Adverse cutaneous reactions and drugs: a focus on antimicrobials.

Rashes are a common adverse event observed during antimicrobial therapy. Many rashes are mild to moderate in intensity, however some reactions can be the prelude to much more severe outcomes such as Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necolysis. Several risk or influencing factors are known such as female gender, age and concomitant viral infections, and these may apply to more than one drug class. The incidence of rashes and other cutaneous reactions vary, however rates of >3% are reported with the beta-lactams while serious reactions such as SJS are observed with trimethoprim-sulphamethoxazole. Newer fluoroquinolone agents are devoid of the moiety which caused phototoxic reactions, while rates of rash vary from < 1%-3% or higher if longer courses of therapy are given. Serious systemic events have not been reported with these agents unlike other older, well-accepted antimicrobials. Rashes, while occasionally itchy and sometimes transiently unsightly, have less of an impact on a patient's daily activities than diarrhea, nausea or other more profound adverse events. However, it is essential that any rash be carefully monitored for possible, but rare, serious systemic events ensuing.

Cutaneous adverse events and gemifloxacin: observations from the clinical trial program.

Cutaneous adverse events are seen with many antimicrobials. A signal was observed with gemifloxacin in the original clinical research program, however subsequent studies and analysis demonstrated a mild-moderate self-limited macular-papular rash seen most frequently when the duration of exposure was beyond 7 days, a non-approved duration. Following administration for 5 days for community-acquired respiratory tract infections the rash rate is typically less than 1.5%, a rate similar to that for other fluoroquinolones and lower than other frequently used community antimicrobials. The rash associated with gemifloxacin has not been linked with cross or subclinical-sensitization nor any systemic manifestations such as Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis. This review describes the extensive studies conducted to support the use of this agent for short durations in community infections.

Short-course therapy of gemifloxacin effective against pneumococcal pneumonia in mice.

Standard 7-14 day (d) courses of antimicrobial therapy for community-acquired pneumonia (CAP) are thought to have contributed to the emergence of resistant pneumoccoci. Consequently, short-course fluoroquinolone regimens have been proposed to minimize resistance. To test this, we examined 2-day versus 5-day regimens of gemifloxacin and levofloxacin for treatment of pneumonia in a murine model. In doing so, we also investigated whether the enhanced potency of gemifloxacin would influence outcomes. CD1 Swiss mice were infected intratracheally with 10(5)-CFU of a virulent Streptococcus pneumoniae strain. Drugs were administered every 8 h for 2 d and 5 d, starting at 24 h postinfection. Temperature was used to assess disease progression. Gemifloxacin remained effective for 2 d and 5 d, with survival rates of 100%-83% compared with 40%-58% for levofloxacin. Eighty-nine to 100% of gemifloxacin-treated mice were clear of pulmonary bacteria compared with only 0%-20% for levofloxacin. For levofloxacin-treated mice, 2 of 7 (29%) isolates with a levofloxacin minimum inhibitory concentration (MIC) 4 times that of the infecting parent strain had ParC mutations. By contrast, no isolates recovered from gemifloxacin-treated mice were reduced in susceptibility. Gemifloxacin could be effective in shortening duration of therapy for CAP treatment as well as minimize resistance development.

Future trends in antimicrobial chemotherapy: expert opinion on the 43rd ICAAC.

The current document bestows an expert synopsis of key new information presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting in 2003. Data is presented on the socio-political aspects of and policies on antimicrobial prescribing, novel mechanisms of resistance in Streptococcus pneumoniae, and current epidemiological trends in global resistance. Novel information on new (and existing) antimicrobial agents--new penicillins, cephalosporins, monobactams and oxipenem inhibitors, ketolides, glycopeptides, fluoroquinolones (and hybrids), peptides, daptomycin, aminomethylcyclines, glycylcyclines, and newer formulations of agents such as amoxycillin-clavulanate--provides renewed hope that resistant pathogens can be controlled through use of more potent agents. Improved strategies for the use of existing antimicrobial agents, such as the use of high-dose regimens, short-course therapy, also may delay or reduce the development of resistance and preserve the value of our antibiotic armamentarium.

Novel murine model of pneumococcal pneumonia: use of temperature as a measure of disease severity to compare the efficacies of moxifloxacin and levofloxacin.

Surface temperature measured by an infrared temperature-scanning thermometer was used to evaluate disease severity and predict imminent death in a murine model of pneumococcal pneumonia. We showed that a decrease in temperature was associated with increasing severity of disease and concomitant histological changes and also that a temperature of 30 degrees C or less was a predictor of death. Furthermore, viable bacterial counts in the lungs of mice euthanized at a temperature of < or = 30 degrees C were not significantly different from those seen in the lungs of mice allowed to die without intervention. These data support temperature change as a more subtle indicator of outcome than death and demonstrate that this could be used as a reliable end point for euthanasia. To test the utility of our model in a drug trial, we examined the efficacies of moxifloxacin and levofloxacin by using temperature as a measure of disease severity prior to and during treatment. Regardless of the antibiotic used, mice assessed as moderately ill (temperature > or = 32 degrees C) at the start of treatment had better clinical and bacteriological outcomes than mice assessed as severely ill (temperature < 32 degrees C). However, moxifloxacin offered better protection and greater bacterial clearance than did levofloxacin in all infected mice independent of disease severity. This model not only allows a more subtle evaluation of drug efficacy but also ensures a better degree of standardization and a more humane approach to drug efficacy studies involving animals.

A new respiratory fluoroquinolone, oral gemifloxacin: a safety profile in context.

Gemifloxacin is a broad-spectrum quinolone antibacterial with enhanced potency against Gram-positive bacteria, including multi-drug resistant Streptococcus pneumoniae, and retained potency against Gram-negative bacilli and bacterial strains resistant to other antibiotics. It has proven particularly effective in respiratory and urinary tract infection. This review presents safety data from 6775 patients included in clinical trials, receiving either the recommended 320 mg once daily oral dose of gemifloxacin, or standard dose of other quinolones, macrolides or beta-lactams (n = 5248). Studies in healthy volunteer and special populations are also reported. Adverse experiences (AEs) were observed in 44.7% of gemifloxacin-treated patients and 47.5% of those who received comparator drugs. Mild gastro-intestinal adverse drug reactions (ADRs) (diarrhoea 5.1%, nausea 3.9%) predominated. Rash, usually maculo-papular and in no case proceeding to more severe eruptions, was observed in 3.6% of those receiving gemifloxacin. A higher incidence of rash (>20%) was observed in young women and was the subject of further study. Adverse drug reactions suspected or probably related to treatment occurred in 17.4% of patients receiving gemifloxacin and in 20% of those receiving comparator antibiotics. Diarrhoea and nausea were experienced by 3.6 and 2.7%, respectively, of gemifloxacin-treated patients (4.6 and 3.2% of comparators), rash by 2.8% (0.6% of comparators) and headache by 1.2% (1.5% of comparators). Gemifloxacin-related vomiting (0.9%), dizziness (0.8%) and taste perversion (0.3%) were uncommon. Treatment discontinuation followed one or more adverse drug reactions in 2.2% of gemifloxacin-treated patients (0.9% due to rash) and 2.1% of comparator-treated patients. A total of 63 deaths (33 receiving gemifloxacin) occurred in the trial population: none were considered related to treatment. A slight prolongation in QT interval (2.56 ms (S.D. +/-24.5)) was observed in gemifloxacin-treated patients: no cardiac arrhythmias were reported. There was a low incidence of liver function tests (LFTs) classified as of potential clinical concern: gemifloxacin (0.4-1.2%), comparators (0.2-1.3%). Serious adverse events (SAEs), occurring during but not necessarily related to therapy, occurred in 3.6% of gemifloxacin-treated patients (4.3% of comparators). SAEs related to treatment agents were rare (0.4% in each group) and included rash (0.1%) and elevated liver enzymes (<0.1%). Gemifloxacin was well tolerated by the elderly, those with renal or hepatic impairment and when co-administered with omeprazole, digoxin, theophylline, warfarin (with which there were no significant interactions) and Maalox. In conclusion, gemifloxacin 320 mg once daily demonstrated a favourable safety and tolerability profile similar to that of comparator antibiotics, including other quinolones.

Safety of fluoroquinolones: An update.

The fluoroquinolone class of antimicrobials has been in clinical use for over 13 years. During that period, some representatives of the class have been extensively prescribed, such as ciprofloxacin and levofloxacin, while others have seen minimal use and have been restricted or withdrawn, namely, trovafloxacin and grepafloxacin. Manipulation of the fluoroquinolone structure by substituting a range of moieties around the core has yielded enhanced antibacterial activity, but in some cases this has come at a price. Specific substitutions are discussed in relation to particular recognized adverse events. In the present paper, newly introduced fluoroquinolones, such as moxifloxacin and gatifloxacin, are examined in terms of anticipated class effects and recent clinical experience. These antimicrobials are associated with reactions such as diarrhea, nausea, headache and other typical antimicrobial phenomena at rates less than 5%. New fluoroquinolone agents should be examined carefully in light of structural findings until adequate clinical data are amassed.

Interspecies recombination contributes minimally to fluoroquinolone resistance in Streptococcus pneumoniae.

Analysis of 71 ciprofloxacin-resistant (MIC > or = 4 microg/ml) Streptococcus pneumoniae clinical isolates revealed only 1 for which the quinolone resistance-determining regions of the parC, parE, and gyrB genes were genetically related to those of viridans group streptococci. Our findings support the occurrence of interspecies recombination of type II topoisomerase genes; however, its contribution to the emergence of quinolone resistance among pneumococci appears to have been minimal.

Efficacy of gemifloxacin in acute exacerbations of chronic bronchitis: a randomised, double-blind comparison with trovafloxacin.

This randomised, double-blind, double-dummy, multinational study compared the efficacy and safety of gemifloxacin with trovafloxacin in the treatment of acute exacerbations of chronic bronchitis. There were 617 patients randomised: 303 to gemifloxacin and 314 to trovafloxacin. Clinical success rates at follow-up (clinical per-protocol population) were 91.5% for gemifloxacin and 87.6% for trovafloxacin. For the intent-to-treat population, the clinical efficacy of gemifloxacin was statistically significantly superior to that of trovafloxacin. In general, the in vitro activity of gemifloxacin against the major respiratory bacterial pathogens was superior to that of other antibiotics tested. Per-patient bacteriological success rates at follow-up (bacteriology per-protocol population) were 86.8% for gemifloxacin and 82.4% for trovafloxacin. Both agents were well tolerated. The clinical and bacteriological efficacy of a once-daily 5-day course of gemifloxacin is at least as good as that of a similar regimen of trovafloxacin in the treatment of acute exacerbations of chronic bronchitis.

Antimicrobial safety and tolerability: differences and dilemmas.

The adverse drug reactions associated with antimicrobials have become a topic of major importance and concern in the last few years. Antimicrobial toxicity may take many forms, varying from mild, transient phenomena to dramatic, life-threatening events such as seizures or cardiac arrhythmias. We review the toxicity of antimicrobials in general and of the fluoroquinolones in particular and attempt to explain the adverse events by use of structure-adverse event relationships where possible. There are currently 5 main mechanisms that can be invoked to explain antimicrobial toxicity: direct effects, hypersensitivity, changes in microbial flora, drug interactions, and microbial lysis. The adverse drug reactions seen with fluoroquinolones are explained on the basis of these 5 mechanisms. The various organ systems affected by the fluoroquinolones are considered; then individual members of the fluoroquinolone class are reviewed. The unexpected and dramatic problems encountered with temafloxacin and trovafloxacin are discussed as well.

Summary of Canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the Canadian Infectious Disease Society and the Canadian Thoracic Society.

Community-acquired pneumonia (CAP) is a serious illness with a significant impact on individual patients and society as a whole. Over the past several years, there have been significant advances in our knowledge and understanding of the etiology of the disease, and an appreciation of problems such as mixed infections and increasing antimicrobial resistance. The development of additional fluoroquinolone agents with enhanced activity against Streptococcus pneumoniae has been important as well. It was decided that the time had come to update and modify the previous CAP guidelines, which were published in 1993. The current guidelines represent a joint effort by the Canadian Infectious Disease Society and the Canadian Thoracic Society, and they address the etiology, diagnosis and initial management of CAP. The diagnostic section is based on the site of care, and the treatment section is organized according to whether one is dealing with outpatients, inpatients or nursing home patients.

Fluoroquinolone resistance in clinical isolates of Streptococcus pneumoniae: contributions of type II topoisomerase mutations and efflux to levels of resistance.

We report on amino acid substitutions in the quinolone resistance-determining region of type II topisomerases and the prevalence of reserpine-inhibited efflux for 70 clinical isolates of S. pneumoniae for which the ciprofloxacin MIC is >/=4 microgram/ml and 28 isolates for which the ciprofloxacin MIC is