Teresita Mazzei

Pharmacokinetic Drug Interactions of Macrolides

SummaryThe macrolide antibiotics include natural members, prodrugs and semisynthetic derivatives. These drugs are indicated in a variety of infections and are often combined with other drug therapies, thus creating the potential for pharmacokinetic interactions.Macrolides can both inhibit drug metabolism in the liver by complex formation and inactivation of microsomal drug oxidising enzymes and also interfere with microorganisms of the enteric flora through their antibiotic effects. Over the past 20 years, a number of reports have incriminated macrolides as a potential source of clinically severe drug interactions. However, differences have been found between the various macrolides in this regard and not all macrolides are responsible for drug interactions. With the recent advent of many semisynthetic macrolide antibiotics it is now evident that they may be classified into 3 different groups in causing drug interactions. The first group (e.g. troleandomycin, erythromycins) are those prone to forming nitrosoalkanes and the consequent formation of inactive cytochrome P450-metabolite complexes. The second group (e.g. josamycin, flurithromycin, roxithromycin, clarithromycin, miocamycin and midecamycin) form complexes to a lesser extent and rarely produce drug interactions. The last group (e.g. spiramycin, rokitamycin, dirithromycin and azithromycin) do not inactivate cytochrome P450 and are unable to modify the pharmacokinetics of other compounds.It appears that 2 structural factors are important for a macrolide antibiotic to lead to the induction of cytochrome P450 and the formation in vivo or in vitro of an inhibitory cytochrome P450-iron-nitrosoalkane metabolite complex: the presence in the macrolide molecules of a non-hindered readily accessible N-dimethylamino group and the hydrophobic character of the drug.Troleandomycin ranks first as a potent inhibitor of microsomal liver enzymes, causing a significant decrease of the metabolism of methylprednisolone, theophylline, carbamazepine, phenazone (antipyrine) and triazolam. Troleandomycin can cause ergotism in patients receiving ergot alkaloids and cholestatic jaundice in those taking oral contraceptives.Erythromycin and its different prodrugs appear to be less potent inhibitors of drug metabolism. Case reports and controlled studies have, however, shown that erythromycins may interact with theophylline, carbamazepine, methylprednisolone, warfarin, cyclosporin, triazolam, midazolam, alfentanil, disopyramide and bromocriptine, decreasing drug clearance. The bioavailability of digoxin appears also to be increased by erythromycin in patients excreting high amounts of reduced digoxin metabolites, probably due to destruction of enteric flora responsible for the formation of these compounds. These incriminated macrolide antibiotics should not be administered concomitantly with other drugs known to be affected metabolically by them, or at the very least, combined administration should be carried out only with careful patient monitoring.Josamycin, midecamycin and probably also the related compounds miocamycin, clarithromycin and flurithromycin, may have a clinically significant interaction with carbamazepine and cyclosporin, requiring close monitoring. Roxithromycin interaction with drugs such as theophylline or cyclosporin does not seem to justify a dosage reduction. No pharmacokinetic interactions have yet been described for spiramycin, rokitamycin, dirithromycin and azithromycin.

The ARESC study: an international survey on the antimicrobial resistance of pathogens involved in uncomplicated urinary tract infections

The ARESC (Antimicrobial Resistance Epidemiological Survey on Cystitis) study is an international survey to investigate the prevalence and susceptibility of pathogens causing cystitis. Female patients (n=4264) aged 18-65 years with symptoms of uncomplicated cystitis were consecutively enrolled in nine European countries as well as Brazil during 2003-2006. Pathogens were identified and their susceptibility to nine antimicrobials was determined. Escherichia coli accounted for 76.7% of isolates. Among E. coli, 10.3% of the isolates were resistant to at last three different classes of antimicrobial agents. Resistance was most common to ampicillin (48.3%), trimethoprim/sulfamethoxazole (29.4%) and nalidixic acid (18.6%). Fosfomycin, mecillinam and nitrofurantoin were the most active drugs (98.1%, 95.8% and 95.2% susceptible strains, respectively) followed by ciprofloxacin, amoxicillin/clavulanic acid and cefuroxime (91.7%, 82.5% and 82.4%, respectively). Resistance to ciprofloxacin was >10% in Brazil, Spain, Italy and Russia. Overall, Proteus mirabilis were more susceptible to beta-lactams and less susceptible to non-beta-lactams than E. coli, whereas Klebsiella pneumoniae strains, which are intrinsically resistant to ampicillin, were less susceptible to mecillinam (88.8%), fosfomycin (87.9%), cefuroxime (78.6%) and nitrofurantoin (17.7%). Resistance was rare in Staphylococcus saprophyticus, with the exception of ampicillin (36.4%) and trimethoprim/sulfamethoxazole (10.2%). In Italy, Spain, Brazil and Russia, the countries most affected by antimicrobial resistance, extended-spectrum beta-lactamase (ESBL) enzymes (mainly CTX-M type) were detected in 48 strains (39 E. coli, 6 K. pneumoniae and 3 P. mirabilis). Despite wide intercountry variability in bacterial susceptibility rates to the other antimicrobials tested, fosfomycin and mecillinam have preserved their in vitro activity in all countries investigated against the most common uropathogens.

New insights into meticillin-resistant Staphylococcus aureus (MRSA) pathogenesis, treatment and resistance

Meticillin-resistant Staphylococcus aureus (MRSA) remains one of the principal multiply resistant bacterial pathogens causing serious healthcare-associated and community-onset infections. This paper reviews recent studies that have elucidated the virulence strategies employed by MRSA, key clinical trials of agents used to treat serious MRSA infections, and accumulating data regarding the implications of antibacterial resistance in MRSA for clinical success during therapy. Recent pre-clinical data support a species-specific role for Panton-Valentine leukocidin in the development of acute severe S. aureus infections and have elucidated other virulence mechanisms, including novel modes of internalisation, varying post-invasion strategies (featuring both upregulation and downregulation of virulence factors) and phenotypic switching. Recent double-blind, randomised, phase III/IV clinical trials have demonstrated the efficacy of linezolid and telavancin in hospital-acquired pneumonia (HAP) and complicated skin and skin-structure infections (cSSSIs) caused by MRSA. Tigecycline was non-inferior to imipenem/cilastatin in non-ventilator-associated HAP but was inferior in ventilator-associated pneumonia and has shown a higher rate of death than comparators on meta-analysis. Ceftaroline was clinically and microbiologically non-inferior to vancomycin/aztreonam in the treatment of MRSA cSSSI. Key resistance issues include a rise in vancomycin minimum inhibitory concentrations in MRSA, reports of clonal isolates with linezolid resistance mediated by acquisition of the chloramphenicol/florfenicol resistance gene, and case reports of daptomycin resistance resulting in clinical failure. Novel antimicrobial targets must be identified with some regularity or we will face the risk of untreatable S. aureus infections.

Adverse effects of macrolide antibacterials.

SummaryThe renewed interest in macrolide antibacterials with expanded indications for clinical use, as well as their markedly increased usage, justifies the continuous search for new compounds designed to offer the patient not only enhanced bioavailability but also a reduced incidence of adverse effects.Macrolides are an old and well established class of antimicrobial agents that account for 10 to 15% of the worldwide oral antibiotic market. Macrolides are considered to be one of the safest anti-infective groups in clinical use, with severe adverse reactions being rare. Newer products with improved features have recently been discovered and developed, maintaining or significantly expanding the role of macrolides in the management of infection. This review deals with the tolerability of the clinically available macrolide antibacterials. With the exception of drug interactions, adverse effects have been analysed during the last 40 years in many thousands of adult and paediatric patients. Recently developed derivatives have been compared with the older compounds, and the expected and well assessed adverse effects have been set apart from those which are unusual, very rare or questionable.Gastrointestinal reactions represent the most frequent disturbance, occurring in 15 to 20% of patients on erythromycins and in 5% or fewer patients treated with some recently developed macrolide derivatives that seldom or never induce endogenous release of motilin, such as roxithromycin, clarithromycin, dirithromycin, azithromycin and rikamycin (rokitamycin).Except for troleandomycin and some erythromycins administered at high dose and for long periods of time, the hepatotoxic potential of macrolides, which rarely or never form nitrosoalkanes, is low for josamycin, midecamycin, miocamycin, flurithromycin, clarithromycin and roxithromycin; it is negligible or absent for spiramycin, rikamycin, dirithromycin and azithromycin. Transient deafness and allergic reactions to macrolide antibacterials are highly unusual and have definitely been shown to be more common following treatment with the erythromycins than with the recently developed 14-, 15- and 16-membered macrolides.There have been case reports in the literature of 51 patients during the last 30 years who experienced uncommon or dubious adverse effects after treatment with older compounds and in which there appears to be strong evidence of a causal relationship with the drug. Only 3 cases had an unfavourable outcome, and these were patients administered erythromycin lactobionate intravenously too rapidly or at high dose. Targets of these occasional reactions are generally the heart, liver and central nervous system. Other unusual organ pathologies are related to immunomediated disorders more than to primary parenchymal toxicity, or to the rarely serious consequences of macrolide-induced alterations in intestinal microflora.Physicians should be alerted to the possibility of unusual toxicity that could also emerge in the future from the new and recently developed macrolide antibacterials, coinciding with their expanded clinical use worldwide.

Clinical Pharmacokinetics of Depot Leuprorelin

Leuprorelin acetate is a synthetic agonist analogue of gonadotropin-releasing hormone. Continued leuprorelin administration results in suppression of gonadal steroid synthesis, resulting in pharmacological castration.Since leuprorelin is a peptide, it is orally inactive and generally given subcutaneously or intramuscularly. Sustained release parenteral depot formulations, in which the hydrophilic leuprorelin is entrapped in biodegradable highly lipophilic synthetic polymer microspheres, have been developed to avoid daily injections. The peptide drug is released from these depot formulations at a functionally constant daily rate for 1, 3 or 4 months, depending on the polymer type [polylactic/glycolic acid (PLGA) for a 1-month depot and polylactic acid (PLA) for depot of >2 months], with doses ranging between 3.75 and 30mg.Mean peak plasma leuprorelin concentrations (Cmax) of 13.1, 20.8 to 21.8, 47.4, 54.5 and 53 µg/L occur within 1 to 3 hours of depot subcutaneous administration of 3.75, 7.5, 11.25, 15 and 30 mg, respectively, compared with 32 to 35 µg/L at 36 to 60 min after a subcutaneous injection of 1mg of a non-depot formulation. Sustained drug release from the PLGA microspheres maintains plasma concentrations between 0.4 and 1.4 µg/L over 28 days after single 3.75, 7.5 or 15mg depot injections.Mean areas under the concentration-time curve (AUCs) are similar for subcutaneous or intravenous injection of short-acting leuprorelin 1mg; a significant dose-related increase in the AUC from 0 to 35 days is noted after depot injection of leuprorelin 3.75, 7.5 and 15mg. Mean volume of distribution of leuprorelin is 37L after a single subcutaneous injection of 1mg, and 36, 33 and 27L after depot administration of 3.75, 7.5 and 15mg, respectively. Total body clearance is 9.1 L/h and elimination half-life 3.6 hours after a subcutaneous 1mg injection; corresponding values after intravenous injection are 8.3 L/h and 2.9 hours.A 3-month depot PLA formulation of leuprorelin acetate 11.25mg ensures a Cmax of around 20 µg/L at 3 hours after subcutaneous injection, and continuous drug concentrations of 0.43 to 0.19 µg/L from day 7 until before the next injection.Recently, an implant that delivers leuprorelin for 1 year has been evaluated. Serum leuprorelin concentrations remained at a steady mean of 0.93 µg/L until week 52, suggesting zero-order drug release from the implant.In general, regular or depot leuprorelin treatment is well tolerated. Local reactions are more common after application of the 3- or 4-month depot in comparison with the 1-month depot.

Overcoming tumor multidrug resistance using drugs able to evade P-glycoprotein or to exploit its expression

Multidrug resistance (MDR) is a major obstacle to the effective treatment of cancer. Cellular overproduction of P‐glycoprotein (P‐gp), which acts as an efflux pump for various anticancer drugs (e.g. anthracyclines, Vinca alkaloids, taxanes, epipodophyllotoxins, and some of the newer antitumor drugs) is one of the more relevant mechanisms underlying MDR. P‐gp belongs to the superfamily of ATP‐binding cassette transporters and is encoded by the ABCB1 gene. Its overexpression in cancer cells has become a therapeutic target for circumventing MDR. As an alternative to the classical pharmacological strategy of the coadministration of pump inhibitors and cytotoxic substrates of P‐gp and to other approaches applied in experimental tumor models (e.g. P‐gp‐targeting antibodies, ABCB1 gene silencing strategies, and transcriptional modulators) and in the clinical setting (e.g. incapsulation of P‐gp substrate anticancer drugs into liposomes or nanoparticles), a more intriguing strategy for circumventing MDR is represented by the development of new anticancer drugs which are not substrates of P‐gp (e.g. epothilones, second‐ and third‐generation taxanes and other microtubule modulators, topoisomerase inhibitors). Some of these drugs have already been tested in clinical trials and, in most of cases, show relevant activity in patients previously treated with anticancer agents which are substrates of P‐gp. Of these drugs, ixabepilone, an epothilone, was approved in the United States for the treatment of breast cancer patients pretreated with an anthracycline and a taxane. Another innovative approach is the use of molecules whose activity takes advantage of the overexpression of P‐gp. The possibility of overcoming MDR using the latter two approaches is reviewed herein.  © 2011 Wiley Periodicals, Inc. Med Res Rev

Clinical pharmacokinetic properties of the macrolide antibiotics. Effects of age and various pathophysiological states (Part II).

SummaryThe pharmacokinetic aspects in humans of macrolide antibiotics that are currently or soon to be on the market (i.e. erythromycin, oleandomycin, spiramycin, josamycin, midecamycin, miocamycin, rosaramycin, roxithromycin and azithromycin) are reviewed.Macrolide antibiotics are basic compounds, poorly soluble in water, which are mostly absorbed in the alkaline intestinal environment. They are acid unstable, but the newer semisynthetic derivatives (i.e. roxithromycin and azithromycin) are characterised by increased stability under acidic conditions. Macrolides are highly liposoluble and consequently penetrate well into tissue, especially bronchial secretions, prostatic tissue, middle ear exudates and bone tissues, as evidenced by tissue/serum concentration ratios greater than 1. They do not penetrate well into the CSF. Macrolides undergo extensive biotransformation in the liver. With a few exceptions (e.g. miocamycin), the metabolites of these drugs are characterised by little or no antimicrobial activity.Plasma protein binding is variable from one compound to another. At therapeutic concentrations, protein-bound erythromycin accounts for 80 to 90% of the total drug present in the blood, and the fraction is 95% for roxithromycin. The lowest values of protein-bound fraction are observed for midecamycin and josamycin (about 15%), and intermediate values are reported for spiramycin and miocamycin. However, the clinical relevance of this parameter is not clearly established.Plasma half-life (t½) values vary for the macrolides described: erythromycin, oleandomycin, josamycin and miocamycin have a t½ ranging from 1 to 2 hours; spiramycin, erythromycin stearate, the mercaptosuccinate salt of propionyl erythromycin and rosaramicin have an intermediate t½ (about 7, 6.5, 5 and 4.5 hours, respectively); the newer semisynthetic compounds roxithromycin and azithromycin are characterised by high t½ values (i.e. 11 and 41 hours, respectively).Under normal conditions, the major route of elimination is the liver. Renal elimination also takes place but it contributes to total clearance only to a small degree, as evidenced by low renal clearance values. The degree of modification of macrolide pharmacokinetics by renal insufficiency or hepatic disease is usually not considered clinically relevant, and no recommendation for dose modification is necessary in these patients.The pharmacokinetics of macrolides are modified in elderly patients. Accordingly, their use must be accompanied by a closer than usual clinical monitoring of the older patient.Clinically the newer semisynthetic macrolides, such as roxithromycin, possess an antibacterial spectrum at least equivalent to that of erythromycin, and superior pharmacokinetic properties (i.e. longer elimination half-life, higher tissue penetration) over erythromycin and other macrolides, allowing longer intervals between doses.

Pharmacokinetic Evaluation of Meropenem and Imipenem in Critically Ill Patients with Sepsis

ObjectiveTo evaluate and compare the pharmacokinetic profiles of imipenem and meropenem in a population of critically ill patients with sepsis to find possible differences that may help in selecting the most appropriate drug and/or dosage in order to optimise empiric antimicrobial therapy.Patients and methodsThis was a single-centre, randomised, nonblind study of the pharmacokinetics of both intravenous imipenem 1g and meropenem 1g in 20 patients admitted to an intensive care unit with sepsis in whom antimicrobial therapy was indicated on clinical grounds. Patients were divided into two groups: group I received intravenous imipenem 1g plus cilastatin 1g, and group II received intravenous meropenem 1g over 30 minutes. Peripheral blood samples were collected at 0, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4, 6 and 8 hours after the first dose and were centrifuged for 10 minutes at 4°C. Urine samples were collected during the 8 hours after antimicrobial administration at 2-hour intervals: 0–2, 2–4, 4–6 and 6–8 hours. The total volume of urine was recorded; the serum and urine samples were immediately frozen and stored at −80°C until assayed. Pharmacokinetic analysis was carried out through computerised programs using the least-square regression method and a two-compartment open model. Statistical differences were evaluated by means of one-way ANOVA.ResultsThe following pharmacokinetic differences between the two drugs were observed: the imipenem mean peak serum concentration was significantly higher than for meropenem (90.1 ± 50.9 vs 46.6 ± 14.6 mg/L, p < 0.01); the area under the serum concentration-time curve was significantly higher for imipenem than for meropenem (216.5 ± 86.3 vs 99.5 ± 23.9 mg · h/L, p < 0.01), while the mean volume of distribution and mean total clearance were significantly higher for meropenem than for imipenem (25 ± 4.1 vs 17.4 ± 4.5L, p < 0.01 and 191 ± 52.2 vs 116.4 ± 42.3 mL/min, p < 0.01, respectively).ConclusionThe more favourable pharmacokinetic profile of imipenem compared with meropenem in critically ill patients with sepsis might balance the possibly greater potency demonstrated in vitro for meropenem against Gram-negative strains. Hence, the clinical efficacy of the two carbapenems depends mostly on their correct dosage.

Clinical Pharmacokinetic Properties of the Macrolide Antibiotics

The pharmacokinetic aspects in humans of macrolide antibiotics that are currently or soon to be on the market (i.e. erythromycin, oleandomycin, spiramycin, josamycin, midecamycin, miocamycin, rosaramycin, roxithromycin and azithromycin) are reviewed. Macrolide antibiotics are basic compounds, poorly soluble in water, which are mostly absorbed in the alkaline intestinal environment. They are acid unstable, but the newer semisynthetic derivatives (i.e. roxithromycin and azithromycin) are characterised by increased stability under acidic conditions. Macrolides are highly liposoluble and consequently penetrate well into tissue, especially bronchial secretions, prostatic tissue, middle ear exudates and bone tissues, as evidenced by tissue/serum concentration ratios greater than 1. They do not penetrate well into the CSF. Macrolides undergo extensive biotransformation in the liver. With a few exceptions (e.g. miocamycin), the metabolites of these drugs are characterised by little or no antimicrobial activity. Plasma protein binding is variable from one compound to another. At therapeutic concentrations, protein-bound erythromycin accounts for 80 to 90% of the total drug present in the blood, and the fraction is 95% for roxithromycin. The lowest values of protein-bound fraction are observed for midecamycin and josamycin (about 15%), and intermediate values are reported for spiramycin and miocamycin. However, the clinical relevance of this parameter is not clearly established. Plasma half-life (t½) values vary for the macrolides described: erythromycin, oleandomycin, josamycin and miocamycin have a t½ ranging from 1 to 2 hours; spiramycin, erythromycin stearate, the mercaptosuccinate salt of propionyl erythromycin and rosaramicin have an intermediate t½ (about 7, 6.5, 5 and 4.5 hours, respectively); the newer semisynthetic compounds roxithromycin and azithromycin are characterised by high t½ values (i.e. 11 and 41 hours, respectively). Under normal conditions, the major route of elimination is the liver. Renal elimination also takes place but it contributes to total clearance only to a small degree, as evidenced by low renal clearance values. The degree of modification of macrolide pharmacokinetics by renal insufficiency or hepatic disease is usually not considered clinically relevant, and no recommendation for dose modification is necessary in these patients. The pharmacokinetics of macrolides are modified in elderly patients. Accordingly, their use must be accompanied by a closer than usual clinical monitoring of the older patient. Clinically the newer semisynthetic macrolides, such as roxithromycin, possess an antibacterial spectrum at least equivalent to that of erythromycin, and superior pharmacokinetic properties (i.e. longer elimination half-life, higher tissue penetration) over erythromycin and other macrolides, allowing longer intervals between doses.

Management of serious meticillin-resistant Staphylococcus aureus infections: what are the limits?☆

Severe (life-threatening) meticillin-resistant Staphylococcus aureus (MRSA) infection continues to be treated with vancomycin despite accumulating evidence of poor outcome, increasing resistance and unachievable pharmacokinetic/pharmacodynamic (PK/PD) targets. The minimum inhibitory concentration (MIC) susceptibility breakpoint for vancomycin was recently reduced to 2 mg/L. Whilst the great majority of clinical isolates are thus still classified as susceptible, the available clinical evidence argues for a method-dependent breakpoint of 0.5 mg/L (broth dilution) or 1.0 mg/L (Etest), which would classify many strains as resistant, or at best intermediate. However, automated susceptibility testing systems are not currently capable of performing accurately at this low level, and such low breakpoints are unsatisfactory because the poor reproducibility of tests (plus or minus one doubling dilution) results in a critical non-reproducibility around the modal MIC of 1 mg/L described in most published data. Therefore, vancomycin should be used with caution in severe (life-threatening) staphylococcal disease and the MIC should always be reported by method. Daptomycin is generally preferred for bacteraemia/endocarditis and linezolid for pneumonia. Better outcome data for vancomycin, based on achievable PK/PD targets and using robust MIC tests, are urgently required.