Guy W. Amsden

Azithromycin: The First Azalide Antibiotic

OBJECTIVE: To discuss the chemistry, mechanism of action, spectrum of activity, pharmacokinetics, clinical trials, adverse-effect profile, drug interactions, and dosage guidelines of azithromycin, the first azalide antibiotic. DATA SOURCES: Pertinent literature published between 1988 and the present was identified via a MEDLINE search. Of 77 articles retrieved, 37 have been referenced. STUDY SELECTION: Azithromycin is a new agent, and as such, limited data regarding this drug are available in the literature. We evaluated all pharmacokinetic, microbiologic, and basic science articles pertaining to azithromycin, and reviewed the clinical efficacy trials that we believed were of good quality for each indication for which azithromycin has received approval to date. Comparative clinical trials involving large numbers of patients, clinical outcome assessments, and recommendations for azithromycin use are included. DATA SYNTHESIS: Azithromycin is a macrolide derivative and the first of the 15-membered ring azalide class of antimicrobials. Although its mechanism of action and susceptibility to resistance are similar to those of the macrolide antibiotics, azithromycins extended spectrum of activity includes gram-positive and gram-negative organisms, as well as atypical pathogens. Azithromycin is stable at gastric pH and has an absolute bioavailability of approximately 37 percent following oral administration. Although its serum concentrations are typically low, the drug concentrates to a high degree in tissue. Azithromycin is cleared primarily by the biliary and fecal routes; its serum half-life is in excess of 60 hours. Several clinical trials have proven that a 5-day course of azithromycin administered once a day is equally efficacious to a 7- to 14-day course of other commonly used oral antimicrobials, administered two to four times a day, for the treatment of upper and lower respiratory tract and skin and skin-structure infections. Urethritis and cervicitis caused by chlamydia are treated with a single 1-g dose. Trials have shown azithromycins adverse-effect profile to be equal or even superior to that of other agents, with only 0.7 percent of patients discontinuing therapy versus 2.6 percent for comparable drugs. CONCLUSIONS: Azithromycin represents a significant improvement in the treatment of selected community-acquired infections. Although this agent may revolutionize the treatment of sexually transmitted diseases caused by chlamydia, it also should impact the management of respiratory tract and skin and skin-structure infections. Because of its unique pharmacokinetics and excellent adverse-effect profile, patient compliance should be greatly enhanced compared with other commonly used oral antimicrobials. Azithromycins primary role in the near future will be in the community setting. Although its use in the hospital may be limited, this drug will be a convenient therapeutic option to have on hand in the emergency room and outpatient clinic. Azithromycin may also be used in the future to treat opportunistic infections in immunocompromised patients.

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.

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.

Telithromycin: The First of the Ketolides

OBJECTIVE: To review the chemistry, spectrum of activity, pharmacology, clinical efficacy, and safety of telithromycin. DATA SOURCES: A MEDLINE search from 1966 to December 2000 was performed via OVID and PubMed using the following search terms: HMR 3647, HMR3647, Ketek, RU 66647, and telithromycin. An extensive review of retrieved literature, abstracts from international scientific conferences, and minutes from regulatory authority meetings was also performed. DATA EXTRACTION: Medicinal chemistry, in vitro, animal, and human trials were reviewed for information on the antimicrobial activity, clinical efficacy, pharmacology, and safety of telithromycin. DATA SYNTHESIS: Several chemical modifications to the macrolide structure have led to the development of telithromycin, the first ketolide antimicrobial that demonstrates improved activity against penicillin- and macrolide/azalide-resistant Streptococcus pneumoniae due to its unique binding to the ribosomal target site. Although telithromycin may be useful in the treatment of community-acquired respiratory tract infections due to its activity against common typical and atypical pathogens, questions concerning its reliable activity against Haemophilus influenzae need to be addressed. Telithromycins pharmacokinetics permit once-daily dosing for abbreviated periods and good distribution into lung tissue and phagocytic cells. Clinical and bacteriologic cure rates have been similar to those of comparator agents in human efficacy trials; however, the incidence of adverse gastrointestinal events were generally higher with telithromycin patients. Like other macrolides and many newer fluoroquinolones, telithromycins ability to prolong the QTc interval is a potential safety issue, especially in elderly patients with predisposing conditions or those who are concurrently receiving drugs that are substrates for CYP2D6 and 3A4. Liver function test elevations demonstrated during clinical trials, although not overtly severe, may warrant monitoring in some patients taking multiple hepatically metabolized/cleared agents. CONCLUSIONS: Telithromycin offers potential advantages over traditional macrolides/azalides for community-acquired respiratory tract infections caused by macrolide-resistant pathogens. Further studies are needed to elucidate its clinical efficacy against H. influenzae, potential drug interactions, and safety in various subpopulations.

Pharmacokinetics of Oral Azithromycin in Serum, Urine, Polymorphonuclear Leucocytes and Inflammatory vs Non-Inflammatory Skin Blisters in Healthy Volunteers.

SummaryTwo open-label studies were conducted to assess the serum, urine, polymorphonuclear (PMN) and red blood cell (RBC) pharmacokinetics of a 5-day course (1500mg total) of oral azithromycin. Inflammatory and non-inflammatory blisters were also induced to study the propensity of azithromycin to preferentially concentrate at a model infection site. 14 subjects participated in the two studies and tolerated azithromycin and the study methods well. Comodelling of the serum and urine data demonstrated very extensive distribution into peripheral compartments, low renal clearance (7% of total oral clearance) and an extended terminal half-life (79 hours). PMN leucocyte concentrations peaked at 119 mg/L following the final dose and remained above 60 mg/L 7 days after the final dose. The ratio of blister to serum AUCs was significantly higher in inflammatory (2.2) vs non-inflammatory (1.2) blisters (p < 0.02). The extensive uptake of azithromycin into PMNs coupled with the accumulation of azithromycin into an inflammatory compartment (e.g. infection site) support the hypothesis that PMN leucocytes laden with azithromycin migrate to sites of inflammation, thereby enhancing local concentrations. These studies further demonstrate the unique pharmacokinetic properties of azithromycin and its preferential delivery by phagocytes to the site of infection.

A Study of the Pharmacokinetics of Azithromycin and Nelfinavir When Coadministered in Healthy Volunteers

A two‐way, open‐label, crossover study in 12 subjects was undertaken to study the potential for azithromycin to alter the pharmacokinetics of nelfinavir and/or its active metabolite, M8. A secondary objective was to characterize any potential interaction that nelfinavir may have with azithromycin. During one dosing arm, subjects received a single 1200 mg oral dose of azithromycin. During the other, subjects received 11 days of nelfinavir 750 mg q8h with a single 1200 mg oral dose of azithromycin given concurrently with the Day 9 morning nelfinavir dose. Serum samples were collected after each azithromycin dose for 168 hours and after the Day 8 and 9 morning nelfinavir doses for 8 hours to characterize azithromycin, nelfinavir, and M8 pharmacokinetic parameters during both control and test periods. Both dosing regimens were well tolerated, with only mild to moderate GI side effects being the most frequently reported. Azithromycin was found to cause a statistically, though not clinically, significant decrease in nelfinavir and M8 exposures. In contrast, nelfinavir caused azithromycin Cmax and exposure (AUC) values to increase by > 100%. Inhibition of p‐glycoprotein by nelfinavir may be responsible for this significant interaction. This increase in azithromycin exposure has the potential to increase clinical antibacterial efficacy without significantly increasing gastrointestinal side effects, though the impact on other systemic sites needs to be studied.

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.

Comparison of the plasma, urine and blister fluid pharmacokinetics of clarithromycin and azithromycin in normal subjects

SummaryThis open-label, multiple-dose study was intended to evaluate the pharmacokinetics of clarithromyin and azithromycin in plasma/serum, urine, and inflammatory and noninflammatory blister fluid, in 8 normal subjects. Co-modelling of the plasma/serum and urine data for each drug produced complex multicompartment models. Observed versus fitted drug concentration analyses evidenced a good fit of the data, despite moderate coefficient of variation values for all parameters. Blister fluid analyses demonstrated significant concentrating of both drugs in inflammatory versus noninflammatory conditions (areas under the blister fluid concentration versus time curves 31.6 versus 11.2 mg·h/L for clarithromycin and 2.88 versus 0.07 mg·h/L for azithromycin), although there was no significant difference in degree of accumulation between the agents. The results of this study are consistent with previous reports demonstrating white blood cell delivery of clarithromycin and azithromycin, and the concentrating of these agents in inflamed/infected areas.

Trovafloxacin: An Overview

Trovafloxacin, a new synthetic naphthyridine fluoroquinolone antibiotic, is a broad‐spectrum agent available orally and intravenously. It was recently approved by the Food and Drug Administration for the treatment of selected pulmonary, surgical, intraabdominal, gynecologic, pelvic, skin, and urinary tract infections. Its spectrum of activity includes aerobic gram‐positive and gram‐negative organisms as well as anaerobic pathogens. It is rapidly absorbed after oral administration, achieves good tissue and cerebrospinal fluid penetration, and has a half‐life that allows once‐daily dosing. It is hepatically metabolized, and dosage adjustments are necessary for patients with severe hepatic dysfunction but not for those with mild or moderate dysfunction or renal dysfunction. The drug has a favorable safety profile, and a high tendency for transient first‐dose dizziness and/or lightheadedness in young women. Similar to other quinolones, trovafloxacin should not be taken with antacids that contain aluminum or magnesium, sucralfate, or ferrous sulfate. Trovafloxacin may prove beneficial as it allows for oral or intravenous monotherapy against indicated infections that normally require multidrug, broad‐spectrum antibiotic coverage.

Review and comparison of advanced-generation macrolides clarithromycin and dirithromycin.

We reviewed English‐language clinical studies, abstracts, and review articles identified from MEDLINE searches from January 1966–August 1998, and bibliographies of identified articles to compare advanced‐generation macrolides dirithromycin and clarithromycin and their use for respiratory tract infections. Both agents have superior adverse effect profiles compared with erythromycin, the original macrolide. Both have broad antibacterial coverage, but clarithromycin usually has a lower MIC90 to susceptible organisms than dirithromycin; for most isolates this difference is not clinically significant. Clarithromycin has better in vitro coverage of Haemophilus influenzae, but this activity varies with formation of its bioactive metabolite, 14‐hydroxyclarithromycin. Neither agent is ideal for H. influenzae eradication. The agents differ markedly in terms of pharmacokinetics, pharmacodynamics, metabolism, and cost, and thus with respect to drug interaction profiles and dosages. Dirithromycins drug interaction profile is markedly better than clarithromycins. Clarithromycin is dosed twice/day; dirithromycins pharmacokinetics allow once/day dosing. Dirithromycin is less expensive with regard to both cost/day and cost/treatment regimen. Clarithromycin has been studied and approved for administration to children. In adults with respiratory tract infections who are receiving drugs that would interact with clarithromycin, and in those with renal dysfunction with or without coexisting hepatic dysfunction, dirithromycin appears to be superior in terms of safety and equivalent to clarithromycin in terms of efficacy.