Stevens-Johnson syndrome and toxic epidermal necrolysis associated with the use of macrolide antibiotics: a review of published cases.

Macrolides are one of the most commonly prescribed antibiotics. In several studies, their use was associated with the occurrence of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). This review aimed to explore and summarize available cases of SJS/TEN suspected to be associated with the use of macrolide antibiotics reported in the literature. Electronic searches were conducted in PubMed/MEDLINE, Web of Science, Scopus, and Serbian Citation Index (SCIndeks). Twenty-five publications describing a total of 27 patients were included. Cases of SJS/TEN which satisfied inclusion criteria were found for azithromycin (n = 11), clarithromycin (n = 7), erythromycin (n = 5), roxithromycin (n = 2), and telithromycin (n = 2). The age of the patients ranged from 2 to 77 years (median: 29 years). There were 14 female (51.9%) and 13 male (48.1%) patients. SJS was diagnosed in 16 patients (59.3%), TEN in 10 patients (37.0%), and SJS/TEN overlap in one patient (3.7%). Time to onset of the first symptoms ranged from 1 to 14 days (median: 3 days). All patients received some form of supportive and symptomatic care. Systemic corticosteroids were reported to be administered in 12 patients (44.4%) and intravenous immunoglobulin in five patients (18.5%). Three patients (11.1%) died. Considering that SJS/TEN is a severe and potentially life-threatening reaction, physicians should be aware that they could be adverse effects of macrolide antibiotics and keep in mind that prompt recognition of SJS/TEN and discontinuation of the culprit drug in combination with supportive care is essential.

Differentiating the Pharmacodynamics and Toxicology of Macrolide and Ketolide Antibiotics.

This is a review of the macrolide and ketolide field focusing on differentiating the pharmacodynamics and especially the toxicology of the macrolides and ketolides. We emphasize the diversity in pharmacodynamics and toxicity of the macrolides and ketolides, resulting from even small structural changes, which makes it important to consider the various different compounds separately, not necessarily as a class. The ketolide, telithromycin, was developed because of rising bacterial macrolide resistance but was withdrawn postapproval after visual disturbances, syncope, myasthenia gravis, and hepatotoxicity were noted. These diverse adverse effects could be attributed to inhibition of nicotinic acetylcholine receptors. Solithromycin, a later generation ketolide, was effective in treating bacterial pneumonia, but it was not approved by the U.S. Food and Drug Administration owing, in part, to its structural similarity to telithromycin. This Miniperspective describes that structurally similar macrolides/ketolides have clearly mechanistically distinct effects. Understanding these effects could help in developing and securing regulatory approval of a new macrolide/ketolide that is active against macrolide-resistant pathogenic bacteria.

Solithromycin: A novel ketolide antibiotic.

PURPOSE: The pharmacology, pharmacokinetics, pharmacodynamics, antimicrobial activity, clinical safety, and current regulatory status of solithromycin are reviewed. SUMMARY: Solithromycin is a novel ketolide antibiotic developed for the treatment of community-acquired bacterial pneumonia (CABP). Its pharmacologic, pharmacokinetic, and pharmacodynamic properties provide activity against a broad range of intracellular organisms, including retained activity against pathogens displaying various mechanisms of macrolide resistance. Phase III clinical trials of solithromycin demonstrated noninferiority of both oral and i.v.-to-oral regimens of 5-7 days' duration compared with moxifloxacin for patients with moderately severe CABP. Nearly one third of patients receiving i.v. solithromycin experienced infusion-site reactions. Although no liver-related adverse events were reported in patients receiving oral solithromycin, more patients receiving i.v.-to-oral solithromycin experienced asymptomatic, transient transaminitis, with alanine transaminase levels of >3 to >5 times the upper limit, compared with those treated with moxifloxacin. These results led the Food and Drug Administration to conclude that the solithromycin new drug application was not approvable as filed, adding that the risk of hepatotoxicity had not yet been adequately characterized. The agency further recommended a comparative study of patients with CABP to include approximately 9,000 patients exposed to solithromycin in order to exclude drug-induced liver injury events occurring at a rate of 1 in 3,000 with 95% probability. CONCLUSION: Solithromycin is a novel ketolide antibiotic with activity against a broad spectrum of intracellular organisms, including those displaying macrolide resistance. While demonstrating noninferiority to a current first-line agent in the treatment of CABP, concerns for drug-induced liver injury and infusion-site reactions have placed its regulatory future in doubt.

Factors Affecting the Timing of Signal Detection of Adverse Drug Reactions.

We investigated factors affecting the timing of signal detection by comparing variations in reporting time of known and unknown ADRs after initial drug release in the USA. Data on adverse event reactions (AERs) submitted to U.S. FDA was used. Six ADRs associated with 6 drugs (rosuvastatin, aripiprazole, teriparatide, telithromycin, exenatide, varenicline) were investigated: Changes in the proportional reporting ratio, reporting odds ratio, and information component as indexes of signal detection were followed every 3 months after each drugs release, and the time for detection of signals was investigated. The time for the detection of signal to be detected after drug release in the USA was 2-10 months for known ADRs and 19-44 months for unknown ones. The median lag time for known and unknown ADRs was 99.0-122.5 days and 185.5-306.0 days, respectively. When the FDA released advisory information on rare but potentially serious health risks of an unknown ADR, the time lag to report from the onset of ADRs to the FDA was shorter. This study suggested that one factor affecting signal detection time is whether an ADR was known or unknown at release.

Introduction of a nitrogen-containing side chain appended on C-10 of cethromycin leads to reduced CYP3A4 inhibition (WO2014049356A1).

INTRODUCTION: Infections caused by antibiotic-resistant bacteria pose an increasing risk for clinical treatment. Macrolide-lincosamide-streptogramin B is becoming increasingly ineffective due to the methylation at the binding site of bacteria. Despite great efforts on the natural product, erythromycin, only one derivative, that is, telithromycin, capable of fighting against resistant bacteria has so far been marketed. However, the 3'-dimethylamino group is readily metabolized to a nitroso group, which would inhibit CYP3A4, a very important metabolic enzyme responsible for nearly half of all marketed drugs. AREAS COVERED: Modifications at C-10 of erythromycin were seldom reported. This invention disclosed novel ketolides that had a side chain comprising additional nitrogen atoms in place of the original 10-methyl group. Surprisingly, introduction of the side chain at C-10 led to reduced cytochrome inhibition and increased metabolic stability. As a result, the limited ability to inhibit CYP3A4 would relieve the drug-drug interaction and improve the safety of drug co-administration. EXPERT OPINION: This invention opens a new avenue for future modifications to the erythromycin family. It remains unclear how the side chain effected on reduction of CYP inhibition. To fully identify structure-activity relationships, the MIC data of the derivatives on gram-negative bacteria is desirable.

"First-wave" bias when conducting active safety monitoring of newly marketed medications with outcome-indexed self-controlled designs.

Large health care databases are used extensively for pharmacoepidemiologic studies. Unique methodological issues arise when applying self-controlled designs (i.e., using within-person comparisons) for active surveillance of newly marketed drugs. We use 3 examples to illustrate bias related to population-level exposure time trends when using outcome-indexed self-controlled (i.e., case-crossover) designs for active surveillance and evaluate the ability of the case-time-control design to adjust for bias from population-level exposure time trends. We mimicked active surveillance by conducting sequential analyses after market entry for 3 medications and outcomes (valdecoxib for myocardial infarction (MI), aripiprazole for MI, and telithromycin for acute liver failure) using Medicaid Analytic eXtracts (from all 50 US states, 2000-2006). The case-crossover exposure odds ratio (EOR) in the months immediately following valdecoxib market entry implausibly suggested a 12-fold higher risk of MI during exposed time relative to unexposed time; among age-, sex-, and time-matched controls, the corresponding EOR of 4.5 indicated strong population-level exposure time trends. Over subsequent monitoring periods, case-crossover EORs rapidly dropped to 1.4. Adjustment for bias from population-level exposure time trends with the case-time-control analysis resulted in more consistent associations between valdecoxib and MI across sequential monitoring periods. Similar results were observed in each example. Strong population-level exposure time trends can bias case-crossover studies conducted among "first-wave" users of newly marketed medications. Suggested strategies can help assess and adjust for population-level exposure time trends.

The wobbly status of ketolides: where do we stand?

Ketolides are erythromycin A derivatives with a keto group replacing the cladinose sugar and an aryl-alkyl group attached to the lactone macrocycle. The aryl-alkyl extension broadens its antibacterial spectrum to include all pathogens responsible for community-acquired pneumonia (CAP): Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis as well as atypical pathogens (Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila). Ketolides have extensive tissue distribution, favorable pharmacokinetics (oral, once-a-day) and useful anti-inflammatory/immunomodulatory properties. Hence, they were considered attractive additions to established oral antibacterials (quinolones, ß-lactams, second-generation macrolides) for mild-to-moderate CAP. The first ketolide to be approved, Sanofi-Aventis' telithromycin (RU 66647, HMR 3647, Ketek®), had tainted clinical development, controversial FDA approval and subsequent restrictions due to rare, irreversible hepatotoxicity that included deaths. Three additional ketolides progressed to non-inferiority clinical trials vis-à-vis clarithromycin for CAP. Abbott's cethromycin (ABT-773), acquired by Polymedix and subsequently by Advanced Life Sciences, completed Phase III trials, but its New Drug Application was denied by the FDA in 2009. Enanta's modithromycin (EDP-420), originally codeveloped with Shionogi (S-013420) and subsequently by Shionogi alone, is currently in Phase II in Japan. Optimer's solithromycin (OP-1068), acquired by Cempra (CEM-101), is currently in Phase III. Until this hepatotoxicity issue is resolved, ketolides are unlikely to replace established antibacterials for CAP, or lipoglycopeptides and oxazolidinones for gram-positive infections.

Telithromycin: review of adverse effects.

Telithromycin is a macrolide antibiotic that has been marketed since the early 2000s. It has not been shown to be more effective against any bacteria than other macrolide antibiotics. Its antibacterial activity is in no way remarkable. In early 2014, we reviewed its adverse effect profile using data from periodic safety update reports, drug regulatory agencies, and detailed published case reports. In addition to the adverse effect profile telithromycin shares with the other macrolides, it provokes several specific adverse effects: visual disturbances due to impaired accommodation; taste and smell disorders; severe liver damage; worsening of myasthenia gravis; rhabdomyolysis; and loss of consciousness. Prolongation of the QT interval with standard oral doses is a worrisome adverse effect. In practice, it is better not to use telithromycin as it exposes patients to disproportionate, serious adverse effects. When treatment with a macrolide antibiotic appears necessary, it is prudent to choose a different macrolide, such as spiramycin or azithromycin, which have fewer adverse effects.

Telithromycin versus clarithromycin for the treatment of community-acquired respiratory tract infections: a meta-analysis of randomized controlled trials.

BACKGROUND: The emergence of bacterial resistance to commonly used antibiotics, such as macrolides, is complicating the management of respiratory tract infections (RTIs). Telithromycin, a ketolide antimicrobial structurally related to macrolides, is approved for the treatment of community-acquired RTIs, and shows lower pathogen resistance rates. The purpose of this study was to compare the efficacy and safety of telithromycin with clarithromycin, a macrolide routinely used as therapy for RTIs. METHODS: We performed a meta-analysis of relevant randomized-controlled trials (RCTs) identified in PubMed, the Cochrane Library, Embase, CNKI and VIP databases. The primary efficacy outcome was clinical treatment success assessed at the test-of-cure time in the per-protocol population, and the primary safety outcome was drug related adverse effects. RESULTS: Seven RCTs, involving 2845 patients with RTIs, were included in the meta-analysis. Oral telithromycin and clarithromycin showed a similar clinical treatment success in modified intention to treat and per-protocol population (cure and improvement) (odds ratios (ORs): 0.84, 95% confidence intervals (CI): 0.64 - 1.11 and OR: 1.14, 95%CI: 0.71 - 1.85, respectively). Similar findings were obtained for secondary efficacy outcomes: clinical treatment success at a late post-therapy visit (OR: 0.92, 95%CI: 0.57 - 1.48) and microbiological treatment success at the test-of-cure time (OR: 1.14; 95%CI: 0.71 - 1.85). The safety outcome analysis indicated telithromycin had a similar risk of drug-related adverse effect and serious adverse effect with clarithromycin. CONCLUSIONS: Our findings indicate that oral telithromycin and clarithromycin have similar treatment efficacy and adverse effect. The advantages of lower antimicrobial resistance rates, once-daily short-duration dosing and reported lower health-care costs make oral telithromycin a useful option for the empiric management of mild-to-moderate RTIs.

The logic of strategic ignorance.

Ignorance and knowledge are often thought of as opposite phenomena. Knowledge is seen as a source of power, and ignorance as a barrier to consolidating authority in political and corporate arenas. This article disputes this, exploring the ways that ignorance serves as a productive asset, helping individuals and institutions to command resources, deny liability in the aftermath of crises, and to assert expertise in the face of unpredictable outcomes. Through a focus on the Food and Drug Administration's licensing of Ketek, an antibiotic drug manufactured by Sanofi-Aventis and linked to liver failure, I suggest that in drug regulation, different actors, from physicians to regulators to manufacturers, often battle over who can attest to the least knowledge of the efficacy and safety of different drugs - a finding that raises new insights about the value of ignorance as an organizational resource.

Active safety monitoring of newly marketed medications in a distributed data network: application of a semi-automated monitoring system.

We developed a semi-automated active monitoring system that uses sequential matched-cohort analyses to assess drug safety across a distributed network of longitudinal electronic health-care data. In a retrospective analysis, we show that the system would have identified cerivastatin-induced rhabdomyolysis. In this study, we evaluated whether the system would generate alerts for three drug-outcome pairs: rosuvastatin and rhabdomyolysis (known null association), rosuvastatin and diabetes mellitus, and telithromycin and hepatotoxicity (two examples for which alerting would be questionable). Over >5 years of monitoring, rate differences (RDs) in comparisons of rosuvastatin with atorvastatin were -0.1 cases of rhabdomyolysis per 1,000 person-years (95% confidence interval (CI): -0.4, 0.1) and -2.2 diabetes cases per 1,000 person-years (95% CI: -6.0, 1.6). The RD for hepatotoxicity comparing telithromycin with azithromycin was 0.3 cases per 1,000 person-years (95% CI: -0.5, 1.0). In a setting in which false positivity is a major concern, the system did not generate alerts for the three drug-outcome pairs.

Cethromycin versus clarithromycin for community-acquired pneumonia: comparative efficacy and safety outcomes from two double-blinded, randomized, parallel-group, multicenter, multinational noninferiority studies.

Community-acquired pneumonia (CAP) continues to be a major health challenge in the United States and globally. Factors such as overprescribing of antibiotics and noncompliance with dosing regimens have added to the growing antibacterial resistance problem. In addition, several agents available for the treatment of CAP have been associated with serious side effects. Cethromycin is a new ketolide antibiotic that may provide prescribing physicians with an additional agent to supplement a continually limited armamentarium. Two global phase III noninferiority studies (CL05-001 and CL06-001) to evaluate cethromycin safety and efficacy were designed and conducted in patients with mild to moderate CAP. Study CL05-001 demonstrated an 83.1% clinical cure rate in the cethromycin group compared with 81.1% in the clarithromycin group (95% confidence interval [CI], -4.8%, +8.9%) in the intent to treat (ITT) population and a 94.0% cethromycin clinical cure rate compared with a 93.8% clarithromycin cure rate (95% CI, -4.5%, +5.1%) in the per protocol clinical (PPc) population. Study CL06-001 achieved an 82.9% cethromycin clinical cure rate in the ITT population compared with an 88.5% clarithromycin cure rate (95% CI, -11.9%, +0.6%), whereas the clinical cure rate in the PPc population was 91.5% in cethromycin group compared with 95.9% in clarithromycin group (95% CI, -9.1%, +0.3%). Both studies met the primary endpoints for clinical cure rate based on predefined, sliding-scale noninferiority design. Therefore, in comparison with clarithromycin, these two noninferiority studies demonstrated the efficacy and safety of cethromycin, with encouraging findings of efficacy in subjects with Streptococcus pneumoniae bacteremia. No clinically significant adverse events were observed during the studies. Cethromycin may be a potential oral therapy for the outpatient treatment of CAP.

Understanding the regulatory hurdles for antibacterial drug development in the post-Ketek world.

The antibiotic telithromycin (Ketek, Sanofi-aventis) had two of three treatment indications withdrawn after postmarketing reports of serious and fatal adverse events. The rationale for the withdrawal of specific indications (acute bacterial sinusitis and acute exacerbations of chronic bronchitis), while permitting the drug to remain available for the treatment of community-acquired pneumonia, focused on the lack of demonstrated efficacy from clinical trials that included an active control to which the investigational drug, telethromycin, was determined to be statistically noninferior. This action regarding telithromycin represents a reversal of previous FDA guidelines for the conduct of clinical trials for antibacterial treatment indications and has increased the regulatory risk for future drug development. New clinical trial guidelines have been published that will increase the time and resources required to achieve regulatory marketing approval. This paper reviews recent regulatory actions and discusses the impact these new guidelines will have on future antibacterial clinical trial designs and challenges.

Influencia de una alerta sanitaria sobre la utilización de telitromicina / Influence of a regulatory safety warning on the use of telithromycin

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Molecular characterization of off-target activities of telithromycin: a potential role for nicotinic acetylcholine receptors.

Adverse effects have limited the clinical use of telithromycin. Preferential inhibition of the nicotinic acetylcholine receptors (nAChR) at the neuromuscular junction (α3ß2 and NMJ), the ciliary ganglion of the eye (α3ß4 and α7), and the vagus nerve innervating the liver (α7) could account for the exacerbation of myasthenia gravis, the visual disturbance, and the liver failure seen with telithromycin use. The studies presented here enable the prediction of expected side effects of macrolides in development, such as solithromycin (CEM-101).

Neuropsychological effects of macrolides.

Pharmacovigilance data collected from several European countries show that macrolides can provoke neuropsychological adverse effects such as hallucinations, delirium, manic episodes and sometimes depression, in both adults and children. These effects seem to be rare and are reversible on macrolide withdrawal. In practice, keep in mind that if neuropsychological disorders can be attributed to macrolides, treatment should be halted.

Telithromycin: visual disorders.

Telithromycin is a macrolide antibiotic with a negative risk-benefit balance. Its efficacy is no better than that of other macrolides. Telithromycin carries a risk of serious adverse effects, including loss of consciousness, QT prolongation, severe liver damage, aggravation of myasthenia gravis, and a high risk of drug interactions. In Finland, a 7-year pharmacovigilance review identified 20 reports of visual disorders among patients taking telithromycin, including blurred vision, accommodation disorder and diplopia, mainly in young patients and women. Visual disorders occurred in about 1% of patients receiving telithromycin in clinical trials. They were generally moderate, brief and reversible. These visual disorders may result from reversible paralysis of the ciliary body due to telithromycin. In practice, these visual disorders, which can be dangerous when driving or operating heavy machinery, add to the already long list of adverse effects of telithromycin.They are yet another reason not to use telithromycin, but rather a safer macrolide such spiramycin.

Macrolides, ketolides, and glycylcyclines: azithromycin, clarithromycin, telithromycin, tigecycline.

The advanced macrolides, azithromycin and clarithromycin, and the ketolide, telithromycin, are structural analogs of erythromycin. They have several distinct advantages when compared with erythromycin, including enhanced spectrum of activity, more favorable pharmacokinetics and pharmacodynamics, once-daily administration, and improved tolerability. Clarithromycin and azithromycin are used extensively for the treatment of respiratory tract infections, sexually transmitted diseases, and Helicobacter pylori-associated peptic ulcer disease. Telithromycin is approved for the treatment of community-acquired pneumonia. Severe hepatotoxicity has been reported with the use of telithromycin.