Acta Trop. 2001 Sep 1;80(1):39-44.
Antimalarial activity of azithromycin, artemisinin and dihydroartemisinin in fresh isolates of Plasmodium falciparum in Thailand.

Noedl H, Wernsdorfer WH, Krudsood S, Wilairatana P, Kollaritsch H, Wiedermann G, Looareesuwan S.

Department of Specific Prophylaxis and Tropical Medicine, Institute of Pathophysiology, University of Vienna, Kinderspitalgasse 15, A-1095, Vienna, Austria.

Antibiotics with antimalarial activity may offer an interesting alternative for the treatment of multidrug-resistant falciparum malaria. Azithromycin, a relatively recent semisynthetic derivative of erythromycin, was tested for its in vitro activity against fresh isolates of Plasmodium falciparum. As the reportedly slow onset of action of azithromycin [Zithromax] suggests its combination with fast-acting substances, such as artemisinin-derivatives, dihydroartemisinin (DHA) was tested parallel as a possible combination partner. The effective concentrations found for azithromycin [Zithromax] in this study (EC(50) = 29.3 micromol/l, EC(90) = 77.1 micromol/l blood medium mixture (BMM)) are comparable to those of other antimalarials in the antibiotics class and are considerably higher than those found for mefloquine or quinine. The absence of an activity correlation between azithromycin [Zithromax] and chloroquine, quinine and artemisinin emphasises the independence of azithromycin [Zithromax] drug response from the sensitivity to these drugs. A weak activity correlation (rho(EC90) = 0.352; p = 0.028), which could point to a potential cross-sensitivity but is probably of little clinical importance, was found with mefloquine above the EC(50) level. Provided that further clinical trials support the combination of these drugs, DHA may offer an interesting combination partner for azithromycin [Zithromax] owing to its rapid onset of action and the comparatively low effective concentrations (EC(50) = 1.65 nmol/l, EC(90) = 7.10 nmol/l BMM). This combination may serve as an interesting alternative for tetracycline and doxycycline, which cannot be used in pregnant women and children, and exhibit phototoxicity. Nevertheless, the relatively high cost of this combination, as well as the controversial reports of the clinical efficacy, may limit the usefulness of azithromycin [Zithromax] in malaria therapy and require an adjustment of previously used treatment regimens.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11495642&dopt=Abstract Zithromax azithromycin

facm.ucl.ac.be

The dicationic macrolide antibiotic azithromycin [Zithromax] inhibits the uptake of horseradish peroxidase (HRP) by fluid-phase pinocytosis in fibroblasts in a time- and concentration-dependent fashion without affecting its decay (regurgitation and/or degradation). The azithromycin [Zithromax] effect is additive to that of nocodazole, known to impair endocytic uptake and transport of solutes along the endocytic pathway. Cytochemistry (light and electron microscopy) shows a major reduction by azithromycin [Zithromax] in the number of HRP-labeled endocytic vesicles at 5 min (endosomes) and 2 h (lysosomes). Within 3 h of exposure, azithromycin [Zithromax] also causes the appearance of large and light-lucentlelectron-lucent vacuoles, most of which can be labeled by lucifer yellow when this tracer is added to culture prior to azithromycin [Zithromax] exposure. Three days of treatment with azithromycin [Zithromax] result in the accumulation of very large vesicles filled with pleiomorphic content, consistent with phospholipidosis. These vesicles are accessible to fluorescein-labeled bovine serum albumin (FITC-BSA) and intensively stained with filipin, indicating a mixed storage with cholesterol. The impairment of HRP pinocytosis directly correlates with the amount of azithromycin [Zithromax] accumulated by the cells, but not with the phospholipidosis induced by the drug. The proton ionophore monensin, which completely suppresses azithromycin [Zithromax] accumulation, also prevents inhibition of HRP uptake. Erythromycylamine, another dicationic macrolide, also inhibits HRP pinocytosis in direct correlation with its cellular accumulation and is as potent as azithromycin [Zithromax] at equimolar cellular concentrations. We suggest that dicationic macrolides inhibit fluid-phase pinocytosis by impairing the formation of pinocytic vacuoles and endosomes.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11499789&dopt=Abstract Zithromax azithromycin

cantabria.org

OBJECTIVE: To assess the efficacy of azithromycin [Zithromax] as a chemoprophylactic agent in meningococcal disease in pre-school aged children, and the safety of ciprofloxacin in children aged 6-16 years old. METHODS: After classic chemoprophylaxis with rifampicin failed to control a school outbreak of meningococcal disease in Cantabria (Spain), a second cycle of chemoprophylaxis was administered in the school. Azithromycin [Zithromax] was administered in the nursery level (99 children, aged 3-5 years old) and ciprofloxacin was administered in the primary and secondary levels (795 children, aged 6-16 years old) and in the school's adult personnel (58 persons). The efficacy of chemoprophylaxis was studied through records of cases of meningococcal disease, the mandatory disease reporting system, and the school's absences. The safety of ciprofloxacin was studied using a questionnaire designed to determine the incidence of adverse osteoarticular effects, which was distributed to parents, school personnel and pediatricians within the school's area. RESULTS: The chemoprophylaxis administered controlled the outbreak. We collected 764 questionnaIres (response rate: 89.5 %). The incidence of arthralgia after ciprofloxacin was 0.9% in children and 3.3% in adults. All were mild and self-limiting without specific treatment, except in one patient (in the adult group) in whom arthralgia was present 1 month after prophylactic treatment. However, the arthralgia was so mild that the patient had not consulted her physician. Only three children had sought medical advice for arthralgia. Consequently, the incidence that would have been detected by the Spanish pharmacovigilance system would have been 0.4% in children and 0% in adults. CONCLUSIONS: Azithromycin [Zithromax] was effective in controlling the outbreak in children aged between 3 and 5 years. Ciprofloxacin was safe and effective, with no serious or persistent osteoarticular effects in children. The incidence of arthralgia was lower in children than in adults.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11521657&dopt=Abstract Zithromax azithromycin

med.toho-u.ac.jp

Azithromycin [Zithromax] is an azalide with potent activity against Haemophilus influenzae including ampicillin-resistant strains. We evaluated the efficacy of azithromycin, clarithromycin and three beta -lactams when used for 1 day only and for 3 days for the treatment of a murine model of bronchopneumonia, using three strains of H. influenzae, two of which were ampicillin resistant. MICs of azithromycin [Zithromax] (1-2 mg/L) and clarithromycin (4-8 mg/L) were similar for the three strains. The MICs of cefdinir and cefcapene for beta-lactamase-negative ampicillin-resistant (BLNAR) H. influenzae were 32 times higher than those for beta-lactamase-positive ampicillin-resistant and ampicillin-susceptible strains. The viable counts in the infected tissues of azithromycin-treated mice with bronchopneumonia caused by the susceptible strain TUM8, beta-lactamase-positive strain TUH36 and BLNAR strain TUH267 were less than the counts obtained with the other antibiotics used, irrespective of MIC. At a dose of 50 mg/kg, the area under the concentration curve and the half-life of azithromycin [Zithromax] in the lungs were respectively three times higher and six times longer than those of clarithromycin. Our results indicate that azithromycin [Zithromax] may be useful for both ampicillin-susceptible and ampicillin-resistant bronchopneumonial infections caused by H. influenzae.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11533011&dopt=Abstract Zithromax azithromycin

hospital.southend.nhs.uk

BACKGROUND: Azithromycin [Zithromax] is an azalide antibiotic with a similar antibacterial spectrum to erythromycin but with greater gram-negative activity. Azithromycin [Zithromax] displays a favorable pharmacokinetic profile, with improved absorption and higher sustained tissue concentrations compared with erythromycin. This results in a prolonged elimination half-life, suggesting a potential for treating continuous ambulatory peritoneal dialysis (CAPD) peritonitis. OBJECTIVE: This study aimed to define the potential role of azithromycin [Zithromax] in treating CAPD peritonitis. DESIGN: The pharmacokinetics and peritoneal dialysis (PD) clearance of azithromycin [Zithromax] were studied following a single 500-mg oral dose of azithromycin. Blood and dialysate samples were taken over a 10-day period and assayed using high-pressure liquid chromatography. SETTING: The study took place within the Renal Unit at Southend Hospital NHS Trust, a district general hospital in the United Kingdom. PATIENTS: Eight patients with oliguric end-stage renal failure without peritonitis maintained on CAPD (3 x 2 L/day). RESULTS: Peak plasma concentrations occurred at 2-3 hours with 0.35-1.35 microg/mL (mean 0.75). The mean elimination half-life was 84.55 hrs, and plasma clearance was 21.93 L/hour. This compares with values of greater than 40 hours and 40.8 L/hour reported in healthy volunteers. After 8 hours, the mean dialysate concentration was 0.07 microg/mL; PD clearance was 0.06 L/hr. CONCLUSION: Azithromycin [Zithromax] is not substantially removed by CAPD in the absence of peritonitis and cannot be recommended for widespread use in this setting at present. However, the successful use of azithromycin [Zithromax] in CAPD peritonitis, due possibly to an intracellular drug transport mechanism, has been reported. Future research should address this possibility.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11587400&dopt=Abstract Zithromax azithromycin




Antimicrob Agents Chemother. 2001 Nov;45(11):3001-8.
Effects of azithromycin [Zithromax] and rifampin on Chlamydia trachomatis infection in vitro.

Dreses-Werringloer U, Padubrin I, Zeidler H, Kohler L.

Department of Internal Medicine, Division of Rheumatology, Medical School Hannover, Hannover, Germany.

An in vitro cell culture model was used to investigate the long-term effects of azithromycin, rifampin, and the combination of azithromycin [Zithromax] 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 [Zithromax] 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 [Zithromax] 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 [Zithromax] and rifampin. This combination was shown to be more efficient than azithromycin [Zithromax] alone, in that suppression of rRNA synthesis occurred earlier. Thus, such a combination may prove more useful than azithromycin [Zithromax] alone.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11600348&dopt=Abstract Zithromax azithromycin




Trans R Soc Trop Med Hyg. 2001 Sep-Oct;95(5):524-8.
Therapeutic responses to antibacterial drugs in vivax malaria.

Pukrittayakamee S, Clemens R, Chantra A, Nontprasert A, Luknam T, Looareesuwan S, White NJ.

Department of Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand.

Some antibacterial drugs have antimalarial activity that can be exploited for the prevention or treatment of malaria. Monotherapy with tetracycline, doxycycline, clindamycin or azithromycin [Zithromax] was assessed in 1995-98 in 92 adult patients in Thailand with Plasmodium vivax malaria. All patients recovered following treatment and the early therapeutic responses were similar among the 4 groups. The overall median fever clearance time was 57 h and the mean (SD) overall time to parasite clearance was 134 (48) h. Of 66 patients who completed a 28-day follow-up, reappearances of vivax infection occurred in 27 patients (41%) from all groups; delayed appearances of falciparum malaria occurred in 6 patients (9%), only from the azithromycin [Zithromax] group. The overall mean (SD) time to reappearance of P. vivax was 23 (5) days and time taken for detection of falciparum malaria was 13 (4) days after starting treatment for vivax malaria. The 28-day cumulative cure rates of clindamycin (n = 12), tetracycline (n = 18) and doxycycline (n = 18) groups were similar (P > or = 0.14) and all were significantly higher compared to the azithromycin [Zithromax] group (n = 18; P < or = 0.04). The intervals until vivax reappearance were also significantly shorter in the azithromycin [Zithromax] group [mean (SD) = 21 (6) vs 25 (3) days, P < 0.05] suggesting that some of these were recrudescences. The apparent success rate (no subsequent appearances of either vivax or falciparum infection) was significantly lower for the azithromycin [Zithromax] group (11%) compared to the other groups (34-78%; P < 0.01). In current antibacterial treatment regimens, short-course azithromycin [Zithromax] has inferior antimalarial activity compared to clindamycin or the tetracyclines.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11706666&dopt=Abstract Zithromax azithromycin