Anti-inflammatory effects of macrolides--an underappreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflammatory pulmonary conditions?

BACKGROUND: It has been recognized for more than 20 years that the macrolides have immunomodulatory effects that are beneficial for those suffering from chronic pulmonary inflammatory syndromes, such as diffuse panbronchiolitis, cystic fibrosis, asthma and bronchiectasis. The macrolides have consistently been associated with decreased length of stay and mortality when used alone or in combination with beta-lactam antibiotics. This effect can be demonstrated against combinations consisting of beta-lactams and other antibiotics active against 'atypical chest pathogens' when treating community-acquired pneumonia (CAP) in hospitalized patients. As such, it appears that the macrolides' effects in CAP patients are more than just antibacterial in nature. AIMS OF THIS REVIEW: This review aims: to give the reader information on the background areas described, as well as related areas; to review the CAP benefits with macrolides and how they may be related to the immunomodulatory properties they demonstrate, albeit in a shorter period of time than previously demonstrated with chronic pulmonary disorders; to use ex vivo data to support these extrapolations. LITERATURE SEARCH: A literature search using Medline was conducted from 1966 onwards, searching for articles with relevant key words such as macrolide, diffuse panbronchiolitis, community-acquired pneumonia, biofilm, immunomodulation, cystic fibrosis, erythromycin, clarithromycin, roxithromycin and azithromycin, bronchiectasis and asthma. When appropriate, additional references were found from the bibliographies of identified papers of interest. Any relevant scientific conference proceedings or medical texts were checked when necessary. CONCLUSIONS: (1) Research into macrolide immunomodulation for chronic pulmonary disorders demonstrates consistent positive effects, although of types other than seen with diffuse panbronchiolitis. These effects, together with their inhibitory activity on biofilms, have the potential to make them a useful option. (2) The benefits for CAP are consistent, and higher when a macrolide is given with another atypical agent than if the other atypical agent is given alone, suggesting a non-antibacterial benefit. (3) Recent research of the immunomodulatory properties of azithromycin imply that azithromycin may have a previously unknown short-term biphasic effect on inflammation modulation: enhancement of host defence mechanisms shortly after initial administration followed by curtailment of local infection/inflammation in the following period. (4) Additional in vivo research is needed prior to developing any firm conclusions.

Pharmacokinetics of intravenous azithromycin and ceftriaxone when administered alone and concurrently to healthy volunteers.

This study was conducted to identify whether or not a pharmacokinetic interaction existed when azithromycin and ceftriaxone were administered concurrently. This randomized, open-label, three-way crossover study in 12 healthy volunteers characterized the plasma pharmacokinetic parameter profiles of both drugs, as well as the white blood cell uptake and exposure to azithromycin, when the drugs were administered alone and together. The plasma pharmacokinetic parameters for azithromycin and ceftriaxone did not differ significantly either after a single dose or at steady state when the two were co-administered as opposed to being administered alone. Moreover, the neutrophil and monocyte/lymphocyte peak azithromycin concentrations and sampling period exposures also did not differ significantly between the study arm and the control arm. This study confirms that there is no interaction between azithromycin and ceftriaxone when they are administered concurrently.

Advanced-generation macrolides: tissue-directed antibiotics.

The azalide antibiotic azithromycin and the newer macrolides, such as clarithromycin, dirithromycin and roxithromycin, can be regarded as 'advanced-generation' macrolides compared with erythromycin, the first macrolide used clinically as an antibiotic. Their pharmacokinetics are characterized by a combination of low serum concentrations, high tissue concentrations and, in the case of azithromycin, an extended tissue elimination half-life. Azithromycin is particularly noted for high and prolonged concentrations at the site of infection. This allows once-daily dosing for 3 days in the treatment of respiratory tract infections, in contrast to longer dosage periods required for erythromycin, clarithromycin, roxithromycin and agents belonging to other classes of antibiotics. The spectrum of activity of the advanced-generation macrolides comprises Gram-positive, atypical and upper respiratory anaerobic pathogens. Azithromycin and the active metabolite of clarithromycin also demonstrate activity against community-acquired Gram-negative organisms, such as Haemophilus influenzae. Advanced-generation macrolides, and in particular azithromycin, are highly concentrated within polymorphonuclear leucocytes, which gravitate by chemotactic mechanisms to sites of infection. Following phagocytosis of the pathogens at the infection site, they are exposed to very high, and sometimes cidal, intracellular concentrations of antibacterial agent. Pharmacodynamic models and susceptibility breakpoints derived from studies with other classes of drugs, such as the beta-lactams and aminoglycosides, do not adequately explain the clinical utility of antibacterial agents that achieve high intracellular concentrations. In the case of azithromycin, attention should focus on tissue pharmacokinetic and pharmacodynamic concepts.

Pneumococcal resistance: the treatment challenge.

OBJECTIVE: To review in vitro and in vivo information dealing with pneumococcal antibiotic resistance and provide a review of the incidence, mechanisms, and controversies surrounding this growing problem. The review is also intended to provide clinicians with relevant recommendations on treatment and prevention of this organism. DATA SOURCES AND SELECTION: Primary and review articles were identified by MEDLINE search (1966-August 2000) and through secondary resources such as conference proceedings. All of the articles identified from the data sources were evaluated, and all information deemed relevant was included in this review. DATA SYNTHESIS: The growing incidence and reporting of pneumococcal isolates that are resistant to one or more classes of antibiotics have become a troubling trend that has resulted in significant shifts in treatment. Although clinicians have shifted to a new generation or class of antibiotics when faced with a resistance trend, data with resistant pneumococci show that this may not be necessary. By incorporating the pharmacokinetic and pharmacodynamic data of antimicrobials into the decision-making process, many of the drugs that we have become hesitant to use due to this resistance may still be appropriate if used correctly. CONCLUSIONS: Appropriate dosing of antimicrobials, combined with optimal use of pneumococcal vaccines, will not only prolong the longevity of some agents, but also hopefully slow resistance development.

Interpretation of antibacterial susceptibility reports: in vitro versus clinical break-points.

Currently, antibacterial activity is measured primarily via in vitro laboratory tests. Clinicians rely heavily upon the reported susceptibility gained via in vitro laboratory tests when choosing an antibacterial agent. An evolving concept is to utilise pharmacodynamic and pharmacokinetic drug properties in addition to in vitro susceptibility reports to assess the potential effectiveness of an antibacterial agent against a specific pathogen. This article presents examples of the utility of these concepts in terms of optimal clinical use of common antibacterials as well as more informed interpretation of the in vitro literature.

Serum and WBC pharmacokinetics of 1500 mg of azithromycin when given either as a single dose or over a 3 day period in healthy volunteers.

Owing to azithromycin's prolonged half-life, shorter and shorter dosage regimens are being studied for treatment of respiratory tract infections. Previous studies have concluded that the 3 and 5 day (1.5 g total) regimens not only provide at least equal serum and WBC exposures but also equal efficacy rates. An earlier clinical study using the entire 1.5 g dose at once or the current 3 day regimen in patients with atypical pneumonia noted equal efficacy. Similar trials are currently underway in both adult and paediatric populations. The goal of the present study was to investigate whether there were equal serum and WBC exposures when azithromycin was dosed as the current 3 day regimen or as a single large dose. Equal exposures would help validate future clinical trials of single dose regimens. Twelve healthy volunteers received both azithromycin regimens (1.5 g single dose and 500 mg/day for 3 days) in random order. Serum and WBC samples were collected at baseline and repeatedly for 10 days following the first dose of each regimen. Serum samples were assayed via HPLC (CV% < 10) and WBC samples via liquid chromatography/mass spectrometry (CV% < 10). Data were modelled using noncompartmental methods. Statistics were via ANOVA with significance defined as P < 0.05. All subjects completed both regimens with minimal incidence of adverse effects. Serum data [mean (range)] demonstrated no significant difference in exposure between the two regimens [single 13.1 (3.02-20.6) mg x h/L versus 3 day 11.2 (2.98-24.5) mg x h/L: P = 0.12], although it favoured the shorter regimen. WBC results demonstrated much higher exposures than seen with serum, but no significant difference between the two regimens was identified. These results suggest that a single oral 1.5 g regimen of azithromycin for respiratory tract infections should provide exposure at least equal to currently approved treatment regimens.

Plasma Pharmacokinetics and Tissue Penetration of Alatrofloxacin in Morbidly Obese Individuals.

OBJECTIVES: To characterise the peritoneal and subcutaneous adipose penetration of alatrofloxacin. If the extent of penetration of this lipophilic fluoroquinolone is adequate in patients with extensive adipose layers, it may provide better antimicrobial coverage than more commonly used antibiotics that are less lipophilic. STUDY PARTICIPANTS AND METHODS: Six morbidly obese individuals undergoing a Roux-Y gastric bypass procedure received single 1-hour infusions of alatrofloxacin equivalent to 300mg of its active metabolite, trovafloxacin. Blood samples were obtained over a 24-hour period and adipose tissue from subcutaneous and deep tissue sites were obtained approximately 3 hours post-infusion of alatrofloxacin. Plasma and adipose tissue concentrations of trovafloxacin were determined by high pressure liquid chromatography with fluorescence detection. RESULTS: The mean maximum plasma concentration, area under the concentration-time curve, and elimination half-life of trovafloxacin were 3.6 mg/L, 37.4 mg/L·h, and 12.1h, respectively. The mean tissue concentrations at the subcutaneous and deep adipose sites were 0.43 and 0.41 µ/g, respectively. CONCLUSIONS: These results indicated that the pharmacokinetics of trovafloxacin in morbidly obese individuals are similar to those in healthy control individuals. In addition, the concentrations of trovafloxacin achieved in the adipose tissue were above the minimum inhibitory concentration of most pathogens responsible for surgical and decubitus ulcer infections.

Macrolide drug interactions: an update.

OBJECTIVE: To describe the current drug interaction profiles for the commonly used macrolides in the US and Europe, and to comment on the clinical impact of these interactions. DATA SOURCES: A MEDLINE search (1975-1998) was performed to identify all pertinent studies, review articles, and case reports. When appropriate information was not available in the literature, data were obtained from the product manufacturers. STUDY SELECTION: All available data were reviewed to provide an unbiased account of possible drug interactions. DATA EXTRACTION: Data for some of the interactions were not available from the literature, but were available from abstracts or company-supplied materials. Although the data were not always explicit, the best attempt was made to deliver pertinent information that clinical practitioners would need to formulate practice opinions. When more in-depth information was supplied in the form of a review or study report, a thorough explanation of pertinent methodology was supplied. DATA SYNTHESIS: Several clinically significant drug interactions have been identified since the approval of erythromycin. These interactions usually were related to the inhibition of the cytochrome P450 enzyme systems, which are responsible for the metabolism of many drugs. The decreased metabolism by the macrolides has in some instances resulted in potentially severe adverse events. The development and marketing of newer macrolides are hoped to improve the drug interaction profile associated with this class. However, this has produced variable success. Some of the newer macrolides demonstrated an interaction profile similar to that of erythromycin; others have improved profiles. The most success in avoiding drug interactions related to the inhibition of cytochrome P450 has been through the development of the azalide subclass, of which azithromycin is the first and only to be marketed. Azithromycin has not been demonstrated to inhibit the cytochrome P450 system in studies using a human liver microsome model, and to date has produced none of the classic drug interactions characteristic of the macrolides. CONCLUSIONS: Most of the available data regarding macrolide drug interactions are from studies in healthy volunteers and case reports. These data suggest that clarithromycin appears to have an interaction profile similar to that of erythromycin. Given this similarity, it is important to consider the interaction profile of clarithromycin when using erythromycin. This is especially necessary as funds for further studies of a medication available in generic form (e.g., erythromycin) are limited. Azithromycin has produced few clinically significant interactions with any agent cleared through the cytochrome P450 enzyme system. Although the available data are promising, the final test should come from studies conducted in patients who are taking potentially interacting compounds on a chronic basis.

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.

Azithromycin: indications for the future?

The global challenge of optimally treating bacterial infections is continuously evolving. Azithromycin, the first azalide antibiotic, presents pharmacokinetics and pharmacodynamics that allow for a simple dosing regimen with minimal side effects. Current azithromycin uses include a variety of community-acquired respiratory tract, skin and soft tissue, and sexually transmitted disease infections. Azithromycin has also demonstrated substantial activity against atypical organisms such as Mycobacterium avium complex (MAC) and Chlamydia trachomatis. Due to a never-ending need for new antibiotic therapies, several other potential indications for azithromycin are being researched. This article will present various current research associated with azithromycin's potential use for malaria, trachoma, coronary artery disease (CAD), Pseudomonas aeruginosa infections, erythema migrans, short-term therapy for respiratory infections, typhoid, cryptosporidiosis, pelvic inflammatory disease, acne, Mediterranean spotted fever and MAC. As bacterial and parasite resistance patterns fluctuate globally, azithromycin may be an alternative therapy for the previously mentioned indications, which will also enhance patient compliance and therefore effectively eradicate infection worldwide.

Pharmacokinetic study of azithromycin with fluconazole and cotrimoxazole (trimethoprim-sulfamethoxazole) in healthy volunteers.

BACKGROUND: Azithromycin, fluconazole and cotrimoxazole (trimethoprim-sulfamethoxazole; TMP/SMX) are all agents that are utilised for the treatment and/or prophylaxis of opportunistic infections in patients with AIDS. OBJECTIVE: To characterise the potential for an interaction when azithromycin is coadministered with cotrimoxazole or with fluconazole. DESIGN: Two separate nonblind randomised studies were conducted in healthy volunteers. During the fluconazole study the potential for fluconazole to adversely affect the pharmacokinetics of azithromycin was also studied. PARTICIPANTS: 24 (cotrimoxazole) and 18 (fluconazole) healthy male and female volunteers. RESULTS: The results of both studies indicated that neither the peak concentrations of nor the exposures (area under the concentration-time curve) to the test drugs were changed when azithromycin was coadministered. In addition, fluconazole did not significantly alter the pharmacokinetic parameters of azithromycin. CONCLUSIONS: Azithromycin does not alter the bioavailability of either cotrimoxazole or fluconazole.

Pneumococcal macrolide resistance--myth or reality?

There is no doubt that owing to the prolific use of the macrolides and azithromycin over the past several years, resistance has developed and is increasing in incidence. I believe we should re-evaluate the use of these antibiotics for our patients and consider parameters other than the negative in-vitro results. Firstly, microbiology laboratories should return to the habit of providing the clinician with MIC values for pathogenic isolates rather than generic susceptibility reports ((S)usceptible, (I)ntermediate, (R)esistant) that are based on standard disc diffusion testing. Although agar dilution MIC testing is a bulky and labour intensive practice, it provides the best data when conducted in the appropriate environment. Secondly, and more importantly, these MIC values need to be compared with in-vivo antibiotic pharmacokinetics and pharmacodynamics. Although it is possible to compare MIC values directly with serum concentrations of beta-lactams and aminoglycosides, this is not a valid practice for azithromycin or the macrolides. MICs of azithromycin and the macrolides must be compared with the infection site and phagocytic cell concentrations to determine the utility, or lack thereof, of one of these agents. Whereas azithromycin cellular penetration allows maximal pharmacodynamics potentially even against moderately or highly resistant pneumococci, the macrolides do so less optimally. Although there are no reports of widespread clinical failures resulting from macrolide/azalide resistance in pneumococci, it is expected that such reports will appear once the isolates become consistently highly resistant. This is likely to affect the macrolides, erythromycin and clarithromycin, before the azalide, azithromycin owing to the differences in pharmacokinetics of these drugs. Until then, it will be important to determine the MICs of not just one macrolide, but of all macrolides and azalides for the isolates. This will allow the clinician to make a pharmacokinetically and pharmacodynamically sound choice. By choosing clinical MIC breakpoints of 4-8 mg/L for oral macrolides and < or = 32 mg/L for oral azithromycin, rather than the present standard breakpoints, the clinician can make a macrolide/azalide choice that will optimize the pharmacodynamics of the drug against the isolated pathogen and result in the best possible clinical outcome. Once data concerning the cellular penetration of intravenous formulations of these drugs becomes available, it will be possible to develop clinical breakpoints for these formulations as well. Only through utilizing good antibiotic prescribing practices and by using the drugs appropriately when they are used, can resistance trends be stemmed. In this way, not only does a clinician treat the patient more effectively, but they also extend the antibiotic's useful life.

A randomized, crossover design study of the pharmacology of extended-spectrum fluoroquinolones for pneumococcal infections.

STUDY OBJECTIVES: The objectives of this study were to characterize the single-dose and steady-state plasma pharmacokinetics of IV levofloxacin and IV alatrofloxacin, and to compare the results to pneumococcal isolate sensitivities in order to estimate the clinical efficacy of current community-acquired pneumonia treatment regimens against pneumococcal infections. DESIGN: Two-way, open-label, randomized, crossover study. PARTICIPANTS: Each of 12 healthy volunteer subjects received IV levofloxacin, 500 mg qd for 7 days, and IV alatrofloxacin, 200 mg qd for 7 days. The two regimens were separated by a 2-week washout period. MEASUREMENTS AND RESULTS: Plasma concentration profiles were collected around the first and final doses of both regimens and were assayed for their respective quinolone concentrations. When the peak concentrations for both agents were compared to standard twofold dilution minimum inhibitory concentration (MIC) values for pneumococcal isolates, it was discovered that the breakpoint MIC value at which each compound would no longer achieve a peak plasma concentration/MIC ratio of at least 12:1 was 0.5 mg/L for levofloxacin and 0.25 mg/L for alatrofloxacin. CONCLUSIONS: Based on the MIC that inhibits 90% of isolates of Streptococcus pneumoniae for both of these agents (1.0 to 2.0 mg/L for levofloxacin and 0.125 to 0.25 mg/L for trovafloxacin), our results indicate that although the once-daily regimen of alatrofloxacin appears to be appropriate for this pathogen, a more aggressive regimen may need to be investigated to optimize the clinical and microbiological effects of levofloxacin.

Lack of effect of dirithromycin on theophylline pharmacokinetics in healthy volunteers.

Twelve healthy volunteers were enrolled in an open-label, randomized, crossover study. Subjects received single doses of theophylline (5 mg/kg) alone and after a 10 day course of dirithromycin (two 250 mg tablets od). The study phases were separated by a 3 week washout period. Serum samples were collected before and for 24 h after theophylline doses. Serum theophylline concentrations were measured via a validated immunoassay system and the data were modelled via non-compartmental analysis. When the control phase (i.e. no dirithromycin) was compared with the treatment phase (i.e. with dirithromycin), theophylline exposures as measured by AUC0-->infinity were not significantly different: 141.7+/-25.9 and 136.4+/-33.1 mg x h/L respectively (P = 0.16). No significant changes in other theophylline pharmacokinetic parameters were evident. These results indicate that theophylline can be safely co-administered with dirithromycin.

Lack of effect of zafirlukast on the pharmacokinetics of azithromycin, clarithromycin, and 14-hydroxyclarithromycin in healthy volunteers.

This randomized, open-label, crossover study was conducted to investigate whether the coadministration of zafirlukast would affect the pharmacokinetics of azithromycin, clarithromycin, or 14-hydroxyclarithromycin (14-OHC). Twelve healthy subjects (six males and six females) received single 500-mg doses of azithromycin and clarithromycin with and without zafirlukast given to a steady-state concentration. Blood was collected prior to all macrolide doses and for 3 and 10 days after each clarithromycin and azithromycin dose, respectively. Serum was assayed for azithromycin, clarithromycin, and 14-OHC concentrations by validated high-performance liquid chromatography assay systems. Data analyses were done by noncompartmental and nonparametric methods. Analysis of the patients indicated that the addition of steady-state concentrations of zafirlukast did not significantly alter the pharmacokinetic parameters of or overall exposure (based on the area under the concentration-time curve) to azithromycin, clarithromycin, and 14-OHC. While zafirlukast is a known inhibitor of CYP3A4, it does not appear to exert a clinically or statistically significant pharmacokinetic effect on azithromycin, clarithromycin, or 14-OHC.

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. Dirithromycin's drug interaction profile is markedly better than clarithromycin's. Clarithromycin is dosed twice/day; dirithromycin's 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.

Pharmacological considerations in the emergence of resistance.

Resistance to macrolides in vitro is increasingly being reported. However, there has been no corresponding increase in clinical failures noted. Lack of clinical failures due to resistance is most likely the result of the high intracellular concentrations that these drugs achieve in phagocytes. In the case of clarithromycin, concentrations in both monocytes and granulocytes fluctuate between peaks of approximately 22-25 mg/l and troughs of approximately 5 mg/l during a standard dosing interval. In contrast, azithromycin attains concentrations of over 60 mg/l in granulocytes and at least 100 mg/l in monocytes. After 7 days, azithromycin concentrations of >32 mg/l are still observed. These data also imply that against pathogens with increasing minimum inhibitory concentrations (MICs), macrolides with relatively lower or less sustained intracellular concentrations will become ineffective clinically much sooner than compounds, such as azithromycin, that concentrate to a high degree and are retained in white blood cells for prolonged periods.

Intravenous azithromycin.

OBJECTIVE: To review the pharmacology, microbiology, chemistry, pharmacokinetics, efficacy, safety, tolerability, dosage, administration, and economic issues of intravenous azithromycin. DATA SOURCES: A MEDLINE search from 1978 to May 1998 of the English-language literature and an extensive review of journals and meeting abstracts was conducted. Due to the lack of published literature concerning the efficacy, safety, and pharmacokinetics of the intravenous formulation of azithromycin, the manufacturer was also contacted and requested to supply information concerning intravenous azithromycin. DATA EXTRACTION: In vitro and preclinical studies were included, as well as data from Phase II and III clinical trials. Efficacy, pharmacokinetic, safety, and tolerability data were also supplemented with information from the manufacturer, due to the lack of published reports. DATA SYNTHESIS: Azithromycin, an azalide subclass of the macrolide antibiotics, is now available as an intravenous formulation. The intravenous form is approved for the treatment of community-acquired pneumonia caused by Chlamydia pneumoniae, Haemophilus influenzae. Legionella pneumophila, Moraxella catarrhalis, Mycoplasma pneumoniae, Staphylococcus aureus (methicillin-sensitive), and Streptococcus pneumoniae, and for the treatment of pelvic inflammatory disease caused by Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma hominis in situations in which intravenous therapy is required. Its spectrum of activity, unique pharmacokinetics, and high and sustained tissue penetration allow for once-daily dosing with monotherapy in many cases. Clinical and bacteriologic response rates as well as the adverse event profile have been similar to or better than comparative agents. CONCLUSIONS: Azithromycin offers advantages over other agents due to its unique pharmacokinetics, high and sustained tissue penetration, and spectrum of activity. This allows for monotherapy and once-daily intravenous dosing for mild-to-moderate community-acquired pneumonia or pelvic inflammatory disease in many instances. Future research should focus on total duration of antibiotic therapy and the need, or lack thereof, for extensive oral antibiotic follow-up.

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.

Pharmacokinetics in serum and leukocyte exposures of oral azithromycin, 1,500 milligrams, given over a 3- or 5-day period in healthy subjects.

The pharmacokinetics in serum and leukocyte (WBC) exposures of 1,500 mg of oral azithromycin administered as 3-day (500 mg/day, days 1 to 3) and 5-day (500 mg on day 1 and 250 mg/day on days 2 to 5) regimens were compared in 12 healthy volunteers. Serum, polymorphonuclear leukocytes, and mononuclear leukocytes were collected over a 12-day period from the start of each regimen. Results of the study indicate that the exposures of serum and both types of WBCs were similar with both regimens. Drug concentrations in day 12 WBCs were well above the MICs for all relevant community-acquired respiratory tract pathogens. Terminal half-lives in serum obtained by both regimens were essentially equal at 66 h and consistent with past reports. These results indicate that the standard 1,500-mg dose of oral azithromycin can be administered over either 5 or 3 days.