Andrea Novelli

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.

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 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.

In vitro activity of lomefloxacin (SC-47111; NY-198), a difluoroquinolone 3-carboxylic acid, compared with those of other quinolones.

Lomefloxacin (SC-47111; NY-198) is a new difluoroquinolone agent. It inhibited 90% of Escherichia coli, Klebsiella spp., Enterobacter spp., Citrobacter spp., Proteus mirabilis, Morganella morganii, Proteus vulgaris, Serratia marcescens, Salmonella spp., Shigella spp., Aeromonas spp., Yersinia spp., Haemophilus influenzae, and Neisseria gonorrhoeae at less than or equal to 2 micrograms/ml. Lomefloxacin inhibited 90% of Pseudomonas aeruginosa at 4 micrograms/ml. Lomefloxacin was equal in activity to norfloxacin against Escherichia coli, Klebsiella spp., Enterobacter spp., Haemophilus influenzae, and Neisseria gonorrhoeae but was twofold less active against Proteus spp., Providencia spp., Serratia marcescens, Salmonella spp., and Shigella spp. Ofloxacin was generally 2- to 4-fold more active, and ciprofloxacin was 4- to 16-fold more active. Lomefloxacin inhibited Staphylococcus aureus, including methicillin-resistant isolates, but MICs for 90% of streptococcal species tested were 8 micrograms/ml. In the presence of 9 mM Mg2+, MICs for Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, and Pseudomonas aeruginosa were increased, as they were when they were tested in urine. A single-step increase in resistance to eightfold above the MIC occurred at a frequency of less than 10(-10), but serial transfer of bacteria in the presence of the agent produced MIC increases. Lomefloxacin had activity and properties comparable to those of many of the new quinolones.

Considerations for Higher Doses of Daptomycin in Critically Ill Patients with Methicillin-Resistant Staphylococcus aureus Bacteremia

BACKGROUND Higher daptomycin doses are advocated for select methicillin-resistant Staphylococcus aureus (MRSA)-related infections, but the probabilities of target attainment (PTA) and toxicity of these doses have not been characterized in critically ill patients. METHODS We evaluated the plasma pharmacokinetics (PK) and clinical outcomes of a cohort of critically ill patients treated with daptomycin 6-8 mg/kg/day for primarily Staphylococcus species-related infections. Daptomycin concentrations were measured intensively over the initial 96-hour dosing period. Data were modeled by population PK analyses, and Monte Carlo simulation was used to estimate the probabilities of effect and toxicity with standard and alternate dosing regimens. RESULTS Fifty patients with a mean (SD) age of 69.7 (12.2) years, weight 74.5 (20.3) kg, and creatinine clearance 56.8 (38.2) mL/minute were enrolled with measurements of 12 (2.2) daptomycin samples per patient. Significantly lower daptomycin exposures were observed despite comparable doses in a subset of patients (n = 13) with augmented clearance (CL). No covariates of CL were identified, but this subset was significantly more likely to be in severe sepsis or septic shock, have higher Sequential Organ Failure Assessment scores, and MRSA bacteremia. In-hospital mortality was significantly higher (30.7% vs 10.8%) in patients with augmented daptomycin CL. Use of an empiric fixed dose of 750 mg of daptomycin is predicted to achieve a comparable PTA with a lower probability of toxicity as compared to the use of 10 mg/kg in critically ill patients. CONCLUSIONS A reappraisal of current daptomycin dosing recommendations is needed to improve the PTA and reduce toxicity among critically ill patients.

Acute otitis media: From diagnosis to prevention. Summary of the Italian guideline

Acute otitis media (AOM) is the most common disease occurring in infants and children and has major medical, social and economic effects. If we consider the Italian pediatric population and the incidence rates in different age ranges it can be calculated that almost one million cases of AOM are diagnosed in Italy every year. Various attempts have been made internationally to clarify the most appropriate ways in which AOM should be managed. In Italy, this has been done at local or regional level but there have so far been no national initiatives. The objective of this guideline is to provide recommendations to pediatricians, general practitioners and otolaryngologists involved in the clinical management of acute otitis media in healthy children aged 2 months to 12 years. After a systematic review and grading of evidences from the literature, the document was drafted by a multidisciplinary panel with identified key clinical questions related to diagnosis, treatment of the acute episode, management of complications and prevention.

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.

Continuous Infusion of Vancomycin in Methicillin- Resistant Staphylococcus Infection

Objective: The aim of the study was to verify the therapeutic response of vancomycin in methicillin-resistant staphylococcus infection (MRSA/MRCNS) administered according to two different methods (intermittent infusion vs. continuous infusion). Method: Experimental plan: retrospective study; study environment: university hospital, two intensive care units. Twenty-five critically ill patients submitted to antibiotic treatment with vancomycin for infection from MRSA/MRCNS were studied. The patients, who were classified according to SAPS II scores, were divided into two groups: group A (n = 14): dose of vancomycin of 0.5 g × 4/day and group B (n = 11): dose of 2 g/day of vancomycin administered in a continuous infusion. Before the antibiotic therapy was started (T1) and prior to its end (T2), the following parameters were evaluated: degree of impairment of the main organs and systems by means of sepsis-related organ failure assessment score (SOFA) and count of the white blood cells (WBC). The length of the hospital stay during intensive care was calculated for both groups (statistics: Student t test). Results: No significant differences were found in the SAPS II scores and in the length of the hospital stay. In a comparison of the T1 and T2 results, we noted that patients of group A had no variations in the SOFA scores (4.84 ± 2.48 vs. 4 ± 3.9) and in the WBC mean values (12,415 ± 5,099 vs. 12,841 ± 6,864 cells/mm3). In contrast, in the patients of group B, we noted significant variations (p < 0.05) in the mean values of the SOFA scores (6.62 ± 2.2 vs. 4.37 ± 3.5) and in the mean values relative to the WBC count (17,242 ± 12,842 vs. 10,757 ± 3,610 cells/mm3). Conclusions: In critically ill patients suffering from MRSA/MRCNS infection, vancomycin administration in continuous infusions improved organ function and leukocyte response, but did not seem to modify the overall evolution of the disease.

Efficacy of caspofungin as secondary prophylaxis in patients undergoing allogeneic stem cell transplantation with prior pulmonary and/or systemic fungal infection

Transplanted patients with a history of invasive fungal infection (IFI) are at high risk of developing relapse and fatal complications. Eighteen patients affected by hematological malignancies and a previous IFI were submitted to allogeneic stem cell transplantation, using Caspofungin as a secondary prophylaxis. Patients had a probable or proven fungal infection and 16 had a pulmonary localization. No side effects were recorded during treatment with Caspofungin. Compared to pre-transplant evaluation, stability or improvement of the previous IFI was observed in 16 of the 18 patients at day 30, in 13 of the 15 evaluable patients at day 180 and in 11 of the 11 evaluable patients at day 360 post transplant. In particular, all the six patients with a proven fungal infection were alive, with a stable or improved IFI after 1 year from transplant. At a maximum follow-up of 31 months, eight patients died for disease progression or transplant-related complications, but only two had evidence of fungal progression. Secondary prophylaxis with Caspofungin may represent a suitable approach to limit IFI relapse or progression, allowing patients with hematological malignancies to adhere to the planned therapeutic program.