Introduction

Ventilator-associated pneumonia (VAP) is a major safety problem in intensive-care units (ICUs) [1]. In recent years, the incidence of multidrug-resistant (MDR) Acinetobacter baumannii has been increasing, and the therapeutic options are limited [1, 2]. Colistin (COL; polymyxin E), an old class of antibiotic, was used for the treatment of infections with gram-negative microorganisms in the 1950s. It was abandoned in the 1980s because of its nephrotoxicity and neurotoxicity. However, after the emergence of MDR A. baumannii, COL was re-introduced for clinical use. However, the success rate of COL is questionable, with 25–70 % clinical effectiveness, and the optimal dose is controversial [3, 4].

The aim of this study was to investigate the safety and efficacy of different doses of IV COL (including a high dose) and aerosolized COL for the treatment of A. baumannii VAP.

Patients, materials, and methods

Patients

Data for this retrospective analysis were collected for patients hospitalized between January and August 2011 in ICUs at Erciyes University Hospital. This is a tertiary-care hospital with 215 ICU beds and with 3815 admissions annually. In recent years, MDR A. baumannii has become endemic in ICUs, causing serious infections, including VAP [1, 2]. In this study, we evaluated critically ill adult patients who received IV COL for the treatment of MDR A. baumannii VAP. Patients’ demographic characteristics; underlying diseases; Acute Physiology and Chronic Health Evaluation (APACHE) II score on admission; sepsis severity on admission; length of ICU stay; COL dose; concomitant use of glycopeptide, aminoglycoside, and other antibiotics; adjunctive COL use; and nephrotoxicity were recorded. Evaluation of effectiveness was based on both clinical and microbiological responses to therapy on the fifth day and at the end of the therapy. During the COL therapy, the patients’ creatinine levels were monitored every other day to evaluate nephrotoxicity. The study was approved by the ethics committee of Erciyes University (date 03.05.2011, number 2011/311).

Definitions

VAP was defined according to the criteria of the American Thoracic Society Consensus Conference on VAP [5]. On the fifth day of the therapy, if the symptoms and signs of VAP had subsided without an additional antimicrobial agent for VAP, this was defined as good response; if there was progression of symptoms and signs and an additional antimicrobial agent was prescribed, this was defined as poor response. At the end of the COL therapy, if the symptoms and signs of VAP had resolved without antimicrobial maintenance therapy, this was defined as clinical success; the persistence of symptoms and signs or recurrence of VAP after the discontinuation of COL was defined as clinical failure. Bacteriological clearance was defined as the eradication of MDR A. baumannii, and bacteriological failure was defined as the persistence of MDR A. baummannii on follow-up culture [6]. Sepsis was defined according to the 2001 SCCM/ESICM/ACCP/ATS/SIS International sepsis definitions conference criteria [7].

RIFLE (Risk, Injury, Failure, Loss, and End-stage kidney disease) criteria were used to evaluate the nephrotoxicity of COL [8]. Patients’ creatinine levels were followed up until their discharge from the hospital.

COL dosage

In our hospital, colistimethate sodium (Colimycin®; Kocak Farma, Istanbul, Turkey) was used, and supplied as 150 mg of COL base activity per vial. In this study, the standard dose was defined as normal IV dosing, at 2.5 mg/kg every 12 h (maximum 300 mg), or low dosing, adjusted according to the creatinine clearance (CLCr) [6]. A high dose was defined as 2.5 mg/kg every 6 h (maximum 600 mg). The inhaled dose of aerosolized COL was 150 mg, given in two divided doses, each dose added to 4 mL of normal saline; the solution was nebulized with an oxygen flow of 8 L/min. The serum COL concentration was not measured.

Statistical analysis

The collected information was processed using version 15.0 of the Statistical Package for Social Sciences (SPSS, Chicago, IL, USA) for Windows. The Shapiro–Wilk test was performed to check the normality assumption of the data. Data were analyzed, using the χ2 test, to compare the distribution of frequencies among qualitative variables. The Mann–Whitney U-test, one-way analysis of variance, and the Kruskal–Wallis test were used for the comparison of continous variables, and Dunn’s test was used for pairwise comparisons. All the analyses were performed with the level of significance set at p < 0.05.

Results

During the study period, 45 patients received the IV COL therapy at the stated doses. Thirty-two (71 %) of these patients were male, and the mean age of the whole patient cohort was 50.07 ± 20.47 years. The median APACHE II score was 22. Ten of these patients (22 %) had high CLCr on admission and received low-dose COL adjusted according to their CLCr. Twenty patients (44 %) had normal-dose COL and 15 patients (33 %) had high-dose COL. The demographic characteristics of these patients are shown in Table 1. There were no significant differences in the patient characteristics of the different dosage groups. On admission most of the patients (87 %) were in the severe sepsis or septic shock phase. All the patients had had antibiotic therapy before the COL therapy, and there were no statistically significant differences between the groups in the concomitant use of glycopeptide or aminoglycoside antibiotics. All the patients had 14-day COL therapy. During the study period, no COL-resistant A. baumannii was isolated, and there were no cases of A. baumannii co-infection with another organism.

Table 1 Patient characteristics according to COL dose group

Clinical and microbiological evaluation of results with different COL dosages

On the fifth day of the COL therapy, overall, 17 patients (38 %) had a good response. Response rates were 27, 50, and 30 % for the patients with the high, normal, and low doses, respectively. There were no statistically significant differences in response rates on the fifth day. When the patients were evaluated at the end of the therapy, the clinical cure rate was 30 % in the normal-dose and low-dose groups, whereas the rate was only 7 % in the high-dose group. Also, the fever declined later in the high-dose COL group compared with the other two groups (p = 0.01). The bacteriological clearance rates were 64, 65, and 75 % in the high-dose, normal-dose, and low-dose groups, respectively. There were no statistically significant differences in clinical cure rates or bacteriological clearance rates among the different dosage groups. Although the difference was not statistically significant, the mortality rate in the high-dose group was higher (67 %) than the rates in the normal (45 %) and low-dose groups (40 %) (Table 2). The nephrotoxicity rate was also higher (40 %) in the high-dose group than the rates in the normal-dose (35 %) and low-dose (20 %) groups. However, the difference was not statistically significant. Nephrotoxicity evaluation according to the RIFLE criteria is shown in Table 3. Clinicians adjusted the COL dose after the occurrence of nephrotoxicity. However, creatinine levels continued to be high during the therapy and creatinine levels were normalized in only three patients after discontinuation of the therapy. These patients were in the normal-dose (n = 2) and low-dose groups (n = 1). When the risk factors for nephrotoxicity were evaluated, only advanced age (45.47 ± 18.06 vs. 59.27 ± 22.49 years, p = 0.03) and chronic obstructive lung disease (20 vs. 80 %, p = 0.001) were found to be statistically significant.

Table 2 Clinical and microbiological evaluation of treatment results with different COL doses
Table 3 Patients’ relationship to RIFLE criteria

Clinical and microbiological evaluation of results of inhaled COL as adjunctive therapy with intravenous COL

We identified 29 patients who received inhaled COL as adjunctive therapy with IV COL. The characteristics of these patients were not significantly different from those of the group that received only IV COL (Table 4). Table 5 shows the results of the clinical and microbiological evaluation of patients with and without inhaled COL. Inhaled COL had no additional effect on the outcomes of the patients; however, the nephrotoxicity rate was higher (41 vs. 19 %) in the patients who had inhaled COL therapy.

Table 4 Characteristics of patients with and without inhaled (INH) COL
Table 5 Clinical and microbiological evaluation of treatment results in patients with and without inhaled (INH) COL

Discussion

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 [3]. 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 [12]. 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 [13]. 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 [4]. In a recent analysis, Kofteridis et al. [13] 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 [14]. 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.