Pharmacokinetics of azithromycin and the combination of ivermectin and albendazole when administered alone and concurrently in healthy volunteers.

Azithromycin is a critical component of an integrated disease elimination program against trachoma. This study was conducted to evaluate whether azithromycin has a pharmacokinetic interaction with the combination of ivermectin and albendazole. Eighteen healthy volunteers were administered single doses of azithromycin, ivermectin/albendazole, and the combination of the three agents in random, crossover fashion. To assess the presence of interactions, test (combination) and reference (single dose) data were compared using an estimation approach. Compared with reference phases, the geometric mean values for the combination arm's azithromycin AUC(0-t) and C(max) were increased approximately 13% and 20%, respectively, albendazole AUC(0-t) decreased by approximately 3% and C(max) increased approximately 3%, and ivermectin AUC(0-t) and C(max) were increased 31% and 27%, respectively. Albendazole sulfoxide AUC(0-t) and C(max) were decreased approximately 16% and 14%, respectively. All treatments were well tolerated. The interactions for azithromycin and albendazole were minimal although the increase in ivermectin exposure requires further study.

Efficacy and safety of 3-day azithromycin versus 5-day moxifloxacin for the treatment of acute bacterial exacerbations of chronic bronchitis.

Antibiotic therapy is of clinical benefit in certain patients with acute exacerbations of chronic bronchitis (AECB). In this randomised, investigator-blinded, multicentre trial, azithromycin (500mg once a day (qd) for 3 days) was compared with moxifloxacin (400mg qd for 5 days) for the treatment of outpatients with AECB (forced expiratory volume in 1s (FEV(1)) >35%). Of 342 patients randomised to either treatment, 169 received azithromycin and 173 received moxifloxacin. The mean age in the azithromycin and moxifloxacin groups was 56.4 years and 55.5 years, respectively. In the intent-to-treat analysis, clinical success rates for azithromycin and moxifloxacin were comparable at Days 10-12 (90% versus 90%, respectively) and Days 22-26 (81% versus 82%, respectively). Among patients who were culture-positive at baseline for Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis or Haemophilus parainfluenzae, clinical efficacy for azithromycin versus moxifloxacin at Days 10-12 was 93% versus 84%, respectively, and at Days 22-26 it was 89% versus 73%, respectively. The incidence of at least one treatment-related adverse event (AE) in the azithromycin and moxifloxacin groups was 18.3% and 19.1%, respectively. The most common AEs were diarrhoea, nausea, abdominal pain and vaginitis. Most treatment-related AEs were of mild or moderate severity, with no serious treatment-related AEs. One subject in the moxifloxacin group discontinued treatment owing to a treatment-related AE (precordial pain and dry throat). Compliance with both regimens was >90%. Three-day azithromycin and 5-day moxifloxacin demonstrate comparable efficacy and safety for the treatment of AECB in outpatients.

Altered steady state pharmacokinetics of levofloxacin in adult cystic fibrosis patients receiving calcium carbonate.

BACKGROUND: Levofloxacin is used in adult patients with cystic fibrosis but its pharmacokinetics is not well characterized in this population. Patients with cystic fibrosis use calcium routinely to prevent osteoporosis. A slower intestinal transit time is common in cystic fibrosis implying that the standard 2-h spacing of minerals and levofloxacin to prevent a chelation interaction may be insufficient. The objectives of this study were to characterize the steady state pharmacokinetics of oral levofloxacin 750 mg with and without 2-h spaced calcium carbonate in patients with cystic fibrosis compared to matched healthy volunteers. METHODS: In an open-label, randomized, cross-over study of five patients with cystic fibrosis and five age, sex, race, and serum creatinine matched healthy volunteers received 750 mg of oral levofloxacin alone daily for 5 days and the same dose of levofloxacin with 2-h spaced calcium carbonate supplementation 500 mg po thrice daily with meals in random sequence. Blood was collected for plasma assay of levofloxacin pre-dose, 0.5, 1, 1.5, 2, 4, 8, 12, and 24h after the fifth levofloxacin dose. RESULTS: There was no significant interaction in healthy volunteers, however, when cystic fibrosis patients were given levofloxacin with 2-h spaced calcium, the maximum plasma concentration (Cmax) decreased by 19% and time to Cmax increased by 37% (p<0.05). This difference in peak concentrations resulted in a lack of bioequivalence (Cmax geometric mean ratio 81.6%, 90% confidence intervals: 71.8%, 91.4%) even when levofloxacin and calcium supplements were spaced by the standard 2h administration instruction in patients with cystic fibrosis. CONCLUSIONS: These results indicate that multivalent cations such as calcium should be maximally separated from oral levofloxacin administration in adult patients with cystic fibrosis to prevent this drug interaction, thereby better optimizing antibiotic efficacy and decreasing the potential for resistance development.

Treatment of Legionnaires' disease.

Legionnaires' disease is pneumonia, usually caused by Legionella pneumophila, which can range in severity from mild to quite severe. While it is commonly acquired in the community, it can just as easily be acquired nosocomially from water sources that have not been appropriately decontaminated. While historically initial treatment was always with erythromycin, current case series and treatment recommendations suggest that outpatients receive immediate treatment with one of the following antibacterials: azithromycin, erythromycin, clarithromycin, telithromycin, doxycycline or an extended-spectrum fluoroquinolone. If the symptoms are severe enough to warrant hospitalisation then the patient should receive treatment with parenteral azithromycin or extended-spectrum fluoroquinolones followed by step-down to oral formulations to complete the regimens. While a shorter course of 7-10 days for more severe infections may be possible for intravenous/oral azithromycin, other antibacterials should be administered for a total of 10-21 days and started as soon as possible upon presentation to optimise outcomes.

Once-daily azithromycin for 3 days compared with clarithromycin for 10 days for acute exacerbation of chronic bronchitis: a multicenter, double-blind, randomized study.

STUDY OBJECTIVES: To compare the efficacy and safety of oral azithromycin 500 mg once daily for 3 days with those of oral clarithromycin 500 mg twice daily for 10 days. DESIGN: Randomized, double-blind, double-dummy, multicenter study. SETTING: Seventy-six study centers in eight countries (Argentina, Brazil, Canada, Chile, Costa Rica, India, South Africa, and USA). PATIENTS: Three hundred and twenty-two adult outpatients with acute exacerbation of chronic bronchitis (AECB) as documented by increased cough or sputum production, worsening dyspnea, and purulent sputum production. INTERVENTIONS: Randomization 1 : 1 to azithromycin 500 mg once daily for 3 days or clarithromycin 500 mg twice daily for 10 days. RESULTS: The primary efficacy endpoint was clinical response at day 21-24, or test of cure (TOC) visit in the modified intent-to-treat (MITT) analysis (n = 318 patients). The TOC clinical cure rates in the MITT population were equivalent in the two treatment groups at 85% with azithromycin and 82% with clarithromycin (95% CI -5.9%, 12.0%). Clinical success rates on day 10-12 were also equivalent at 93% with azithromycin and 94% with clarithromycin (95% CI -7.9%, 4.4%). Clinical cure rates at TOC by pathogen were equivalent for the two treatment groups for Haemophilus influenzae (azithromycin, 85.7%; clarithromycin, 87.5%), Moraxella catarrhalis (91.7% and 80.0%, respectively) and Streptococcus pneumoniae (90.6% and 77.8%, respectively). Bacteriologic success rates were also equivalent between the azithromycin and clarithromycin treatment groups at TOC for S. pneumoniae (90.6% and 85.2%, respectively), H. influenzae (71.4% and 81.3%, respectively) and M. catarrhalis (100% and 86.7%, respectively). The overall incidence of treatment-related adverse events was similar in the azithromycin and clarithromycin groups (20.9% and 26.8%, respectively), with the most common being abdominal pain (6.3% and 6.1%, respectively), diarrhea (4.4% and 5.5%, respectively), and nausea (4.4% and 3.7%, respectively). CONCLUSIONS: Three-day treatment with azithromycin 500 mg once daily is equivalent to a 10-day treatment with clarithromycin 500 mg twice daily in adult patients with AECB.

The disease-modifying effects of twice-weekly oral azithromycin in patients with bronchiectasis.

INTRODUCTION: Bronchiectasis is a chronic pulmonary process characterized by recurrent respiratory infections leading to destruction of airways secondary to inflammation. We investigated whether the addition of 6-months' twice-weekly azithromycin to the existing treatment regimen in patients with pulmonary bronchiectasis decreased the number of exacerbations and improved pulmonary function compared with a similar period of time without concurrent azithromycin. METHODS: Thirty patients with high-resolution computed tomography scan-confirmed bronchiectasis were to be recruited. In random order, patients received usual medications for 6 months, and usual medications plus oral azithromycin 500mg twice weekly for 6 months. Patients receiving azithromycin first had a 1-month washout period prior to entering the second phase. Patients recorded weekly peak flow (PF) measurements. Pulmonary function tests (PFTs), 24-hour sputum volume, and needs for intervention with medication or ancillary support were collected at baseline and every 3 months. Exacerbation incidence and sputum volume measurements were compared from baseline to the end of each study phase. RESULTS: Twelve patients were enrolled; 11 were included in the analysis. Owing to randomization, most patients received the azithromycin first, which was fairly well tolerated. PFTs did not change significantly during either study phase and PFs appeared to remain stable during azithromycin therapy and throughout the subsequent control phase. Azithromycin significantly decreased the incidence of exacerbations compared with usual medications (5 vs 16; p = 0.019). Mean 24-hour sputum volume significantly decreased (15% [p = 0.005]) during the active treatment phase, and remained decreased during the control phase (p = 0.028). Subjectively, patients reported increased energy and quality of life while receiving treatment with azithromycin. CONCLUSIONS: The addition of twice-weekly azithromycin significantly decreased the incidence of exacerbation and 24-hour sputum volume and may have stabilized the PFTs and PFs in this 11-patient pilot study. The results of this study justify further investigation of adding azithromycin to the treatment regimens of patients with bronchiectasis for its disease-modifying effects.

Current trachoma treatment methodologies: focus on advancements in drug therapy.

Currently, there are approximately 6 million people with irreversible blindness as a result of chronic follicular conjunctivitis with subsequent corneal scarring caused by Chlamydia trachomatis, also known as trachoma. On the basis of the clinical studies evaluated, the most widely tested effective pharmacological treatments for trachoma today are topical tetracycline 1% to be applied to both eyes twice daily for 6 weeks or a single oral dose of azithromycin 20 mg/kg (up to 1g). Although chemotherapy can generate prompt therapeutic response and surgery can reverse the repercussions of these infections, these conditions will persist through reinfections. Implementing proper personal hygiene and environmental improvement measures for the control of infection transmission will be essential in reducing the potentially devastating results of trachoma infections.

Efficacy and safety of azithromycin vs levofloxacin in the outpatient treatment of acute bacterial exacerbations of chronic bronchitis.

STUDY OBJECTIVES: To compare the safety and efficacy of oral azithromycin and levofloxacin in the treatment of outpatients with acute bacterial exacerbations of chronic bronchitis (ABECB). DESIGN: Randomized, double-blinded, double-dummy, multicenter trial with 1:1 treatment allocation. SETTING: Outpatient treatment setting. PATIENTS: Two hundred thirty-five male or female outpatients between the ages of 35 and 75 years who had received a clinical diagnosis of ABECB. INTERVENTIONS: Blinded treatment with either oral azithromycin, 500 mg on day 1 and 250 mg per day for days 2 to 5, or, oral levofloxacin, 500 mg q24h for 7 days. RESULTS: Both treatments were well-tolerated, with the majority of adverse events being GI in nature. Favorable clinical outcomes in clinically evaluable patients were demonstrated in 89% of patients receiving azithromycin and in 92% of patients receiving levofloxacin by day 4 of therapy. At day 24, the posttherapy visit, favorable responses were approximately 82% and 86%, respectively, for patients in the two treatment groups. The bacterial eradication rates of respiratory pathogens were 96% for azithromycin and 85% for levofloxacin. CONCLUSIONS: Despite increasing concerns over macrolide resistance and a higher incidence of Gram-negative pathogens, a standard 5-day course of oral azithromycin was clinically and bacteriologically equivalent to a 7-day course of oral levofloxacin in the treatment of patients with ABECB.

Pneumococcal resistance in perspective: how well are we combating it?

Because Streptococcus pneumoniae is the most commonly isolated community-acquired respiratory tract pathogen, the reports of high rates of antibiotic resistance throughout the world highlight the need for intervention to stem any further increases in resistance. Efforts to reduce the incidence of pneumococcal resistance have been mainly 2-fold, involving attempts to reduce unnecessary antibiotic prescribing, as well as to assure early childhood immunization with the pneumococcal heptavalent conjugate vaccine. To reduce unnecessary prescribing for infections that are typically viral in etiology, such as acute bronchitis, education efforts have been focused not only on clinicians but also on parents and patients. These education efforts significantly reduce unnecessary antibiotic prescribing, and initial evidence suggests that they may stabilize, if not reduce, the incidence of penicillin and macrolide-resistant pneumococcal isolates. Utilization of the relatively new pneumococcal heptavalent conjugate vaccine not only reduces the incidence of acute otitis media caused by pneumococcal serotypes included in the vaccine as well as disease caused by related serotypes but also has a highly significant effect on reducing the incidence of invasive pneumococcal disease in children and potential adult contacts. In addition more recent data have established that vaccination is also decreasing the carriage and transmission of antibiotic-resistant pneumococcal isolates. Education and vaccine programs that attempt to stabilize and/or reduce the rate of pneumococcal resistance are at least as important as having effective antibiotic treatments for pneumococcal disease. These efforts to address pneumococcal resistance have been highly successful to date.

Is it really OK to take this with food? Old interactions with a new twist.

In response to consumers' increased interest in preventive health care, the food industry is producing a variety of foods fortified with calcium, iron, and other minerals and vitamins. This well-meaning idea of food fortification is troubling in the context of clinical pharmacology. The recommended Food and Drug Administration (FDA) meal used in food-drug interaction studies is a high-fat, high-calorie meal with little nutritive value. While some drugs may appear to be safe when taken with food, this may not be true when fortified foods are considered. The mechanisms causing drug-fortified food interactions are the some well-known mechanisms that cause other drug-mineral interactions. Certain drugs may exhibit decreased absorption due to chelation and adsorption. Other drugs may have decreased absorption or increased excretion due to changes in gastric and/or urinary pH. The results of such interactions may be clinically insignificant or severe, including treatment failure, frequent dose changes, antibiotic resistance, and increased morbidity and mortality. Revisions of current regulatoryguidelines are necessary to take into account this potentially major source of "new" drug interactions.

The association of erythromycin and infantile hypertrophic pyloric stenosis: causal or coincidental?

The safety profile of erythromycin is notable for the frequent occurrence of intolerable gastrointestinal effects. One of the more serious of these is infantile hypertrophic pyloric stenosis (IHPS). A recent cluster of IHPS cases prompted an epidemiological investigation which identified oral erythromycin chemoprophylaxis of pertussis as the major risk factor. Evidence suggests an association between early postnatal erythromycin exposure and IHPS. There is no substantive evidence of a risk associated with prenatal exposure, with the single published case-control study to date producing negative findings. The epidemiological investigations of the association with early postnatal exposure have reported significantly elevated odds ratios but have a variety of methodological limitations that prevent definitive conclusions being made. Nevertheless, the concordance of findings across studies increases the strength of evidence favouring an association. The prominent gastrokinetic properties of erythromycin have been postulated as the mechanism behind this phenomenon. A comprehensive assessment of this potential adverse effect should consider its biological plausibility in light of known gastrointestinal physiology, its modulation by erythromycin, and the known pathophysiology of IHPS. Gastrointestinal motor activity in the fasted mammal consists of three phases, phase III being large amplitude contractions called migrating motor complexes (MMC) that can be initiated by motilin and erythromycin. The gastrokinetic effects of erythromycin are variable and complex and include effects on the timing, duration, amplitude and distribution of MMCs. It has been speculated that the motilinomimetic effects of erythromycin on antral smooth muscle function, such as the MMC, may mediate the effect via work hypertrophy. Although intuitively plausible and consistent with hypertrophic obstructive changes similar to IHPS observed in hyperplastic rat ileum after artificially induced mechanical obstruction, there is no direct evidence of this phenomenon. Further complicating the association is the limitations of our knowledge about the pathophysiology of IHPS, including numerous genetic abnormalities, increased parietal cell mass, and gastric hyperacidity. The implications of the reported findings with erythromycin on the benefit-risk profiles of newer macrolides and azalides must be considered. The available data on the comparative gastrokinetic properties of macrolides are significant for the potent gastrokinetic properties and its acid degradation products, the marked variation in gastrokinetic properties associated with macrolide ring size, and the requirement for specific glycosidic linkages at the C-3 and C-5 carbons of the macrolide ring. The variation in gastrokinetic properties associated with variations in molecular structure suggests that if the association between erythromycin and IHPS is causal it may not be a class effect.

Lack of bioequivalence of levofloxacin when coadministered with a mineral-fortified breakfast of juice and cereal.

Previous studies have demonstrated that the chelation interactions demonstrated between fluoroquinolones and antacids also occur when they are coadministered with mineral-fortified foods. This study was conducted to evaluate the bioequivalence of levofloxacin when administered in a fasting state as compared to when it was administered with a common breakfast of calcium-fortified orange juice and ready-to-eat cereal. Fourteen of 16 healthy volunteers completed this study and received 500 mg of levofloxacin with each of the following: (1) 12 ounces of water, (2) subject-measured portions of juice and cereal, and (3) subject-measured portions of juice and cereal with milk. Plasma samples were collected prior to dosing and for up to 48 hours after. The results demonstrated that neither fed phase was bioequivalent to the fasting arm in terms of Cmax (with milk, 79.2% [72.6%, 85.7%]; without milk, 79.1% [73.3%, 84.9%]). In addition, a weak correlation was identified between the amount of change in 24-hour exposure and mineral fortification. The results of this study further demonstrate a need to require additional fed-fasted bioequivalence studies for drugs that demonstrate no interaction with the FDA meal but have significant interactions with drugs or supplements that contain large amounts of multivalent ions.

Lack of bioequivalence of gatifloxacin when coadministered with calcium-fortified orange juice in healthy volunteers.

Previous work has demonstrated that the chelation interaction seen with ciprofloxacin when it is coadministered with antacids also happens when it is coadministered with calcium-fortified foods. This study was conducted to study whether this was a drug-specific finding or whether the interaction occurs with other members of the fluoroquinolone class of drugs. Sixteen healthy volunteers received single 400-mg oral doses of gatifloxacin with 12 ounces each of water, nonfortified orange juice, and calcium-fortified orange juice and had plasma samples drawn for assay over the subsequent 48 hours. Results demonstrated significant increases in total oral clearance (15%) and volume of distribution (13%) along with a matching significant decrease (12%) in exposure (AUC) when gatifloxacin was taken with the fortified juice. Although not statistically significant, peak concentrations decreased by 15% and were reached (tmax) approximately 38% later when gatifloxacin was coadministered with the calcium-fortified juice. Bioavailability testing indicated that although the 90% confidence intervals (CIs) for the ratio of the geometric means of the calcium-fortified juice and water arms' AUC stayed within the range of 80% to 125%, those for Cmax did not. This study demonstrated a chelation or adsorption interaction between the fortified juice and gatifloxacin that reached regulatory significance. As a result, clinicians may wish to instruct patients to take gatifloxacin either with nonfortified foods or on an empty stomach.

Lack of bioequivalence when levofloxacin and calcium-fortified orange juice are coadministered to healthy volunteers.

Chelation interactions between drugs/supplements that contain large amounts of multivalent ions and the fluoroquinolones have been known for quite some time. However, there has been a lack of taking this interaction into account when they may be coadministered with foods that have been fortified with amounts of multiple multivalent ions that equal or exceed many supplement products. A previous study demonstrated that 12 ounces of calcium-fortified orange juice significantly decreased the bioequivalence of a dose of ciprofloxacin. This study examined, in 16 healthy volunteers, whether 12 ounces of orange juice with and without calcium fortification would demonstrate the same chelation interaction with single doses of levofloxacin. The results of the study demonstrated that both types of juice decreased levofloxacin Cmax values by 14% to 18% and prolonged tmax values by approximately 50%, with calcium-fortified orange juice decreasing Cmax enough to lose bioequivalence as compared to the control arm (89% [78.1%, 99.8%]). Due to the lack of change in overall exposure, it is thought that rather than a chelation interaction, levofloxacin and components of the orange juices competed for intestinal transport mechanisms such as P-glycoprotein and organic anion-transporting polypeptides, which resulted in the discovered interaction. These results further confirm the need to adjust regulatory studies to include bioequivalence/bioavailability studies that contain fortified foods more than high-calorie/high-fat foods to better reflect current American consumption habits.

A study of the interaction potential of azithromycin and clarithromycin with atorvastatin in healthy volunteers.

Atorvastatin is a common option among the HMG-CoA reductase inhibitors for the treatment of lipid disorders because of its excellent lipid-lowering efficacy and overall safety profile. Although these agents can rarely cause rhabdomyolysis by themselves, macrolides, among other agents, have been demonstrated to increase the likelihood of this via inhibition of CYP metabolism of the lipid agent. This study investigated the potential for azithromycin and clarithromycin to inhibit the metabolism of atorvastatin. Although there was no interaction between azithromycin and atorvastatin, clarithromycin did have a significant effect on atorvastatin pharmacokinetic parameters. When coadministered, clarithromycin raised subject exposure (AUC24) by 82% and peak plasma concentrations by 56%. These data suggest that while azithromycin appears to be safe to coadminister with atorvastatin, clarithromycin should be avoided in patients taking this and similarly metabolized HMG-CoA inhibitors.

Lack of bioequivalence of ciprofloxacin when administered with calcium-fortified orange juice: a new twist on an old interaction.

Fluoroquinolones are known to interact with drugs containing multivalent ions. Current Food and Drug Administration (FDA) labeling states that ciprofloxacin and most other fluoroquinolones are safe to be given with food and dietary calcium but not calcium supplements. Although many of the currently marketed calcium fortified foods have calcium contents that usually exceed those in dietary calcium sources, it is unclear whether they represent a risk for less than optimal absorption of fluoroquinolones, which may result in subsequent clinical failures due to lack of bacterial eradication and antibiotic resistance. The purpose of this three-way, randomized, crossover study was to characterize and compare the bioequivalence of single doses of oral ciprofloxacin in 15 healthy volunteers when administered with water, concurrently with orange juice, and concurrently with calcium-fortified orange juice. Compared to the control arm, the Cmax of ciprofloxacin significantly decreased when it was given with orange juice (23%, p = 0.001) and with calcium-fortified orange juice (41%, p < 0.001). Twenty-four-hour ciprofloxacin AUCs were also decreased for both forms of the orange juice (22% [p < 0.001] and 38% [p < 0.001], respectively). When compared to each other, neither of the orange juice regimens were bioequivalent to each other, with the Cmax and AUC for the fortified form being 22% (p = 0.005) and 21% (p = 0.015) lower than those of the nonfortified form. By FDA standards, although ciprofloxacin is marginally bioequivalent when administered with orange juice, it is not when it is administered with calcium-fortified orange juice. The changes in Cmax and AUC have the potential to significantly decrease clinical efficacy and promote antibiotic resistance. Not warning patients about potential food-drug interactions with fortified foods may be a major unrealized and unstudied inadvertent source of clinical failures and resistance trends with fluoroquinolones.

Characterization of the penetration of garenoxacin into the breast milk of lactating women.

The primary objective of this study was to characterize the extent of excretion of garenoxacin, a novel des-F(6)-quinolone antimicrobial, into the breast milk of lactating women. A secondary objective was to determine the time after dose administration that garenoxacin was no longer detected in breast milk so as to define when a mother may resume breastfeeding if it was interrupted for garenoxacin administration. Six healthy, lactating women (age [mean +/- SD]: 32 +/- 6 years; weight: 68.3 +/- 19.8 kg; body mass index: 26 +/- 5 kg/m(2)) who had completed weaning their infants were administered a single 600-mg oral dose of garenoxacin. Plasma samples were collected predose and repeatedly up to 72 hours postdose. Breast milk was collected predose and for 6- to 12-hour intervals repeatedly up to 120 hours postdose. Breast milk/plasma concentration ratios for garenoxacin ranged from 0.35 to 0.44 up to 24 hours postdose, and the mean peak breast milk concentration was 3.0 microg/mL (0- to 6-h collection interval). Overall, garenoxacin exposure in breast milk was minimal, with a mean of 0.07% of the administered dose recovered within 120 hours. Indeed, garenoxacin was undetectable in the breast milk of a majority of subjects within 84 hours of dosing. As such, an infant nursing from a mother who had received a single 600-mg oral dose of garenoxacin could theoretically be exposed to 0.42 mg of garenoxacin (0.105 mg/kg/day for a 4-kg infant over the period of 5 days of nursing). If extrapolated to a 14-day course of garenoxacin 600 mg once daily, total exposure would be approximately 5.88 mg. These findings indicate that, like other quinolone antimicrobials, garenoxacin is secreted in breast milk.

Comparative efficacies and tolerabilities of intravenous azithromycin plus ceftriaxone and intravenous levofloxacin with step-down oral therapy for hospitalized patients with moderate to severe community-acquired pneumonia.

OBJECTIVE: To compare the efficacy and tolerability of ceftriaxone plus azithromycin with those of levofloxacin in the treatment of hospitalized patients with moderate to severe community-acquired pneumonia (CAP). DESIGN: Randomized, open-label multicenter trial with 1 : 1 treatment allocation in an inpatient setting. PATIENTS: 212 male or female inpatients with a clinical diagnosis of CAP were included in the study. In each treatment group >50% of patients had a pneumonia severity index of IV or V. INTERVENTIONS: Open-label treatment with either intravenous (IV) ceftriaxone 1g and IV azithromycin 500 mg daily or IV levofloxacin 500 mg daily. Patients who improved clinically were switched to oral follow-on therapy with either azithromycin 500 mg/day or levofloxacin 500 mg/day. At the clinician's discretion, oral cefuroxime axetil was added to the treatment regimen of patients who received oral azithromycin if a macrolide resistant pneumococcal isolate was documented. RESULTS: Overall, both study treatments were well tolerated. Favorable clinical outcomes in clinically evaluable patients were demonstrated in 91.5% of patients treated with ceftriaxone plus azithromycin and 89.3% (95% CI -7.1%, 11.4%) of patients treated with levofloxacin at the end of therapy visit and in 89.2% and 85.1% (95% CI -6.7%, 14.8%) patients, respectively, at the end of study visit. Bacteriological eradication rates for both treatments were equivalent with the exception of Streptococcus pneumoniae; 44% of isolates were eradicated with levofloxacin compared with 100% of isolates with ceftriaxone plus azithromycin. CONCLUSIONS: As acknowledged by international CAP treatment guidelines, the combination of a third-generation cephalosporin and a macrolide is at least as efficacious as monotherapy with a fluoroquinolone with enhanced anti-pneumococcal activity, for hospitalized patients with moderate to severe CAP. Combined medication with a macrolide and third-generation cephalosporin may be preferred over fluoroquinolones as first-line therapy of hospitalized patients with CAP to minimize the development of multiresistant nosocomial Gram-negative bacilli.

The effect of azithromycin on ivermectin pharmacokinetics--a population pharmacokinetic model analysis.

BACKGROUND: A recent drug interaction study reported that when azithromycin was administered with the combination of ivermectin and albendazole, there were modest increases in ivermectin pharmacokinetic parameters. Data from this study were reanalyzed to further explore this observation. A compartmental model was developed and 1,000 interaction studies were simulated to explore extreme high ivermectin values that might occur. METHODS AND FINDINGS: A two-compartment pharmacokinetic model with first-order elimination and absorption was developed. The chosen final model had 7 fixed-effect parameters and 8 random-effect parameters. Because some of the modeling parameters and their variances were not distributed normally, a second mixture model was developed to further explore these data. The mixture model had two additional fixed parameters and identified two populations, A (55% of subjects), where there was no change in bioavailability, and B (45% of subjects), where ivermectin bioavailability was increased 37%. Simulations of the data using both models were similar, and showed that the highest ivermectin concentrations fell in the range of 115-201 ng/mL. CONCLUSIONS: This is the first pharmacokinetic model of ivermectin. It demonstrates the utility of two modeling approaches to explore drug interactions, especially where there may be population heterogeneity. The mechanism for the interaction was identified (an increase in bioavailability in one subpopulation). Simulations show that the maximum ivermectin exposures that might be observed during co-administration with azithromycin are below those previously shown to be safe and well tolerated. These analyses support further study of co-administration of azithromycin with the widely used agents ivermectin and albendazole, under field conditions in disease control programs.

Regulatory disincentives for developing antibiotics for common indications.

Pediatric and adult community-acquired respiratory tract infections remain some of the most common reasons for visits to primary care practitioners, and the antibiotics used to treat them are historically highly profitable for their manufacturers. Despite these facts and the continued evolving need for new treatments for these infections, virtually no new agents have been developed in the past decade. This review explores some regulatory guidelines that could potentially explain the dearth of development, and it provides some practical answers for resolving them.