiratory pathogens. Erythromycin is still an effective drug for many acute orofacial infections. The newer macrolides, azithromycin and clarithromycin, should also prove efficacious although there is very little current data on their use in orofacial infections. They have the advantages over erythromycin of less GI toxicity, higher tissue concentrations, greater gram-negative spectrum, and once or twice daily dosing for better patient compliance. Macrolide concentration in inflammatory cells and transport to the site of infection is a distinct advantage over other antibiotics. Both erythromycin and clarithromycin are associated with significant drug interactions but azithromycin is devoid of such potential toxicity. Azithromycin is less effective against gram-negative cocci than erythromycin and clarithromycin and attains very high tissue concentrations for a very long time, but whether either of these characteristics is clinically significant for orofacial infections is presently unknown.     

Mediators involved in the nephrotoxicity of cyclosporin A

Macrolides are a rational option for patients with community-acquired pneumonia managed as outpatients. For hospitalized patients, they may be used to supplement other drugs, usually betalactams, because of their excellent activity versus Legionella, Chlamydia pneumoniae, and Mycoplasma pneumoniae. The reason for lack of confidence for macrolides as single agents in hospitalized patients, especially for seriously ill patients, is the lack of studies confirming good results for seriously ill patients, and relatively poor in vitro activity against some important pathogens. Resistance is noted to erythromycin, clarithromycin, and azithromycin by 10% to 15% of Streptococcus pneumoniae, about 40% of penicillin resistant S pneumoniae, most Fusobacteria, some Streptococcus aureus, and all gram-negative bacilli.     

Pharmacokinetic and pharmacodynamic interaction study between midazolam and the macrolide antibiotics, erythromycin, clarithromycin, and the azalide azithromycin

This report includes a recalculation of the pooled data of 2 pharmacokinetic and pharmacodynamic studies of the interaction between the hypnotic midazolam and the antibiotics erythromycin, clarithromycin (macrolides), and azithromycin (an azalide). Erythromycin and clarithromycin similarly and strikingly impaired the metabolism of midazolam and enhanced its pharmacodynamic activity; little or no effect was found with azithromycin. It was concluded that coadministration of midazolam and azithromycin involves less clinical risk than with the 2 macrolides.     

Mycobacterium avium strains resistant to clarithromycin and azithromycin

Mycobacterium avium strains susceptible to clarithromycin and azithromycin contain mutants resistant to these macrolides with a frequency of 1.1 x 10(-10) to 1.2 x 10(-6). Cross-resistance between clarithromycin and azithromycin was demonstrated with mutants selected in the laboratory as well as with resistant strains isolated from patients. The susceptibility-resistance patterns of the macrolide-resistant strains with drugs other than macrolides were the same as those of the original susceptible strains. The emergence of clarithromycin resistance in patients was a result of multiplication of the preexisting resistant mutants that survived the elimination of bacteria during the initial period of treatment and was an exclusive cause of the relapse of bacteremia.     

Erythromycin, clarithromycin, and azithromycin: are the differences real?

Erythromycin, clarithromycin, and azithromycin are clinically effective for the treatment of common respiratory and skin/skin-structure infections. Erythromycin and azithromycin are also effective for treatment of nongonococcal urethritis and cervicitis due to Chlamydia trachomatis. Compared with erythromycin, clarithromycin and azithromycin offer improved tolerability. Clarithromycin, however, is more similar to erythromycin in pharmacokinetic measures such as half-life, tissue distribution, and drug interactions. Misunderstandings about differences among the macrolides (erythromycin and clarithromycin) and the azalide (azithromycin) in terms of pharmacokinetics and pharmacodynamics, spectrum of activity, safety, and cost are common. The uptake and release of these compounds by white blood cells and fibroblasts account for differences in tissue half-life, volume of distribution, intracellular:extracellular ratio, and in vivo potency. Although microbiologic studies reveal that gram-positive pathogens are equally susceptible to these agents, significantly more isolates of Haemophilus influenzae are susceptible to azithromycin than to erythromycin or clarithromycin. Concentrations achieved at the infection site and duration above the minimum inhibitory concentration are as important as in vitro activity in determining in vivo activity against bacterial pathogens. Analysis of safety data indicates differences among these agents in drug interactions and use in pregnancy. Analysis of safety data reveals pharmacokinetic drug interactions for erythromycin and clarithromycin with theophylline, terfenadine, and carbamazepine that are not found with azithromycin. Both erythromycin and azithromycin are pregnancy category B drugs; clarithromycin is a category C drug. The numerous differences in pharmacokinetics, microbiology, safety, and costs among erythromycin, clarithromycin, and azithromycin can be used in the judicious selection of treatment for indicated infections.     

Chlamydia pneumoniae as an etiologic factor in disease of the respiratory tract

The described recently species of Chlamydia pneumoniae is the subject of a large number of scientific reports. The majority of infections caused by this microorganism are asymptomatic. However, a lot of cases of symptomatic infections have been described with both mild and severe clinical course. Symptoms related to infection may affect both upper and lower parts of the respiratory tract and may be accompanied by disorders in other systems and organs. Reports on the influence of chronic inflammation by Chlamydia pneumoniae on the development of arteriosclerosis are still controversial. The effective drugs in the treatment of Chlamydia pneumoniae infections are macrolides and tetracyclines.     

Comparison of azithromycin and clarithromycin in their interactions with rifabutin in healthy volunteers

A 14-day, randomized, open, phase I clinical trial was designed to examine possible pharmacokinetic interactions between rifabutin and two other antibiotics, azithromycin and clarithromycin, used in the treatment of Mycobacterium avium complex infections. Thirty healthy male and female volunteers were divided into five groups of six participants each: 18 received 300 mg/day of rifabutin, 12 in combination with therapeutic doses of either azithromycin or clarithromycin; the remaining 12 received azithromycin or clarithromycin alone. On day 10 the study was terminated because of adverse events, including severe neutropenia. Fourteen participants who received rifabutin developed neutropenia, including all 12 participants who received azithromycin or clarithromycin concomitantly. Analyses of serum revealed no apparent pharmacokinetic interaction between azithromycin and rifabutin. However, the mean concentrations of rifabutin and 25-O-desacetyl-rifabutin (an active metabolite) in participants who received clarithromycin and rifabutin concomitantly were more than 400% and 3,700%, respectively, of concentrations in those who received rifabutin alone. Physicians should be aware that recommended prophylactic doses of rifabutin may be associated with severe neutropenia within 2 weeks after initiation of therapy, and all patients receiving rifabutin, especially with clarithromycin, should be monitored carefully for neutropenia.     

In vitro activity of macrolides against intracellular Legionella pneumophila

The antibacterial effects of clarithromycin, azithromycin, and erythromycin were determined against five strains of Legionella pneumophila including L. pneumophila ATCC 33823 and four clinical isolates. Extracellular minimum inhibitory concentrations (MICs) and MBCs were determined by a microdilution method. Clarithromycin was the most active drug (MIC < or = 0.015-0.06), followed by azithromycin (MIC 0.03-0.12) and erythromycin (MIC 0.06-0.25). The antibacterial effect of these macrolides was then determined against L. pneumophila grown intracellularly in MRC-5 human fetal lung fibroblast cells. At two and eight times the extracellular MBC, erythromycin, azithromycin, and clarithromycin were equally effective in inhibiting growth of these five strains of intracellular L. pneumophila.     

A quantitative study of the progress of myelination in the rat central nervous system, using the immunohistochemical method for proteolipid protein

A liquid chromatographic method for the determination of macrolide antibiotics is described using a cyanopropyl column which proved to be as efficient or superior to the normally used apolar reversed-phase columns. The recovery of the macrolides from water and plasma was 80-90%. Using 0.5 ml of plasma, 30 ng/ml of clarithromycin, 50 ng/ml of roxithromycin and 10 ng/ml of azithromycin could be determined with acceptable precision and accuracy. The method has been employed in pharmacokinetic studies in humans for the determination of roxithromycin, clarithromycin and azithromycin in plasma, serum and other biological matrices. The particular selectivity of the cyanopropyl phase may also allow the simultaneous determination of erythromycin and its prodrug esters.     

In vitro activities of azithromycin, clarithromycin, erythromycin, and tetracycline against 13 strains of Chlamydia pneumoniae

Thirteen strains of Chlamydia pneumoniae were evaluated for their in vitro susceptibilities to azithromycin, clarithromycin, erythromycin, and tetracycline. The MIC ranges were 0.125 to 0.5 micrograms/ml for azithromycin, 0.031 to 1.0 micrograms/ml for clarithromycin, 0.125 to 1.0 micrograms/ml for erythromycin, and 0.25 to 1.0 micrograms/ml for tetracycline. The ranges for the minimal lethal concentrations were 0.125 to 0.5 micrograms/ml for azithromycin, 0.031 to 1.0 micrograms/ml for clarithromycin, 0.125 to 1.0 micrograms/ml for erythromycin, and 0.25 to 1.0 micrograms/ml for tetracycline. Clarithromycin and azithromycin were the most active antibiotics against C. pneumoniae in vitro.     

Depression of the N-demethylation of erythromycin, azithromycin, clarithromycin and clindamycin in murine Toxoplasma infection

The N-demethylation of macrolides was studied in a murine model of infection. Mice were infected with a cystogenic strain of Toxoplasma gondii (20 or 40 cysts/mouse) and microsomes were prepared from liver homogenates and jejunum villus tip enterocytes on day 10 post-infection. The rate of N-demethylation of the anti-Toxoplasma macrolides azithromycin, clarithromycin and clindamycin was investigated and compared to that of the macrolide erythromycin, a marker of activity of the cytochrome P-450 3A (CYP3A) mono-oxygenases. In infected mice (20 cysts/mouse), the rate of N-demethylation fell in the liver and jejunum for erythromycin (-25% and -35%, respectively), azithromycin (-12% and -10%, respectively), clarithromycin (-23% and -21%, respectively) and clindamycin (-20% and -28%, respectively). The degree of hepatic depression was more marked in mice receiving a 40-cysts burden: for erythromycin (-54%), azithromycin (-29%), clarithromycin (-49%) and clindamycin (-47%).     

Comparative antimicrobial activity of RP 59,500 (quinupristin-dalfopristin), the first semisynthetic injectable streptgramin, against gram-positive cocci and other recent clinical pathogens

RP 59,500 (Quinupristin-Dalfopristin) is the first semisynthetic injectable streptogramin antimicrobial agent, which is a combination of quinupristin and dalfopristin in a 30:70 ratio. The components of RP 59,500 act synergically to provide bactericidal activity through action at different sites on bacterial ribosomes. In the present study, the antimicrobial activity of RP 59,500 was compared with those of four macrolides (erythromycin, clarithromycin, azithromycin, roxithromycin). Susceptibility testing was carried out by microdilution method on 303 strains of 10 species, especially antibiotic-resistant Gram-positive cocci. RP 59,500 was active against a wide range of Gram-positive cocci including methicillin-resistant Staphylococci and penicillin-resistant Streptococcus pneumoniae. The MICs90 of RP 59,500 against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis were both 0.25 microgram/ml, although those of four macrolides were higher than 32 micrograms/ml. The MICs90 of RP 59,500 against penicillin-sensitive, -intermediate and -resistant S. pneumoniae were all 0.5 microgram/ml, although those of four macrolides against penicillin-resistant S. pneumoniae were higher than 32 micrograms/ml. RP 59,500 also exhibited equivalent activities to the four macrolides against strains of Streptococcus pyogenes. Streptococcus agalactiae and Moraxella catarrhalis. RP 59,500 exhibited the highest activities against Enterococcus faecalis, Enterococcus faecium and Enterococcus avium strains which are intrinsically resistant to most antimicrobial agents. No cross-resistance was observed between RP 59,500 and the four macrolides, which will merit attention in future clinical trials of the agent. The effect of human serum on the MIC of RP 59,500 was studied with strains of S. aureus, S. epidermidis and E. faecalis. The presence of 20% (V/V) serum had little or no effect on the MIC, although 50% (V/V) serum increased MICs by 4-8 folds. Laboratory-induced resistance to RP 59,500 occurred in a stepwise fashion in broth cultures of S. aureus, S. epidermidis and E. facalis strains and the induction rate was slow and no more than four fold increases were observed. Population analysis was performed on RP 59,500 and the reference macrolides against S. aureus ATCC 25,923 strain. Although low frequencies (less than 0.01%) of resistant sub-population were detected with EM, CAM, AZM and RXM, no RP 59,500-resistant sub-population was detected in this study.     

Macrolide susceptibility and beta-lactamase production among haemophilus influenzae isolates in the United States, 1996-1997

In 1996 and 1997, 68 hospital laboratories throughout the United States determined the beta-lactamase production and susceptibility to macrolides of 1,998 isolates of Haemophilus influenzae obtained from patients with community-acquired respiratory tract infections. The MICs at which 90% of the isolates are inhibited of azithromycin, erythromycin, and clarithromycin were 4, 8, and 16 microgram/ml, respectively. By National Committee for Clinical Laboratory Standards interpretive criteria, 99 and 78% of the isolates were susceptible to azithromycin and clarithromycin, respectively. The prevalence of beta-lactamase production was 32%.     

Azithromycin. A review of its use in paediatric infectious diseases

Azithromycin is an azalide antimicrobial agent active in vitro against major pathogens responsible for infections of the respiratory tract, skin and soft tissues in children. Pathogens that are generally susceptible to azithromycin include Haemophilus influenzae (including ampicillin-resistant strains), Moraxella catarrhalis, Chlamydia pneumoniae, Chlamydia trachomatis, Mycoplasma pneumoniae, Legionella spp., Streptococcus pyogenes and Streptococcus agalactiae. Azithromycin is also generally active against erythromycin- and penicillin-susceptible Streptococcus pneumoniae and methicillin-susceptible Staphylococcus aureus. Azithromycin is administered once daily, achieves clinically relevant concentrations at sites of infection, is slowly eliminated from the body and has few drug interactions. In children, azithromycin is usually given as either a 3-day course of 10 mg/kg/day or a 5-day course with 10 mg/kg on the first day, followed by 5 mg/kg/day for a further 4 days. These standard regimens were as effective as amoxicillin/clavulanic acid, clarithromycin, cefaclor and amoxicillin in the treatment of children with otitis media. Azithromycin was also as effective as either phenoxymethylpenicillin (penicillin V), erythromycin, clarithromycin or cefaclor against streptococcal pharyngitis or tonsillitis in children, but appears to result in more recurrence of infection than phenoxymethylpenicillin in this indication, necessitating a dosage of 12 mg/kg/day for 5 days. Community-acquired pneumonia, bronchitis and other respiratory tract infections in children responded as well to azithromycin as to amoxicillin/clavulanic acid, cefaclor, erythromycin or josamycin. Azithromycin was similar or superior to ceftibuten in mixed general practice populations of patients. However, symptoms of lower respiratory tract infections resolved more rapidly with azithromycin than with erythromycin, josamycin or cefaclor. Skin and soft tissue infections responded as well to azithromycin as to cefaclor, dicloxacillin or flucloxacillin, and oral azithromycin was as effective as ocular tetracycline in treating trachoma. Although not as well tolerated as phenoxymethylpenicillin in the treatment of streptococcal pharyngitis, azithromycin is at least as well tolerated as most other agents used to treat respiratory tract and other infections in children and was better tolerated than amoxicillin/clavulanic acid. Adverse events that do occur are mostly gastrointestinal and tend to be mild to moderate in severity. CONCLUSIONS: Azithromycin is an effective and well tolerated alternative to first-line agents in the treatment of respiratory tract, skin and soft tissue infections in children, offerring the convenience of a short, once-daily regimen.     

Randomized, open-label trial of azithromycin plus ethambutol vs. clarithromycin plus ethambutol as therapy for Mycobacterium avium complex bacteremia in patients with human immunodeficiency virus infection. Veterans Affairs HIV Research Consortium

Disseminated Mycobacterium avium complex (MAC) infection continues to be a common opportunistic infection in patients infected with human immunodeficiency virus (HIV). The optimal therapy for disseminated MAC infection is unclear. We compared azithromycin plus ethambutol with clarithromycin plus ethambutol in the treatment of disseminated MAC infection in HIV type 1-infected patients, examining the frequency of bacteremia clearance, time to clearance, and study drug tolerance after 16 weeks of therapy. Fifty-nine patients for whom blood cultures were positive for MAC were enrolled in the study from 10 university-affiliated Veterans Affairs Medical Centers. Thirty-seven patients were evaluable for determination of quantitative bacteremia and clinical outcomes. Clearance of bacteremia was seen at the final visit in 37.5% of azithromycin-treated patients and in 85.7% of clarithromycin-treated patients (P = .007). The estimated median time to clearance of bacteremia was also significantly different between the two treatment arms: 4.38 weeks for clarithromycin recipients vs. > 16 weeks for azithromycin recipients (P = .0018). Only one isolate developed macrolide resistance during therapy. Abatement of symptoms, other laboratory-evident abnormalities, and adverse effects were similar in the two groups. At the doses used in this study, clarithromycin/ethambutol produced a more rapid resolution of bacteremia than did azithromycin/ethambutol, and clarithromycin/ethambutol was more effective at sterilization of blood cultures after 16 weeks of therapy.     

Current antimicrobial drugs

In the past few years several new antibiotics became available, but no major inventions as to new treatment strategies were made. There are a few new broad-spectrum antibiotics for the intravenous route like piperacillin-tazobactam, the carbapenem meropenem and the fourth-generation cephalosporins. cefepime and cefpirome. New oral antibiotics include the third-generation cephalosporins ceftibuten, cefetamet and cefpodoxime and the macrolides clarithromycin and azithromycin. The last two have the great advantage of less frequent dosing and fewer side effects than erythromycin. Of the two new quinolones, sparfloxacin and trovafloxacin, trovafloxacin is the more promising. In the treatment of Gram-positive infections the glycopeptide teicoplanin became available and the combined derivatives quinupristin-dalfopristin may prove valuable in the future.     

Reduced nociceptive behavior in islet amyloid polypeptide (amylin) knockout mice

Macrolide resistance is an emerging problem in AIDS patients who receive these agents for treatment or prophylaxis against Mycobacterium avium (MAC) infection. We compared the emergence of resistant MAC strains during therapy with clarithromycin (clarithromycin resistance was defined as MIC > or = 32 microg/ml) and azithromycin (azithromycin resistance was defined as MIC > or = 128 microg/ml) in C57BL/6 beige mice. Treatment with clarithromycin and azithromycin resulted in a decrease of 98.5% in the number of viable bacteria in spleens at week 8 and 99% at week 12 compared with the number of bacteria present in spleen before the initiation of therapy (P < 0.001). Splenic homogenates were also plated onto 7H11 agar plus clarithromycin at 32 microg/ml or azithromycin at 128 microg/ml. Resistance emerged significantly more often in mice treated with clarithromycin (100% of treated mice at both 8 and 12 weeks) than in those receiving azithromycin (0% at week 8 and 14% at week 12). The frequencies of resistance of the MAC population in the spleen to clarithromycin were 2.1 x 10(-3) at week 8 and 1.1 x 10(-2) at week 12, whereas resistance to azithromycin was absent at week 8 (all mice) and was approximately 3.5 x 10(-5) (mean for the three positive animals) at week 12. Clarithromycin was more effective in initial reduction of MAC burden in tissue after 8 and 12 weeks of treatment, but resistant strains emerged significantly more frequently after treatment with clarithromycin than after treatment with azithromycin.     

Macrolide antibiotics inhibit 50S ribosomal subunit assembly in Bacillus subtilis and Staphylococcus aureus

Macrolide antibiotics are clinically important antibiotics which are effective inhibitors of protein biosynthesis in bacterial cells. We have recently shown that some of these compounds also inhibit 50S ribosomal subunit formation in Escherichia coli. Now we show that certain macrolides have the same effect in two gram-positive organisms, Bacillus subtilis and Staphylococcus aureus. Assembly in B. subtilis was prevented by erythromycin, clarithromycin, and azithromycin but not by oleandomycin. 50S subunit formation in S. aureus was prevented by each of seven structurally related 14-membered macrolides but not by lincomycin or two streptogramin antibiotics. Erythromycin treatment did not stimulate the breakdown of performed 50S subunits in either organism. The formation of the 30S ribosomal subunit was also unaffected by these compounds. Assembly was also inhibited in a B. subtilis strain carrying a plasmid with the ermC gene that confers macrolide resistance by rRNA methylation. These results suggest that ribosomes contain an additional site for the inhibitory functions of macrolide antibiotics.     

Safety and efficacy of azithromycin in the treatment of community-acquired pneumonia in children

OBJECTIVE: To compare the safety and efficacy of azithromycin with amoxicillin/clavulanate or erythromycin for the treatment of community-acquired pneumonia, including atypical pneumonia caused by Mycoplasma pneumoniae and Chlamydia pneumoniae. METHODS: Multicenter, parallel group, double blind trial in which patients 6 months to 16 years of age with community-acquired pneumonia were randomized 2:1 to receive either azithromycin for 5 days or conventional therapy for 10 days (amoxicillin/clavulanate if < or =5 years of age or erythromycin estolate if >5 years of age). Patients from 23 geographically diverse sites were evaluated for clinical outcomes and/or adverse events at Days 3 to 5, Days 15 to 19 and 4 to 6 weeks posttherapy. Microbiology (culture or polymerase chain reaction) was done at baseline and Days 15 to 19 for bacteria, Chlamydia pneumoniae and Mycoplasma pneumoniae. Serology for C. pneumoniae and M. pneumoniae was done at baseline and 4 to 6 weeks posttherapy. RESULTS: Of 456 patients enrolled during 17 consecutive months, 420 were evaluable. Clinical success at Study Days 15 to 19 was 94.6% in the azithromycin group and 96.2% in the comparative treatment group (P = 0.735) and at 4 to 6 weeks posttherapy 90.6 and 87.1%, respectively (P = 0.330). Evidence of infection was identified in 46% of 420 evaluable patients (1.9% bacteria, 29.5% M. pneumoniae and 15% C. pneumoniae). Microbiologic eradication was 81% for C. pneumoniae and 100% for M. pneumoniae in the azithromycin group vs. 100 and 57%, respectively, in the comparator group. Treatment-related adverse events occurred in 11.3% of the azithromycin group and 31% in the comparator group (P < 0.05). CONCLUSION: Azithromycin used once daily for 5 days produced a satisfactory therapeutic outcome similar to those of amoxicillin/clavulanate or erythromycin given three times a day for 10 days for treatment of community-acquired pneumonia. Azithromycin had significantly fewer side effects than comparator drugs.