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.

The role of advanced generation macrolides in the prophylaxis and treatment of Mycobacterium avium complex (MAC) infections.

Since the start of the acquired immunodeficiency syndrome (AIDS) epidemic, the role of Mycobacterium avium complex (MAC) as an opportunistic pathogen in advanced AIDS patients has become more and more clear. Once identified in an advanced AIDS patient it is possible to find evidence that the MAC organism and infection is not only present in the pulmonary tree, but has also disseminated to a wide variety of body organs. Treatment of MAC or disseminated MAC (DMAC) infections has historically been very difficult due to the inherent resistance of the MAC pathogen to most standard antimycobacterial agents. This has resulted in the development of new agents for the prevention of DMAC infection as well as combinations of both new and standard agents for its treatment. Three drugs are currently approved for single-agent DMAC prophylaxis, including rifabutin, azithromycin and clarithromycin. Combinations of agents for DMAC treatment are highly variable in content but most experts agree that all combinations should contain one of the advanced generation macrolides (azithromycin or clarithromycin). Both of these agents have favourable intracellular pharmacokinetics and pharmacodynamics which maximise their effects against this mostly intracellular pathogen. Due to the paucity of comparative data, no one macrolide can be recommended over the other. However, the expected increase in compliance, lower weekly and annual costs, and lack of any drug interactions may make azithromycin a preferable choice, but this should be decided on a case-by-case basis.

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.

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.

Absence of effect of terbinafine on the activity of CYP1A2, NAT-2, and xanthine oxidase.

Terbinafine is an allylamine antifungal agent used for the treatment of onychomycosis. It has previously been reported to interact with caffeine and is metabolized in part by the cytochrome P450 systems. This open-label, randomized, crossover study was conducted to examine the effect of terbinafine on the activity of cytochrome P450 1A2 (CYP1A2), N-acetyltransferase (NAT-2), and xanthine oxidase (XO). Twelve healthy nonsmoking adult volunteers were enrolled. Each received single doses of caffeine (100 mg), and urine was collected for a 16-hour period with and without multiple-dose oral administration of terbinafine (250 mg daily for 3 days). Study periods were separated by a 4-week washout period. Urinary caffeine metabolite ratios were used to assess CYP1A2, NAT-2 and XO activity. Comparison of mean metabolic ratios for treatment with and without terbinafine indicated that terbinafine did not appear to alter the activity of CYP1A2, NAT-2, or XO, all of which regulate the biotransformation of caffeine.

Pharmacodynamics of bolus famotidine versus infused cimetidine, ranitidine, and famotidine.

A four-way crossover pilot study was conducted to compare the pharmacodynamic response of intermittent famotidine (20 mg every 12 hr) to continuous infusions of cimetidine (1200 mg/24 hr), ranitidine (150 mg/24 hr), and famotidine (40 mg/24 hr) in six normal male volunteers. Intragastric pH was monitored continuously for 24 hours. Comparisons included percent time during the 24-hour period that gastric pH was greater than pH 4.0, and pH 5.0, and also for the steady-state period of each regimen (12-24 hr). Although no statistically significant difference was observed for any of these comparisons, a clinically relevant trend was observed. In crossover experiments, famotidine intermittent infusions provided gastric pH readings above 4.0 and 5.0 for a longer duration than any of the continuous infusion regimens. Famotidine intermittent infusion regimens (20 mg every 12 hr) are at least equivalent to continuous infusions of cimetidine, ranitidine, and famotidine. Based on these findings, comparative studies in an appropriate critical care population would be beneficial, but any such studies must use a crossover design because of the even higher degree of intersubject variance in pH control. For this reason, the normal volunteer crossover model used here may provide important comparative information for the various regimens used in suppression of gastric acidity.

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

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

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.

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.

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.

Prospective validation of an optimal sparse plasma-sampling strategy for estimating ciprofloxacin pharmacokinetics.

Data obtained from 23 critically ill patients treated with intravenous ciprofloxacin in two clinical trials were used to validate prospectively a previously developed maximum a posteriori (MAP)-Bayesian estimator and optimal plasma-sampling strategy (OSS). Dosages ranged from 200 mg every 12 hours to 400 mg every 8 hours. Each patient had 8-16 samples taken, either as large gold standard sampling sets or as a mix of gold standard sets and OSSs. The MAP-Bayesian estimator used a two-compartment model and identified apparent volumes of distribution of the central and peripheral compartments, distributional clearance, and the slope and intercept of the relationship between creatinine clearance and total body clearance. Fit parameters were used to derive the apparent volume of distribution at steady state and the 24-hour area under the curve. All parameters derived from the OSS using the MAP-Bayesian estimates matched up almost identically to those obtained from modeling the gold standard sets. There was no systematic bias, and good precision was seen among all the parameters. These data demonstrate the usefulness and validity of the current OSS and MAP-Bayesian estimator, and provide further evidence of the utility of optimal sampling theory.

Orthostatic hypotension induced by sertraline withdrawal.

Sertraline is a member of the newest class of antidepressants, the selective serotonin reuptake inhibitors. Due to its inherent selectivity and its lack of action with norepinephrine, dopamine, monoamine oxidase, and cholinergic receptors, this drug is unlikely to have any cardiovascular activity. A patient receiving sertraline for depression developed dizziness and orthostatic hypotension on repeated attempts to discontinue the drug. All other organic factors were ruled out. The hypotension was proved to be secondary to sertraline by repeated rechallenges. After a variety of attempted treatments, the agent was discontinued successfully through an extended titration period. This report should guide clinicians in treating patients with a similar problem.

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.

Paradoxic excitation with diphenhydramine in an adult.

Although paradoxic excitation may rarely occur in children and adults with conventional dosages of antihistamines, few case reports have appeared in the literature. We cared for a 46-year-old patient who became extremely agitated after receiving a dose of intravenous diphenhydramine.

Possible interaction between imipramine and butalbital.

A 44-year-old woman was admitted to the psychiatric unit for exacerbation of her depressive disorder. Blood concentrations of her antidepressant, imipramine, were within normal range and consistent with past concentrations. Her medical history was significant for a chronic headache disorder for which she was given a prescription containing butalbital on admission. The patient's depressive disorder was quickly controlled but relapsed 2 weeks later. Concentrations of imipramine showed a decrease of approximately 50%. Imipramine is metabolized in the liver by the cytochrome P-450 (CYP 1A2) system, and barbiturates are known inducers of this enzyme subset. To our knowledge, an interaction specifically between butalbital and imipramine has not been documented; however, these drugs are extensively prescribed and occasions may arise where they are given concurrently. We recommend repeat measurement of imipramine concentrations 1 week after the start of any butalbital-containing product or barbiturate, and dosage adjustments based on the results and on the patient's response to the change.

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.

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.

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

Two 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.

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.