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Infectious Disease Coordinator Sanatorio San José Infectología Institutional SRL Santo Tomé 5239 4 to 22 (1419) Capital Federal, Argentina fax 5411-4822-2748 djcurcio{at}gmail.com
Published Online, September 30, 2008. www.theannals.com, DOI 10.1345/aph.1L171a
We agree with the authors that comparative studies related to tigecycline use for Acinetobacter infections are needed. However, in our opinion, the authors omitted several points that should be considered.
In Argentina, the prevalence of carbapenem-resistant Acinetobacter spp. is high (>50%)2; thus, most of the tigecycline prescriptions in Argentina are for multidrug-resistant Acinetobacter infections (eg, ventilator-associated pneumonia) for which there are very few therapeutic options.3 Considering the "real world" limitations of our setting, I believe that all of the available studies should be analyzed thoroughly so that the information is useful for clinicians.
Gallagher and Rouse considered that the high tigecycline minimum inhibitory concentrations (MICs) observed in most of the strains (median 4 µg/mL) could be one of the factors for the poor outcomes seen in the study. Concerning the susceptibility test used by the authors, Sahm et al.4 found that the tigecycline MIC90 for effective treatment of Acinetobacter spp. was 2-fold higher by E-test than by broth-based methods (BBM) and MIC90 values were never lower by E-test than by BBM. In a recent publication, Pillar et al.5 concluded that caution is warranted in using tigecycline E-test data for susceptibility of Acinetobacter spp. because variable manganese concentrations in media have been shown to affect results. Therefore, I believe that BBM should have been used, at least in the isolates with MICs greater than or equal to 2 mg/L, before concluding that tigecycline's MIC and poor clinical outcomes were associated.
In addition, the authors did not mention whether the patients who had the tigecycline-intermediate isolates had received previous antibiotics. The overexpression of the AdeABC multidrug efflux pump, which is the mechanism of Acinetobacter spp. resistance to tigecycline, can be upregulated by the previous use of other antibiotics (eg, fluoroquinolones, aminoglycosides) that are administered frequently in patients with serious infections.6,7
I agree with the authors that the level of illness of the patients could have contributed to the high failure rate of tigecycline in their study (83% of the patients were in intensive care units). However, these data were not sufficiently explored in the study and the clinical failures were attributed only to tigecycline and the supposed Acinetobacter spp. resistance. To determine the influence of the level of illness, I believe that the authors should have divided the patients into different groups (with or without positive clinical response) and adjusted the results according to variables that influence the clinical outcomes of critically ill patients: severity score (eg, APACHE II, MPM II), average length of stay prior to first dose of tigecycline, concomitant and/or polymicrobial infection, and resistant isolates of Acinetobacter spp.
In this case series, 83% of the patients with clinical failure (15/18) were infected by resistant Acinetobacter spp. (in 4 cases, colistin was not tested), which in itself is a predictor of mortality.8
Finally, independent of the Gallagher and Rouse results, neither bacteremia nor urinary tract infection is an indication for potential tigecycline treatment. Given at the standard dosage of 100 mg followed by 50 mg every 12 hours, tigecycline produces relatively low mean steady-state serum concentrations of 0.4–0.6 mg/L,9 which is equal to or lower than the MIC needed for effective treatment of most isolates of Acinetobacter spp. Renal clearance of tigecycline (0.03 L/h/kg) accounts for 10–15% of its total systemic clearance (ranging from 0.2 to 0.3 L/h/kg), and only 15–22% of the administered dose is recovered unchanged in urine.10 Clinicians need to be aware that isolates may become resistant to tigecycline if it is given over a prolonged period at subinhibitory serum or urine concentrations.
In summary, establishment of the relationship between treatment with tigecycline in Acinetobacter infections and the clinical outcome deserves more complex analysis. Meanwhile, clinicians must evaluate the benefits versus risks of tigecycline treatment in indications for which its use still lacks rigorous scientific support.
Footnotes
Daniel Curcio is a member of the speakers bureau of Wyeth SA Argentina for tigecycline.
Comments on articles previously published are submitted to the authors of those articles. When no reply is published, either the author chose not to respond or did not do so in a timely fashion. Comments and replies are not peer reviewed.–ED.
References
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