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21st Annual Congress of the European Society of Intensive Care Medicine

Lisbon, Portugal / September 21-24, 2008

Treatment of Multi-drug-Resistant Acinetobacter

According to Dr. Frantzeska Frantzeskaki, Intensive Care Unit, Hippokration General Hospital, Athens, Greece, “Acinetobacter baumannii is one of the most important causes of infections in intensive care unit (ICU) patients. Sepsis and septic shock are reported in 19% of A. baumannii bacteremia cases and crude mortality from A. baumannii nosocomial infections ranges from 20% to 60%. The most frequent clinical manifestation of A. baumannii is ventilator-associated pneumonia (VAP), and its growing resistance to carbapenems poses a severe therapeutic problem for workers in the ICU.”

Because tigecycline, the first clinically approved semisynthetic glycylcycline available for clinical use, has demonstrated potent activity against many Gram-positive and Gram-negative pathogens, including multi-drug-resistant (MDR) strains, Dr. Frantzeskaki and colleagues prospectively studied the efficacy of this agent vs. a high-dose regimen of ampicillin/sulbactam in patients with VAP caused by A. baumannii. High-dose ampicillin/sulbactam has been reported to be active against Acinetobacter spp.

While colistin is also relatively effective against MDR A. baumannii strains, it is accompanied by toxicity rates of about 36% and Acinetobacter resistance to colistin has been reported. It was therefore not included in the study.

Dr. Frantzeskaki reported that the study enrolled 23 patients who had been mechanically ventilated for over 72 hours who developed VAP and had positive A. baumannii tracheal aspirates. Their mean age was 70 years (±seven years). A case was considered etiology-confirmed if A. baumannii was isolated and quantitative culture of broncho-alveolar lavage (BAL) of 104 cfu/mL was achieved. Ten subjects received intravenous (i.v.) tigecycline 50 mg b.i.d. and 13 were given 9 g ampicillin/sulbactam t.i.d., adjusted for creatinine clearance.

She reported, “Resolution of signs and symptoms of VAP was observed in 70% of patients in the tigecycline-treated group and 77% in the ampicillin/sulbactam group, which was a non-significant difference. Also not statistically different were the rates of clinical failure of 20% and 23% in the tigecycline and ampicillin/sulbactam treatment groups, respectively. Bacteriologic success was observed in 80% of patients receiving i.v. tigecycline monotherapy vs. 77% of those assigned to ampicillin/sulbactam, which was also non-significant.” Adverse events observed in this study included nephrotoxicity in two patients and skin rash in two others, all in the combination treatment arm.

The authors concluded that the two treatment strategies are comparably effective options for MDR A. baumannii VAP, but tigecycline appears to be safer. These regimens could prevent the excessive use of polymixins in ICUs and the subsequent development of pandrug-resistant strains.

Dr. Maria Theodorakopoulou then reported on a related study at the same institution that examined the efficacy of tigecycline vs. colistin in similar patients with VAP attributed to infection with A. baumannii. Ten patients received i.v. tigecycline 50 mg b.i.d. as monotherapy (group A), while 15 were given colistin alone or in combination with cefepime (group B). She reported, “BAL revealed success in eight group A patients (80%) and 10 patients in group B (66.6%). Clinical success was observed in seven (70%) and nine (60%) cases in groups A and B, respectively. Nephrotoxicity occurred in five (33%) group B patients. No toxicity was observed in the tigecycline-treated group.”

She concluded that colistin and tigecycline appeared to be equally effective in eradicating MDR A. baumannii in BAL cultures of patients with VAP but tigecycline seemed safer for the clinical treatment of patients.

Dr. Theodorakopoulou noted that in recent years, A. baumannii has become a major cause of nosocomial infections with significant mortality and morbidity, colonizing as many as 41% of ICU patients. “It has tremendous ability to accumulate diverse mechanisms of resistance, and many MDR strains have developed pan-resistance to antibiotics in the past two years. So far, we have isolated 100 MDR strains that all have more than 90% resistance to the most common antibiotics used in the ICU and found strains with >75% resistance to sulbactam and >3% resistance to colistin. We have not observed resistance to tigecycline, but I am afraid it may come up because A. baumannii is a very clever microbe.”

Decreasing the Selective Pressure on Carbapenems

Dr. Christoph Wenisch, Kaiser Franz Josef Hospital, Vienna, Austria, agreed that the growing prevalence of infections caused by MDR pathogens, including Acinetobacter spp., in the ICU has emerged as a significant determinant of mortality. Many acutely ill ICU patients with infections possibly caused by MDR pathogens require swift and effective broad-spectrum antibiotic therapy, yet the therapeutic options for them are increasingly limited, so combinations with agents such as carbapenems typically held in reserve are often used. However, carbapenem resistance has now been reported.

Dr. Wenisch noted that tigecycline is used for the treatment of complicated skin and skin structure infections and complicated intra-abdominal infections, indications for which carbapenems are frequently prescribed. “Although tigecycline is unable to evade the multi-drug efflux pumps of MDR Pseudomonas aeruginosa, its use as an alternative to carbapenems when P. aeruginosa is not suspected may decrease the selective pressure on those agents and reduce rates of resistance. Therefore, in some situations, tigecycline may be a promising alternative to both extensively used antibiotics and those held in reserve,” he told delegates.

Membrane-associated efflux pumps are a major mechanism in bacterial resistance, according to Prof. Patrice Courvalin, Pasteur Institute, Paris, France. After penetrating the cell, drug accumulation may be reduced by the active pumping out of drug from the cell by membrane efflux pumps, so the antibiotic concentration will be very low within the cell. Other main mechanisms are direct enzymatic de-activation of the antibiotic, alteration of the target site, and inhibition of the metabolic pathway in the antibiotic process.

Prof. Courvalin told delegates, “Resistance to antimicrobials, including MDR, is unavoidable and unstoppable. The only means of dealing with this situation is to delay the emergence and subsequent dissemination of resistant bacteria or resistance genes.”

Clinical Experience

Dr. Miguel Sánchez García, Head, Intensive Care Unit, San Carlos Hospital Clinic, Madrid, Spain, described how Spanish clinicians have extended the use of tigecycline to high-risk patients with long hospital stays and marked organ dysfunction as rescue therapy in many cases, such as lung infections, bacteremia and other diverse infections. There is accumulating experience in medical, surgical and trauma admissions for both approved and off-label indications, he noted.

“The broad spectrum of activity, including carbapenem-resistant organisms, is the main reason for tigecycline use, in addition to rescue therapy, toxicity of other antibiotics and ß-lactam allergy,” he remarked. “We have successfully treated infections caused by A. baumannii, Stenotrophomonas maltophilia, carbapenemase-harbouring Klebsiella pneumonia, Enterobacter aerogenes, methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci with tigecycline.”

Dr. Sánchez García noted that Spanish intensivists use the new antibiotic in directed therapy about 75% of the time after determining exactly what micro-organism is involved, and only a quarter of the time empirically. Combination therapy predominates in treatment of the critically ill as tigecycline is frequently administered after other antimicrobials have failed. “Critically ill patients who achieve a favourable clinical course add up to about 63%, the rest being either indeterminate or a clear failure,” he told delegates. “ICU mortality is 41%, which rises to 54% for hospital mortality.”

Given the high-risk patients and adverse conditions in which tigecycline is currently used in ICUs, Dr. Sánchez García concluded, “It promises to play a relevant role in the treatment of critically ill patients with severe infections caused by MDR organisms. In a setting of high resistance rates, it may also be considered an alternative to other antimicrobials and contribute to diversifying antimicrobial pressure.”