minocycline and Drug-Related-Side-Effects-and-Adverse-Reactions

Oral minocycline is a mainstay of therapy for moderate-to-severe acne; however, systemic side effects which include hepatotoxicity, lupus-like syndrome, drug hypersensitivity syndrome, autoimmune hepatitis, polyarteritis nodosa, gastrointestinal side effects and skin hyperpigmentation are of concern. Topical antibiotics commonly used in acne, such as erythromycin and clindamycin, present high P. acnes resistance rates which has opened the market for new topical antibiotics. FMX-101 is a novel topical minocycline foam that has shown promising results in phase I, II and III trials for the treatment of moderate-to-severe acne with a better safety profile than oral minocycline.. The author provides an overview FMX-101 including its clinical efficacy and safety. The author then provides their expert opinion on this treatment and its potential for the treatment option for acne.. The topical foam formulation of FMX-101 has been shown to reduce both inflammatory and non-inflammatory lesions and to improve IGA scores in patients with moderate-to-severe acne without significant systemic absorption thus limiting associated side effects. Overall, the proven efficacy and safety profile of FMX-101, together with the low systemic absorption, high skin tolerability and cosmetically acceptable foam formulations render this novel therapy an important addition to the acne treatment armamentarium.

Topics: Acne Vulgaris; Administration, Cutaneous; Anti-Bacterial Agents; Drug-Related Side Effects and Adverse Reactions; Humans; Minocycline; Randomized Controlled Trials as Topic; Skin; Treatment Outcome

Multidrug-resistant (MDR) Acinetobacter baumannii infections have emerged as a serious threat worldwide. As novel agents have yet to be developed, understanding the effectiveness and safety of older antibiotics has become a priority. The purpose of this systematic review was to summarise the available clinical evidence on the use of tetracyclines for the treatment of A. baumannii infections. Ten retrospective studies regarding doxycycline and minocycline for the treatment of 185 A. baumannii infections (of which 65.4% were respiratory infections and 13% were bloodstream infections) in 156 patients were available. In most cases (86.4%), tetracyclines were administered in combination with another agent. The usual dosage of doxycycline or minocycline was 100mg intravenous or per os twice daily (usually with a 200mg loading dose for minocycline). Clinical success was achieved in 120 (76.9%) of 156 patients; in 87 (71.9%) of 121 respiratory infections and in 21 (87.5%) of 24 bloodstream infections. Twenty-two deaths occurred in 100 recorded cases. Microbiological eradication was attained in 72 (71.3%) of 101 available cases and documented microbiological eradication was reached in 59 (66.3%) of 89 available cases. Adverse events were noted in only 1 of 88 cases. Overall, although tetracycline-containing regimens showed encouraging results, more data from larger comparative trials are required to establish a role for these antibiotics in the treatment of MDR A. baumannii infections.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Anti-Bacterial Agents; Bacteremia; Doxycycline; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Humans; Minocycline; Respiratory Tract Infections; Survival Analysis; Treatment Outcome

Tigecycline is approved for the treatment of complicated skin and soft-tissue infections (cSSTIs) and complicated intra-abdominal infections (cIAIs) in adults. In this analysis the safety and tolerability profile of tigecycline (used alone or in combination) for the treatment of patients with approved indications of cSSTI and cIAI were examined under real-life clinical conditions.. Individual patient-level data were pooled from five European observational studies (July 2006 to October 2011). A total of 254 cSSTI and 785 cIAI patients were included. The mean age was 63 years; 34.4% and 56.6% were in intensive care units, 90.9% and 88.1% had at least one comorbidity and mean Acute Physiology and Chronic Health Evaluation (APACHE) II scores at the beginning of treatment were 15.0 ± 7.9 and 16.9 ± 7.6, respectively.. Data on adverse events (AEs) were available for 198 cSSTI and 590 cIAI patients in three studies. Nausea and vomiting were reported in ≤ 2% of patients. The most common serious AEs were multi-organ failure (4.0% and 10.0% in cSSTI and cIAI patients, respectively) and sepsis (4.0% and 6.1%, respectively). Death was recorded for 24/254 (9.4%) cSSTI and 147/785 (18.7%) cIAI patients. Mortality rates were higher in the group with a baseline APACHE II score of >15 compared with those with a score of ≤ 15 (18.7% versus 3.5% for cSSTI patients and 23.8% versus 16.0% for cIAI patients). A similar trend was seen when cIAI patients were stratified by Sequential Organ Failure Assessment (SOFA) score.. The safety and tolerability of tigecycline, alone and in combination, are consistent with the level of critical illness among patients in these real-life studies.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Infections; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Europe; Female; Humans; Intraabdominal Infections; Male; Middle Aged; Minocycline; Skin Diseases, Bacterial; Soft Tissue Infections; Tigecycline

Minocyline is a tetracycline derivative with anti-inflammatory, anti-apoptotic, and anti-oxidant properties. Therapy has proved useful in some experimental models of both noninfectious and infectious neurological diseases and also in clinical trials in humans, including acute traumatic cervical spinal cord injury. In models of viral encephalitis, treatment has shown both beneficial and deleterious effects. In reovirus infection in mice, minocycline delayed the disease, but did not improve either the morbidity or mortality of the disease. In neuroadapted Sindbis virus infection of mice, minocycline prevented disease, but therapy needed to be given before clinical signs were present in most of the animals. In experimental rabies in neonatal mice minocycline aggravated the disease, likely related to anti-inflammatory effects. Minocycline has also been shown to aggravate disease in a mouse model of Huntington disease, in a monkey model of Parkinson disease, and in a mouse model of hypoxic-ischemic brain injury. Hence, there is experimental evidence of benefit of minocycline in both infectious and noninfectious neurological diseases, but there is a lack of benefit and harmful effects in other diseases. This may reflect multiple mechanisms of actions that cannot be predicted in a new disease or in an infection caused by a specific viral agent. Minocycline therapy is a double-edged sword and this drug should not be given empirically to patients with acute viral encephalitis for anticipated neuroprotective effects. Much more work needs to be done in experimental models in animals as well as in clinical trials. Because patient enrollment in clinical trials on acute viral encephalitis has proven to be difficult, funding will be a challenge.

Topics: Animals; Anti-Inflammatory Agents; Drug-Related Side Effects and Adverse Reactions; Encephalitis, Viral; Encephalomyelitis; Mice; Minocycline; Treatment Outcome

Topics: Acne Vulgaris; Administration, Oral; Anti-Bacterial Agents; Azithromycin; Drug Costs; Drug-Related Side Effects and Adverse Reactions; Erythromycin; Evidence-Based Medicine; Humans; Minocycline

Drug-induced lupus erythematosus (DILE) is defined as an entity characterized by clinical manifestations and immunopathological serum findings similar to those of idiopathic lupus but which is temporally related to continuous drug exposure and resolves after discontinuation of the offending drug. Similar to idiopathic lupus, DILE can be divided into systemic lupus erythematosus (SLE), subacute cutaneous lupus erythematosus (SCLE) and chronic cutaneous lupus erythematosus (CCLE). Based on the literature review and retrospective analysis of our case series, we focused on the dermatological aspects of DILE. The cutaneous features of drug-induced SLE are protean, including particularly purpura, erythema nodosum and photosensitivity as well as the skin lesions characterizing both urticarial and necrotizing vasculitis. The typical laboratory profile of systemic DILE consists of positive antinuclear antibodies (ANA) and antihistone antibodies, the latter being regarded as the serum marker of this subset. The drugs most frequently implicated in the development of systemic DILE are hydralazine, procainamide, isoniazid and minocycline. Drug-induced SCLE usually presents with annular polycyclic or papulosquamous cutaneous manifestations as in the idiopathic form, but blisters or targetoid lesions mimicking erythema multiforme cannot rarely be associated. The clinical presentation is often generalized, with involvement of the lower legs that are usually spared in idiopathic SCLE. ANA and anti-Ro/SSA antibodies are usually present, whereas antihistone antibodies are uncommonly found. Drugs associated with SCLE include particularly calcium channel blockers, angiotensin-converting enzyme inhibitors, thiazide diuretics, terbinafine and the recently reported tumour necrosis factor (TNF)-alpha antagonists. Drug-induced CCLE is very rarely described in the literature and usually refers to fluorouracile agents or TNF-alpha antagonists. The picture is characterized by the occurrence of classic discoid lesions, but aspects of lupus tumidus can occasionally develop. ANA are demonstrated in around two-thirds of the cases. Management of DILE is based on the withdrawal of the offending drug. Topical and/or systemic corticosteroids and other immunosuppressive agents should be reserved for resistant cases.

Topics: Anti-Arrhythmia Agents; Anti-Bacterial Agents; Antihypertensive Agents; Antitubercular Agents; Autoantibodies; Drug-Related Side Effects and Adverse Reactions; Humans; Hydralazine; Isoniazid; Lupus Erythematosus, Cutaneous; Lupus Erythematosus, Discoid; Lupus Erythematosus, Systemic; Minocycline; Procainamide; Skin Diseases

It is essential that every health care professional who is involved with the prescription or recommendation of drugs be fully aware of any resultant disorders that may arise as a side-effect. A range of drugs can affect the teeth. In this review article, drugs that have the potential to induce changes in teeth have been classified as those leading to tooth discoloration (intrinsic and extrinsic), physical damage to tooth structure (enamel, dentin, and cementum), and alteration in tooth sensitivity.

Topics: Carbohydrates; Chlorhexidine; Drug-Related Side Effects and Adverse Reactions; Fluorides; Fluorosis, Dental; Humans; Minocycline; Mouthwashes; Root Resorption; Saliva; Tetracycline; Tooth Bleaching; Tooth Discoloration; Tooth Diseases; Tooth Erosion; Toothache

A phase 3, randomized, double-blind trial was conducted in subjects with diabetic foot infections without osteomyelitis (primary study) or with osteomyelitis (substudy) to determine the efficacy and safety of parenteral (intravenous [iv]) tigecycline (150 mg once-daily) versus 1 g once-daily iv ertapenem ± vancomycin. Among 944 subjects in the primary study who received ≥1 dose of study drug, >85% had type 2 diabetes; ~90% had Perfusion, Extent, Depth/tissue loss, Infection, and Sensation infection grade 2 or 3; and ~20% reported prior antibiotic failure. For the clinically evaluable population at test-of-cure, 77.5% of tigecycline- and 82.5% of ertapenem ± vancomycin-treated subjects were cured. Corresponding rates for the clinical modified intent-to-treat population were 71.4% and 77.9%, respectively. Clinical cure rates in the substudy were low (<36%) for a subset of tigecycline-treated subjects with osteomyelitis. Nausea and vomiting occurred significantly more often after tigecycline treatment (P = 0.003 and P < 0.001, respectively), resulting in significantly higher discontinuation rates in the primary study (nausea P = 0.007, vomiting P < 0.001). In the primary study, tigecycline did not meet criteria for noninferiority compared with ertapenem ± vancomycin in the treatment of subjects with diabetic foot infections.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; beta-Lactams; Diabetic Foot; Drug-Related Side Effects and Adverse Reactions; Ertapenem; Female; Humans; Male; Middle Aged; Minocycline; Nausea; Osteomyelitis; Tigecycline; Treatment Outcome; Vancomycin; Vomiting; Young Adult

We report the largest clinical experience using tigecycline-containing regimens for salvage treatment of patients with Mycobacterium abscessus and Mycobacterium chelonae.. Data were collected from 52 patients on emergency/compassionate use (n = 38) or two open-label studies (n = 7 patients each). Based on information that was available, 46 (88.5%) of the subjects received antibiotic therapy prior to treatment with tigecycline. Treatment groups were evaluated based on length of tigecycline therapy (<1 and ≥1 month). ClinicalTrials.gov identifiers: Study 205, NCT00600600 and Study 310, NCT00205816.. The most commonly used concomitant antimicrobials were macrolides, amikacin and linezolid. Pulmonary disease was the most common presentation (36/52; 69.2%), and 58.3% of these patients had underlying cystic fibrosis. The majority were M. abscessus complex (n = 30) or M. chelonae/abscessus (n = 4). With therapy ≥1 month (mean, 255.0 ± 265.7 days), 10/15 patients (66.7%) with cystic fibrosis and 16/26 (61.5%) overall were considered improved. Skin/soft-tissue/bone infections were the most common extrapulmonary infections. With therapy ≥1 month (mean, 143 ± 123 days), 9/12 patients (75.0%) were considered improved. Nine of the 16 cases reported as failures regardless of site of infection occurred in patients who stopped treatment due to adverse events. There were eight deaths; none was related to tigecycline.. Tigecycline given for ≥1 month as part of a multidrug regimen resulted in improvement in >60% of patients with M. abscessus and M. chelonae infections, including those with underlying cystic fibrosis, despite failure of prior antibiotic therapy. Adverse events were reported in >90% of cases, the most common being nausea and vomiting.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Child; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Minocycline; Mycobacterium Infections, Nontuberculous; Nausea; Nontuberculous Mycobacteria; Salvage Therapy; Tigecycline; Treatment Outcome; Young Adult

Background While tetracycline antibiotics are commonly prescribed in practice, the risk of drug-induced liver injury (DILI) remains controversial. Aim To evaluate the association of DILI with tetracycline antibiotics. Method All DILI cases of tetracycline antibiotics as primary suspected drugs were extracted from the US Food and Drug Administration adverse event reporting system (FAERS). The outcomes included severe DILI, hepatocellular injury, cholestatic injury, and liver failure. Disproportionality analyses were conducted by estimating the reporting odds ratio (ROR) and the information component (IC). Results A total of 1,435 liver injury cases associated with tetracycline antibiotics were identified. The DILI signal was detected in tigecycline, minocycline, and doxycycline. The RORs and the 95% confidence intervals (95% CI) of tigecycline, minocycline, and doxycycline were (ROR 5.85, 95% CI 4.96-6.91), (ROR 6.4, 95% CI 5.76-7.11), and (ROR 2.07, 95% CI 1.86-2.31), respectively. Compared to minocycline (ROR 5.5, 95% CI 4.94-6.12; IC 2.35, 95% CI 1.98-2.68) and doxycycline (ROR 1.91, 95% CI 1.71-2.12; IC 0.91, 95% CI 0.55-1.26), tigecycline showed a stronger association with hepatocellular injury (ROR 7.11, 95% CI 6.13-8.23; IC 2.68, 95% CI 2.16-3.13). Tigecycline also showed a stronger association with cholestatic injury (ROR 12.16, 95% CI 10.13-14.61; IC 3.51, 95% CI 2.79-4) than minocycline (ROR 3.23, 95% CI 2.59-4.04; IC 1.67, 95% CI 0.9-2.37) or doxycycline (ROR 2.86, 95% CI 2.47-3.31; IC 1.5, 95% CI 1-1.97). Tigecycline (ROR 6.56, 95% CI 4.57-9.41; IC 2.69, 95% CI 1.28-3.64) and minocycline (ROR 4.22, 95% CI 3.14-5.66; IC 2.06, 95% CI 1-2.93) showed a significant association with liver failure. Conclusion The data mining of FAERS suggested an association between DILI and tigecycline, minocycline, and doxycycline.

Topics: Adverse Drug Reaction Reporting Systems; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Doxycycline; Drug-Related Side Effects and Adverse Reactions; Humans; Liver Failure; Minocycline; Pharmacovigilance; Tigecycline; United States; United States Food and Drug Administration

While epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) exert a breakthrough effect, the incidence of skin disorders as a side effect has significantly reduced patients' quality of life. This study aimed to develop a treatment for inflammatory ulcers as one of the side effects of afatinib (Giotrif®), a second-generation EGFR-TKI, and established a skin disorder mouse model to investigate the protective effect of minocycline.. First, under inhalation anesthesia with isoflurane, the back of a male ddy mouse was shaved, and afatinib petrolatum was applied alone or in combination with minocycline to observe the state of the skin and measure transepidermal water transpiration (TEWL). Next, afatinib was administered orally to mice, and minocycline petrolatum was applied to observe whether the skin disorder was prevented and its effect on repair of the skin disorder.. Skin injury occurred on the back of the mouse following afatinib (1 mg/g in petrolatum) application, and scab formation was observed. Application of minocycline prevented and improved the skin disorder caused by afatinib. When the minocycline-petrolatum mixture was applied to the mouse that developed the skin disorder, a significant improvement in TEWL was observed, and skin repair was observed macroscopically.. These results suggest that minocycline petrolatum applied locally prevents and repairs afatinib-induced skin disorders of non-small cell lung cancer patients. Histological examination of skin has provided insights into the mechanism of the occurrence of afatinib-related skin disorder and suggested the efficacy of minocycline topical application in clinical practice.

Topics: Afatinib; Animals; Anti-Bacterial Agents; Carcinoma, Non-Small-Cell Lung; Disease Models, Animal; Drug-Related Side Effects and Adverse Reactions; ErbB Receptors; Humans; Lung Neoplasms; Male; Mice; Minocycline; Protein Kinase Inhibitors; Quality of Life; Skin Diseases

Topics: Acne Vulgaris; Adolescent; Diagnosis, Differential; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Female; Fever; Humans; Magnetic Resonance Imaging; Minocycline; Positron-Emission Tomography; Risk Factors; Sweating; Vasculitis; Weight Loss; Withholding Treatment

The off-label uses of tigecycline (TGC) to treat ventilator-associated pneumonia (VAP) have aroused worldwide concerns. The efficacy about TGC has been recently reported. However, the adverse events (AEs) remain controversial. Our study aims to analyze the safety of the high-dose (HD) regimens in the treatment of VAP due to multidrug-resistant (MDR) pathogens.The clinical data of 134 patients who were diagnosed with VAP from January 2013 to December 2015 in the NeuroScience Care Unit (NCU) were analyzed retrospectively. The incidence and the occurrence time of AEs, 28-day mortality, and the factors of clinical effectiveness were explored.A total of 54 patients received the standard dose group (SD), 69 in the HD, and 11 in the nonstandard HD group (NHD). Acinetobacter baumannii were the main pathogenic bacteria. There was no statistic difference in the incidence of AEs and the 28-day mortality among the 3 groups (P > .05). Total bilirubin (TBIL) increased significantly after SD of TGC treatment (P = .004). Liver dysfunction occurred the latest (10.83 ± 7.08), not in the duration of HD group (9.63 ± 3.92), whereas in the SD group (13.00 ± 7.57) and NHD group (12.64 ± 3.70). Patients with septic shock, MODS, and higher APACHE II score were of high risk in mortality. The HD group was associated with higher clinical effective rate and bacteria clearance rate.HD TGC was relatively safe and tolerable in ICU patients. The risk of side effects was related to the TGC duration, although not increased as the dosage rose. Full course of the HD regimen was associated with better outcomes for the treatment of VAP patients, especially for the MDR gram-negative bacilli infection. Inappropriate antimicrobial treatment might lead to clinical treatment failure.

Topics: Acinetobacter baumannii; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Drug-Related Side Effects and Adverse Reactions; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Minocycline; Pneumonia, Ventilator-Associated; Tigecycline; Treatment Outcome; Young Adult

Topics: Aged; Anti-Bacterial Agents; Diagnosis, Differential; Drug-Related Side Effects and Adverse Reactions; Humans; Hyperpigmentation; Male; Minocycline; Patient Care Management; Physical Examination

Because of general unavailability of tetracycline, common adverse effects, and complicated administration, the clinical application of bismuth quadruple therapy often faces difficulties. Whether the combination of minocycline and amoxicillin can replace tetracycline and metronidazole for Helicobacter pylori eradication remains unclear. This study was to determine the efficacy, compliance, and safety of rabeprazole, minocycline, amoxicillin, and bismuth (RMAB) therapy as first-line and second-line regimens.. Between July 2013 and December 2015, a total of 160 patients in first-line and 70 patients in second-line therapies received rabeprazole 10 mg, minocycline 100 mg, amoxicillin 1000 mg, and bismuth potassium citrate 220 mg twice daily for 14 days. Eradication status was assessed 6-12 weeks after treatment.. RMAB therapy achieved the eradication rates of 87.5% (95% confidence interval, 81.9-92.5%, intention-to-treat analysis), 90.9% (85.7-95.5%, modified intention-to-treat analysis), and 92.6% (88.5-96.6%, per-protocol analysis) in first-line therapy in a setting with high antibiotic resistance rates (amoxicillin 3.4%, clarithromycin 39.7%, metronidazole 60.3%, levofloxacin 36.2%, tetracycline 3.4%, and minocycline 6.9%). As for second-line therapy, the eradication rates were 82.9% (74.3-91.4%, intention-to-treat analysis), 86.6% (77.6-94.0%, modified intention-to-treat analysis), and 89.1% (81.3-95.3%, per-protocol analysis). Totally, 24.0% patients had adverse effects, 2.2% discontinued medications, and good compliance was achieved in 94.7%. Poor compliance and minocycline resistance were identified as the risk factors for treatment failure. Significant differences in efficacy existed among the groups of both sensitive (48/51 and 18/20), isolated amoxicillin resistance (1/1 and 0/0), isolated minocycline resistance (2/3 and 1/1), and dual resistance (0/1 and 0/1) in both first-line (p = .004) and second-line (p = .035) therapies.. The eradication efficacies of RMAB therapy as first-line and second-line regimens were satisfactory with good compliance and safety in a region with high antibiotic resistance.

Topics: Adult; Amoxicillin; Anti-Bacterial Agents; Anti-Ulcer Agents; Bismuth; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Helicobacter Infections; Humans; Male; Medication Adherence; Middle Aged; Minocycline; Prospective Studies; Rabeprazole; Treatment Outcome

Scrub typhus, caused by Orientia tsutsugamushi, has recently emerged in northern China where the disease had not been known to exist. Although doxycycline and azithromycin are the recommended agents for the treatment of scrub typhus, clinical responses depend both on the susceptibilities of various O. tsutsugamushi strains and the severity of the disease. A retrospective analysis was conducted on patients diagnosed with mild scrub typhus from August 2013 to January 2016 in the Affiliated Hospital of Nantong University, northern China. A total of 40 patients who received minocycline treatment and 34 patients who received azithromycin treatment were included in the analysis. All patients except one defervesced within 120 h after initiating antimicrobial therapy. Kaplan-Meier curves in association with log-rank test showed that the median time to defervescence was significantly shorter for the minocycline-treated group than the azithromycin-treated group (P = 0.003). There were no serious adverse events during treatment. No relapse occurred in either group during the 1-month follow-up period. In conclusion, both minocycline and azithromycin are effective and safe for the treatment of mild scrub typhus, but minocycline is more active than azithromycin against O. tsutsugamushi infection acquired in northern China.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Azithromycin; China; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Minocycline; Pregnancy; Retrospective Studies; Scrub Typhus; Time Factors; Treatment Outcome; Young Adult

Tigecycline (TGC) is a first-in-class glycylcycline with an expanded spectrum of activity. Although TGC has not been prospectively studied in febrile neutropenia (FN), we observed that occasionally critically ill neutropenic patients unresponsive to other antibiotics were treated with TGC in our departments. The aim of our study was to analyse effectiveness and toxicity of TGC in FN.. Data of infectious episodes treated with TGC were retrospectively collected. Baseline data of patients, haematological malignancy, infection and adverse events were documented. Success was defined as defervescence (≥7 days) in the absence of any sign of persistent infection.. Data of 35 patients with haematological malignancies and FN were evaluated. Median duration of neutropenia was 25 days (range 6-69 days). The type of infection was pneumonia in 24 patients, four microbiologically documented infections, three clinically documented infections and four with fever of unknown origin. The TGC was administered after a median of two (range 1-5) prior antibiotic regimens. Treatment was successful in 15 (43 %) patients. In patients with prolonged neutropenia (≥28 days), response was significantly lower (13 vs. 79 %; p =0.001). Eight (23 %) patients died during the fever episode. Grade 3-4 toxicity occurred in five (14 %) patients.. Our results showed promising response rates to TGC and very low toxicity rates compared to the generally low response rate of third-line antibiotic therapies, indicating that TGC may be a successful alternative for salvage treatment of febrile neutropenia, but further study is needed.

Topics: Adult; Aged; Anti-Bacterial Agents; Chemotherapy-Induced Febrile Neutropenia; Drug-Related Side Effects and Adverse Reactions; Female; Hematologic Neoplasms; Hospitals, University; Humans; Male; Middle Aged; Minocycline; Retrospective Studies; Tigecycline; Treatment Outcome

This Supplement in the Journal of Antimicrobial Chemotherapy comprises a series of papers reporting on 'real-life' clinical experience with tigecycline. The data reported are derived from five European observational studies on the use of tigecycline, either as monotherapy or in combination with other antibiotics, for the treatment of complicated skin and soft-tissue infections or complicated intra-abdominal infections. Taken together, this collection of articles gives clinical insight into the use of tigecycline for the treatment of complicated infections.

Topics: Anti-Bacterial Agents; Bacterial Infections; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Europe; Humans; Intraabdominal Infections; Minocycline; Skin Diseases, Bacterial; Soft Tissue Infections; Tigecycline; Treatment Outcome

Topics: Anti-Bacterial Agents; Bacterial Infections; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Europe; Humans; Intraabdominal Infections; Minocycline; Skin Diseases, Bacterial; Soft Tissue Infections; Tigecycline; Treatment Outcome

Tigecycline is approved for cutaneous infections, intra-abdominal infections, and community-acquired pneumonia. However, pharmacokinetic data suggest therapeutic concentrations in additional sites, such as bone, despite exiguous clinical data supporting such use. Thus, the objective of this study was to analyze patients with osteomyelitis treated with tigecycline to ascertain its utility in this malady. Our database of osteomyelitis patients was surveyed for instances treated with tigecycline. Cases were evaluated in terms of adverse events and clinical success. Nineteen patients received tigecycline for osteomyelitis. Thirteen met criteria for evaluation of the primary endpoint of clinical success. The most common dose employed was 50 mg twice daily. Adverse events, however, were not statistically more likely with 100 mg administered once daily. Eleven patients (85%) achieved clinical success. Thus, congruent with pharmacokinetic data, tigecycline appeared efficacious for osteomyelitis in the majority of patients who received it. Adverse events were not correlated with dosing strategy.

Topics: Adult; Anti-Bacterial Agents; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Minocycline; Osteomyelitis; Tigecycline; Treatment Outcome

Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds. Individual data for all 223 compounds are presented here and interrogated to determine what level of an alert to consider termination of a compound. The analysis showed that 76% of drugs with a daily dose of <100 mg were non-hepatotoxic (p < 0.0001). Drugs with a daily dose of ≥100 mg or with GSH adduct formation, marked P450 MDI, or covalent binding ≥200 pmol eq/mg protein tended to be hepatotoxic (∼ 65% in each case). Combining dose with each bioactivation assay increased this association significantly (80-100%, p < 0.0001). These analyses were then used to develop the decision tree and the tree tested using 196 of the compounds with sufficient data (49% hepatotoxic; 51% non-hepatotoxic). The results of these outcome analyses demonstrated the utility of the tree in selectively terminating hepatotoxic compounds early; 45% of the hepatotoxic compounds evaluated using the tree were recommended for termination before candidate selection, whereas only 10% of the non-hepatotoxic compounds were recommended for termination. An independent set of 10 GSK compounds with known clinical hepatotoxicity status were also assessed using the tree, with similar results.

Topics: Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Decision Trees; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Glutathione; Humans; Liver; Pharmaceutical Preparations; Protein Binding

Topics: Anti-Bacterial Agents; Bacterial Infections; Drug-Related Side Effects and Adverse Reactions; Humans; Minocycline; Tigecycline; Treatment Outcome; United States

Drug-induced liver injury (DILI) is a leading cause of drugs failing during clinical trials and being withdrawn from the market. Comparative analysis of drugs based on their DILI potential is an effective approach to discover key DILI mechanisms and risk factors. However, assessing the DILI potential of a drug is a challenge with no existing consensus methods. We proposed a systematic classification scheme using FDA-approved drug labeling to assess the DILI potential of drugs, which yielded a benchmark dataset with 287 drugs representing a wide range of therapeutic categories and daily dosage amounts. The method is transparent and reproducible with a potential to serve as a common practice to study the DILI of marketed drugs for supporting drug discovery and biomarker development.

Topics: Animals; Benchmarking; Biomarkers, Pharmacological; Chemical and Drug Induced Liver Injury; Drug Design; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations; Reproducibility of Results; United States; United States Food and Drug Administration

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alkaline Phosphatase; Anti-Bacterial Agents; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Incidence; Male; Middle Aged; Minocycline; Tigecycline; Young Adult

Topics: Adult; Anti-Infective Agents; Drug-Related Side Effects and Adverse Reactions; Eosinophilia; Female; Hepatitis; Herpesvirus 6, Human; Humans; Male; Minocycline; Myocarditis; Roseolovirus Infections; Sulfasalazine

(1) In mid-2008 the French National Pharmacovigilance Committee examined spontaneous reports of adverse effects observed during tetracycline therapy; (2) When sales figures are taken into account, reports were more frequent with minocycline than with doxycycline. The proportion of severe adverse effects was also higher with minocycline than with doxycycline; (3) Life-threatening hypersensitivity reactions and autoimmune adverse effects were more frequent with minocycline than with doxycycline; (4) In practice, minocycline has a less favourable risk-benefit balance than doxycycline, particularly in the treatment of acne.

Topics: Acne Vulgaris; Autoimmune Diseases; Doxycycline; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; France; Humans; Minocycline

In a number of adverse drug reactions leading to hepatotoxicity drug metabolism is thought to be involved by generation of reactive metabolites from nontoxic drugs. In this study, an in vitro assay was developed for measurement of the impact of metabolic activation of compound on the cytotoxicity toward a human hepatic cell line. HepG2 cells were treated for 6 h with compound in the presence or absence of rat liver S9-mix, and the viability was measured using the MTT test. The cytotoxicity of cyclophosphamide was substantially increased by S9-mix in the presence of NADPH. Three NADPH sources were tested: NADPH (1 mmol/L) or NADPH regenerating system with either NADP(+)/glucose 6-phosphate (G6P) or NADP(+)/isocitrate. All three NADPH sources increased the cytotoxicity of cyclophosphamide to a similar extent. Eight test compounds known to cause hepatotoxicity were tested. For these, only the cytotoxicity of diclofenac was increased by S9 enzymes when an NADPH regenerating system was used. The increased toxicity was NADPH dependent. Reactive drug metabolites of diclofenac, formed by NADPH-dependent metabolism, were identified by LC-MS. Furthermore, an increase in toxicity, not related to enzymatic activity but to G6P, was observed for diclofenac and minocycline. Tacrine and amodiaquine displayed decreased toxicity with S9-mix, and carbamazepine, phenytoin, bromfenac and troglitazone were nontoxic at all tested concentrations, with or without S9-mix. The results show that this method, with measurement of the cytotoxicity of a compound in the presence of an extracellular metabolizing system, may be useful in the study of cytotoxicity of drug metabolites.

Topics: Animals; Biological Assay; Biotransformation; Cell Death; Cell Line; Cyclophosphamide; Diclofenac; Drug-Related Side Effects and Adverse Reactions; Glucose-6-Phosphate; Humans; Liver; Minocycline; NADP; Rats

Topics: Analgesics; Benzeneacetamides; Benzoates; Bone Density Conservation Agents; Deferasirox; Diphosphonates; Docosahexaenoic Acids; Drug Approval; Drug Combinations; Drug Interactions; Drug Monitoring; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Eicosapentaenoic Acid; gamma-Aminobutyric Acid; Humans; Ibandronic Acid; Iloprost; Indenes; Minocycline; Patient Education as Topic; Phenylacetates; Pregabalin; Tigecycline; Triazoles; Vasodilator Agents

The FDA's Spontaneous Reporting System (SRS) database contains over 1.5 million adverse drug reaction (ADR) reports for 8620 drugs/biologics that are listed for 1191 Coding Symbols for Thesaurus of Adverse Reaction (COSTAR) terms of adverse effects. We have linked the trade names of the drugs to 1861 generic names and retrieved molecular structures for each chemical to obtain a set of 1515 organic chemicals that are suitable for modeling with commercially available QSAR software packages. ADR report data for 631 of these compounds were extracted and pooled for the first five years that each drug was marketed. Patient exposure was estimated during this period using pharmaceutical shipping units obtained from IMS Health. Significant drug effects were identified using a Reporting Index (RI), where RI = (# ADR reports / # shipping units) x 1,000,000. MCASE/MC4PC software was used to identify the optimal conditions for defining a significant adverse effect finding. Results suggest that a significant effect in our database is characterized by > or = 4 ADR reports and > or = 20,000 shipping units during five years of marketing, and an RI > or = 4.0. Furthermore, for a test chemical to be evaluated as active it must contain a statistically significant molecular structural alert, called a decision alert, in two or more toxicologically related endpoints. We also report the use of a composite module, which pools observations from two or more toxicologically related COSTAR term endpoints to provide signal enhancement for detecting adverse effects.

Topics: Adverse Drug Reaction Reporting Systems; Artificial Intelligence; Computers; Databases, Factual; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Endpoint Determination; Models, Molecular; Quantitative Structure-Activity Relationship; Software; United States; United States Food and Drug Administration

The WHO MDT regimens have proved highly successful in preventing relapse of leprosy cases. It has indirectly lad to marked reduction in prevalence of disabilities. For PB leprosy, rifampicin 600 mg monthly and 100 mg dapsone daily for a total of 6 months therapy is required. For MB leprosy clofazimine 300 mg once monthly, supervised and 50 mg daily self administered is added. For single skin lesion the current WHO recommendation is 600 mg rifampicin + 400 mg ofloxacin + 100 mg minocycline given as a single dose for adults. Dose adjustment for children and clinical information have been discussed in a nutshell. A number of trials are going on, some are yet to be completed which do offer the prospect of perhaps simplifying therapy and improving with shorter duration.

Topics: Anti-Bacterial Agents; Clofazimine; Dapsone; Dose-Response Relationship, Drug; Drug Combinations; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; HIV Infections; Humans; Hypersensitivity; India; Leprosy; Minocycline; Nausea; Ofloxacin; Rifampin; Secondary Prevention; Tuberculosis; World Health Organization

Topics: Angiotensin-Converting Enzyme Inhibitors; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antirheumatic Agents; Arthritis; Azathioprine; Calcium Channel Blockers; Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppressive Agents; Minocycline; Mycophenolic Acid; Nifedipine; Pemphigus; Penicillamine; Skin

A review of the 127 cases of drug-induced esophagitis reported since 1970 indicates that commonly used medications may be a source of esophageal injury. Retrosternal pain, odynophagia, and dysphagia were the most commonly reported symptoms and most cases were self-limited with 7 to 10 days of symptomatic therapy. Occasionally, severe odynophagia or dysphagia necessitated hospitalization. Emepronium bromide, tetracycline, and its derivatives, potassium chloride, and quinidine accounted for 89% of the reported cases; the remaining 11% were caused by 14 other medications. Serious sequelae, including death, have been linked to potassium-induced esophageal injury. With other medications, however, serious complications were rare. The diagnostic study of choice for suspected medication-induced esophageal injury is endoscopy, although air contrast barium swallow may often detect subtle mucosal abnormalities. In uncomplicated cases the history alone may be sufficient to make the diagnosis. Concurrent ingestion of adequate amounts of fluid and avoidance of unnecessary bedtime medications may help to prevent medication-induced esophageal injury.

Topics: Adolescent; Adult; Aged; Child; Doxycycline; Drug-Related Side Effects and Adverse Reactions; Emepronium; Esophagitis; Female; Humans; Male; Middle Aged; Minocycline; Potassium Chloride; Quinidine; Tetracycline