An important finding in our study was that patients who received colistin therapy had greater clinical responses at day 6 than the control group, although the rate of infection-related mortality was not significantly different between the two groups. Furthermore, colistin-treated patients who harbored an MDR P. aeruginosa
isolate resistant to all available antipseudomonal drugs had higher clinical and microbiologic responses than the control group patients who harbored an MDR P. aeruginosa
isolate susceptible to only one antipseudomonal drug. We did not encounter a higher incidence of nephrotoxicity in the colistin group. The incidence of nephrotoxicity observed in our study is consistent with the results reported in other studies (15
). All of these findings suggest that colistin may be an alternative therapy for cancer patients with MDR P. aeruginosa
became a significant pathogen in the late 1960s, causing approximately 17% of cases of nosocomial respiratory tract infection and 11% of cases of bacteremia (3
). It was a serious threat to patients with impaired host defenses, including those with extensive burn wounds (27
), cystic fibrosis, or severe neutropenia. In a study of cancer patients with Pseudomonas
bacteremia, many of whom had severe neutropenia, only 14% survived their infection (35
). In a series of 12 studies of bacteremia caused by gram-negative organisms completed before 1976, mortality rates varied from 37% to 77% (4
The polymyxins such as colistin were the first antibiotics that were highly active against P. aeruginosa
in vitro, but they were not very effective clinically. For example, the rate of recovery from Pseudomonas
bacteremia in persistently neutropenic cancer patients treated with polymyxins was less than 25%, and similar results were observed in patients with burn wound sepsis (35
). It is difficult to explain the favorable response to colistin compared to the responses to the other antibiotics tested in this study. In a study of Pseudomonas
bacteremia in cancer patients conducted at the M. D. Anderson Cancer Center in the 1960s, the response rate to polymyxins was only 24%, whereas it was 14% among the 21 patients treated with other antipseudomonal agents. Of interest, 33% of the patients were already receiving polymyxin when Pseudomonas
was initially isolated from their blood. In a study by Curtin et al. (7
), only 41.7% of the patients with Pseudomonas
bacteremia responded to polymyxins. A possible explanation for the poor response in the 1960s may be due to improper dosing and/or the failure to diagnose the Pseudomonas
bacteremia, which led to the delayed initiation of antipseudomonal therapy. Also, it is possible that patients receiving colistin monotherapy in this study actually continued to receive other antipseudomonal agents to which the organisms were resistant in vitro. Although it was considered ineffective, the combination of these agents with colistin may have enhanced the patient outcome.
Potential therapeutic indications for colistin have been reported, and three studies have assessed its use in the ICU (1
). Levin et al. (19
) reported a 58% response rate in a series of 57 patients. Markou et al. (22
) also reported clinical cures in 73% of patients, but it is difficult to draw a conclusion about the efficacy of colistin in their study because most of the patients received other antipseudomonal agents. Unfortunately, over the years, strains of P. aeruginosa
have acquired mechanisms that convey resistance to antibiotics (10
). Recently, strains have emerged that are resistant to multiple classes of antibiotics and in some cases to all available therapy. Some strains have been susceptible only to the polymyxins in vitro (26
Multiple studies have suggested that polymyxins are effective and safe therapy for infections caused by these MDR strains. However, the role of these antibiotics has not been definitively established. Most studies have included only a small number of patients and the polymyxin was administered in combination with several other different antibiotics (30
). MDR has been defined as in vitro resistance to from as few as three classes of antibiotics to as many as all classes except polymyxins (1
). In some studies all beta-lactams have been combined into one class, whereas in other studies penicillins, cephalosporins, monolactams, and carbapenems have been considered separate classes (4
). In this study, MDR was defined as resistance to at least three of five classes, which included aminoglycosides.
This study differed from other studies reported in the literature in that all patients had underlying cancer. Sixty percent of the patients had hematological malignancies and 40% were neutropenic during their infection. Nearly half (48%) of the patients had polymicrobial infections, which typically have a poorer prognosis. As in other series, more than half of the patients were treated for their infection in an ICU. There were no statistically significant differences in these variables between the group treated with colistin and the group not treated with colistin (the control group).
In our study 16 (52%) of the 31 patients treated with colistin experienced a clinical response, whereas 20 (31%) of 64 patients treated with other antipseudomonal agents experienced a clinical response, which is comparable to the results of other studies reported in the literature (11
). A more favorable outcome of a mortality rate of only 21% was reported in a study from Israel of 82 patients with MDR P. aeruginosa
infections, but the therapies used were not mentioned (1
). In our study, after adjusting for the potential confounders, we found from a multiple logistic regression analysis that patients receiving colistin were three times (95% CI, 1.1 to 7.6 times) more likely to experience an overall response than patients in the control group. Patients with pneumonia and bacteremia typically experienced fewer responses than patients with UTIs and wound infections. Only patients with pneumonia and bacteremia received colistin; hence, they would be expected to respond less frequently. However, the overall response rate was higher for the colistin group, and colistin-containing regimens were more effective against bacteremia and pneumonia.
Among the patients receiving monotherapy, multiple logistic regression analysis showed that patients in the colistin group were more likely than patients in the control group to experience a clinical response (61% and 26%, respectively; P = 0.005) and microbiologic response (61% and 34%, respectively; P = 0.013). Most of the comparators in the control group received beta-lactam antibiotics or quinolones that were active against the MDR P. aeruginosa isolates causing the infection. These data further support the notion that colistin is highly useful in the treatment of MDR P. aeruginosa in cancer patients.
Overall in our study, 15 colistin-treated patients did not experience a response and 8 (53%) died of infection; among the patients in the control group, 44 patients did not experience a response and 11 (25%) died of infection. We found a higher mortality rate among the group of patients who did not respond to colistin than among the controls who did not respond to other antipseudomonal drugs (53% and 25%, respectively). This could be explained either by the difference in the severity of the infection in the colistin group or by a late response to an antipseudomonal drug after day 6 in the control group. Furthermore, in this patient population it is difficult to attribute death to a specific cause. In the majority of cases the cause of death was multifactorial. In our study infection-related mortality was defined as the death of a patient with septicemia due to Pseudomonas at the time of death without any other apparent source. On the other hand, the high overall rate of mortality noted in Table was most likely due to the underlying refractory diseases and the multiorgan failure.
Our study has some important limitations in that it was a small retrospective chart review study in which we were unable to assess all of the needed detailed information, which can be obtained in a well-designed prospective trial. In addition, there was no standard pattern for the selection of the antibiotics, especially in terms of the duration and combination with other antipseudomonal agents, regardless of the susceptibility patterns of the causing organisms.
In summary, our study demonstrated that colistin is highly useful as a preferred alternative agent and it was at least as effective as or even more effective than beta-lactams or quinolones in the treatment of MDR P. aeruginosa infection in cancer patients. Furthermore, the safety profile of colistin in this population was comparable to that of the other conventional antipseudomonal therapy. The issue of whether colistin is superior to other antipseudomonal therapy needs to be further verified through larger prospective clinical trials.