A. baumannii is one of the most common MDR pathogens that cause VAP in ICUs. The mortality rate for VAP due to MDR A. baumannii is usually high, ranging from 65 to 87 % [1, 2, 9, 10]. The most important factor in the poor prognosis is the lack of effective therapy for MDR A. baumannii infections. Colistin (COL) therapy has been re-introduced in recent years after the emergence of MDR gram-negative bacteria [3, 11]. However, previous studies have suggested that COL is poorly distributed to the tissues, as well as being poorly distributed to the pleural cavity and lung parenchyma . The most common dose of COL (given as colistimethate) for patients with normal renal function is 2.5 mg/kg, given intravenously every 12 h. However, data suggest that the current recommended dosing regimens may lead to serum levels of COL that are less than the minimum inhibitory concentration (MIC) for Acinetobacter infections . The maximum dose of COL is not known and many clinicians prefer to use higher doses than the standard dose, although there is no systematic analysis that shows the effect of different dosages on effectiveness and toxicity outcomes. In the present study a high dose of COL was compared with standard dosages of COL. The overall response rate on the fifth day of therapy was 38 %, whereas the rate was 50 % for the normal-dose group lower in both the low- and high-dose groups. However, at the end of the therapy, the overall clinical cure rate was 22 %, with the lowest rate seen in the high-dose COL group (7 %). Also, fever declined late in the high-dose COL group, and no dose-dependent effects were seen in the bacteriological response. Consequently, higher doses of COL had no favorable effect on the outcome of the patients. Also, the nephrotoxicity rate was highest (40 %) in the high-dose COL group. Nephrotoxicity was the most common side effect of COL, with the incidence ranging from 9 to 50 %. In this study, we did not measure the serum COL concentration; however, other studies in the literature have shown that the main renal toxicity of COL is acute tubular necrosis, and this toxicity is considered to be dose-dependent [6, 8]. The concomitant use of nephrotoxic drugs can increase the nephrotoxicity of an agent. However, in the present study, we could only evaluate concomitant antibiotic use, and there were no differences in nephrotoxicity between patients who received concomitant glycopeptide and aminoglycoside antibiotics and patients without such concomitant drug use. The high rate of nephrotoxicity in this study could be due to the patients’ disease severity on admission, with a high percentage showing severe sepsis and septic shock (87 %). The renal toxicity of COL is usually reversible after early discontinuation of therapy with the drug [3, 6, 8]. In the present study, clinicians adjusted the COL dose after the occurrence of nephrotoxicity. However, creatinine levels continued to be high during the therapy, and the creatinine levels were normalized in only three patients after the discontinuation of the therapy. These patients were in the normal-dose and low-dose groups. In the high-dose group, none of the patients showed normalization of creatinine clearance during the follow-up period. Neurological toxicity is another common adverse effect of COL. Unfortunately, we could not evaluate the agent’s neurotoxicity in this retrospective analysis.
Inhaled COL is used as an adjunctive therapy used with conventional IV antibiotic treatment for nosocomial pneumonia caused by multidrug-resistant (MDR) gram-negative microorganisms. Theoretically, the use of the aerosolized form of COL can minimize potential renal and neurological toxicities and improve the patient’s outcome, because this form achieves higher pulmonary concentrations with negligible systemic absorption and toxicity . Aerosolized COL has mostly been studied in patients with Pseudomonas pneumonia as a therapeutic adjunctive with parenteral antipseudomonal antibiotics. However, data about its efficacy against MDR A. baumannii pneumonia are limited . In a recent analysis, Kofteridis et al.  showed that the addition of aerosolized COL to parenteral COL did not provide any additional therapeutic benefit for patients with MDR VAP due to gram-negative bacteria. In the present analysis, 29 patients received inhaled and IV COL, whereas 16 patients received only IV COL. Although the differences were not statistically significant, the response rate on the fifth day of the therapy and the clinical cure rate at the end of the therapy were lower in the group with aerosolized COL than these rates in the patients who had had only parenteral therapy. However, the bacteriological clearance rate was higher in the group with aerosolized COL. Despite the minimal systemic absorption of aerosolized COL, the nephrotoxicity rate was higher in the group with the aerosolized COL. This high rate may be explained by the severity of the patients’ disease. Overall, aerosolized COL might have a benefit in regard to the bacterial response, but its impact on the clinical course would be questionable.
When we analyzed the risk factors for renal toxicity associated with COL therapy, only older age of the patients and the presence of chronic obstructive lung disease were found to be significant risk factors. In advanced age, the aging process affects the kidneys and a decline in renal function occurs. Consequently, the risk of drug nephrotoxicity is high in older age groups . Unexpectedly, we found chronic obstructive lung disease to be a significant risk factor for renal toxicity. This finding may have been due to the previous exposure of these patients to multiple drugs or to the presence of an unknown kidney injury.
The limitation of this study is its small sample size and the fact that the disease severity of the patients could have affected the clinical response. For this reason, interpretation of the results should be done with caution. Indeed, this small size of the study population could explain the lack of statistically significant differences in the efficacy rate, mortality rate, and adverse effects between the study doses and forms. We note that intensivists and infectious disease specialists in our ICUs have avoided using high-dose COL and inhaled COL after recognition of the high rate of nephrotoxicity and the lack of effectiveness.
In conclusion, this study revealed that a high dose of IV COL and the use of aerosolized COL had no advantage in alleviating MDR A. baumannii VAP. Further, the high-dose COL and aerosolized COL increased the risk of nephrotoxicity and seemed not to be safe. To increase the clinical effectiveness of treatment for MDR A. baumannii VAP, a combination of COL with other antimicrobial agents (such as sulbactam, rifampicin, and aminoglycosides) could be more rational. More studies are needed to find the best therapeutic option for MDR A. baumannii VAP.