First-in-Class Antibiotic Has High Risk of Adverse Events and Death

NEW YORK (Reuters Health) January 7, 2011 — The usefulness of tigecycline for severe infections comes at a price: a high risk of adverse events and death, a meta-analysis shows.Tigecycline (Tygacil; Pfizer) — a first-in-class expanded broad-spectrum glycylcycline antibiotic — is approved by the U.S. Food and Drug Administration (FDA) for treatment of complicated
intra-abdominal infections, complicated skin and skin structure infections and community acquired pneumonia.
It has also been effective in hospital-acquired
and ventilator-associated pneumonia and bacteremia, septic shock and urinary tract infections. It is active against pathogens that are susceptible and resistant to other antibiotics.
In some cases the drug may be appropriate, but
the decision to use it should be "prudent," the authors of the study write in the December 20 online issue of Antimicrobial Agents and Chemotherapy.
Dr. Rui Wang and colleagues of the PLA General
Hospital, Beijing, People's Republic of China say they conducted their meta-analysis because while tigecycline was at least as effective as comparator antibiotics in several studies, the results were "not completely consistent" and bias could not be ruled out.Using data pooled from eight high-quality randomized controlled trials, they analyzed clinical success (i.e., complete resolution or substantial improvement of symptoms and signs of infection and no further antimicrobial therapy or surgical intervention for infection) and microbiological success (i.e., eradication of baseline pathogens or as presumed eradication based on the clinical
outcomes when post-treatment cultures were not performed).The authors report that tigecycline monotherapy was clinically as effective as vancomycin and aztreonam for complicated skin and skin structure infections, imipenem/cilastatin or ceftriaxone
plus metronidazole for complicated intra-abdominal infections, and levofloxacin for community-acquired pneumonia. This was true in both theclinically evaluable population and the intention-to-treat population.
Tigecycline monotherapy and comparator regimens also had similar microbiological treatment success rates.
Despite the similar efficacy, tigecycline was
associated with an increased incidence of all adverse events (including fever, headache, infection, abdominal pain, chills, and pain), and in particular those involving the digestive system. As in prior studies, nausea and diarrhea were the most common adverse events.Taken together, the data highlight the need for clinicians to monitor for signs and symptoms of digestive problems in
tigecycline-treated patients, the researchers say.
The meta-analysis also showed numerically but not
significantly higher mortality rates with tigecycline relative to comparator regimens, both for all-cause mortality and "possibly drug related" mortality.
In a September 2010 safety alert to clinicians on
their website, the U.S. Food and Drug Administration warned of an increased risk of death associated with the use of tigecycline compared
with other antibiotics used to treat a variety of serious infections for which tigecycline is approved. (The alert appeared on the FDA web site at http://bit.ly/fXgKIt.)
The increased mortality risk, the agency
reported, was most evident in patients with hospital-acquired pneumonia,especially ventilator-associated pneumonia, but was also seen in patients with complicated skin and skin structure infections,
complicated intra-abdominal infections and diabetic foot infections.The FDA cited data from a pooled analysis of 13 trials in which patients received tigecycline for both approved and unapproved indications. In the analysis, 150 of 3788 patients treated with tigecycline died compared with 110 of 3646 patients who received
other antibiotics (4.0% vs 3.0%). The adjusted risk difference for all-cause mortality based on a random effects model was 0.6% between tigecycline and comparator antibiotics.Accordingly, Dr. Wang and colleagues encourage clinicians to "carefully consider" the benefits and risks of tigecyclinebefore using it.
SOURCE: http://bit.ly/efjXLW
Antimicrob Agents Chemother. Published online December 20, 2010. Abstract



Clinical Context

Tigecycline is a first-in-class of expanded broad-spectrum
glycylcycline antibiotic with good activity against respiratory bacteria, including multiple resistant gram-positive, gram-negative, anaerobic, and multidrug-resistant pathogens. It is unaffected by other bacterial mechanisms of resistance. The drug was first approved for complicated skin and skin structure infections and abdominal infections and currently for community-acquired pneumonia, as well as hospital-acquired and ventilator-associated pneumonia and bacteremia, sepsis with shock, and urinary tract infections.This is a systematic review and meta-analysis of randomized controlled trials of tigecycline vs other antibiotics to examine
relative clinical and microbiological efficacy.



Study Highlights

• The investigators searched the databases of PubMed, the Cochrane
  Central Register of Clinical Trials, and EMBASE for randomized
  controlled trials to 2010, and 2 reviewers examined and assessed the
  quality of identified studies.
  
• They compared tigecycline vs comparator drugs by clinical and microbiological outcomes.
  
• The intent-to-treat population consisted of patients screened and enrolled in the studies.
  
• Types of infections examined included gram-positive, gram-negative, anaerobic, and atypical bacteria.
  
• The primary outcome was clinical treatment success, defined as complete resolution or substantial reduction of symptoms and signs of infection.
  
• The secondary outcome was microbiological treatment success, defined as eradication of baseline pathogens.
  
• Adverse effects and mortality were other outcomes examined.
  
• Excluded were conference abstracts and nonrandomized controlled trials.
  
• 8 randomized controlled trials were included in the final analysis.
  
• All trials involved adults, and comparator drugs included imipenem/cilastatin, ceftriaxone plus metronidazole, vancomycin, aztreonam, levofloxacin, and linezolid.
  
• Infections treated included methicillin-resistant Staphylococcus aureus (MRSA)
  and vancomycin-resistant enterococci infections, skin and skin structure infections, complicated intra-abdominal infections, and pneumonia.
  
• The mean quality score was 3.88 (range, 3 - 5), and overall quality was high at a score of more than 3.
  
• 7 randomized controlled trials examined clinical treatment success, and no significant difference was found (range of odds ratios was from 0.77 to 1.40, with no statistically significant differences).
  
• The total microbiological treatment success of the tigecycline group was not significantly different than comparators.
  
• However, the eradication rates were higher for tigecycline for MRSA, Streptococcus pneumonia, and Enterococcus faecalis, and lower for MRSA and E coli infections.
  
• There were significantly more adverse events for tigecycline vs
  the comparators, especially in the digestive tact and hemic and
  lymphatic systems (odds ratio, 2.41).
  
• The rate of adverse cardiovascular effects was lower for
  tigecycline, and there were no differences in adverse effects for the metabolic, nutritional, and respiratory systems.
  
• There were no significant differences in all-cause or drug-related mortality between tigecycline and the comparators.
  
• The authors concluded that tigecycline was as clinically effective and microbiologically effective as vancomycin and aztreonam, impenam/cilastin, or ceftriaxone plus metronidazole.
  
• However, they cautioned against routine use of this drug because
  of the higher incidence of adverse effects compared with the
  comparators.
  

Clinical Implications

• Tigecycline is associated with a similar clinical efficacy for the treatment of infections as comparator drugs.
  
• Tigecycline has similar microbiological efficacy and mortality risk as comparator drugs but has higher rates of adverse events