The influence of carbapenem resistance on mortality in solid organ transplant recipients with Acinetobacter baumanniiinfection

Bacterial infections are among the most relevant causes of morbidity and mortality after organ transplantation. The high prevalence of multidrug-resistance among bacterial pathogens causing infections in solid organ transplant recipients is an additional concern [1, 2]. In a recent report, infections with multidrug-resistant Gram-negative bacteria were associated with higher mortality among liver transplant recipients [3]. In this context, the emergence of carbapenem-resistant Acinetobacter baumannii (CRAB) as a significant pathogen in many transplant centers around the world is a special dilemma due to the limited therapeutic choices available to treat these infections [1, 4]. Nonetheless, there are few data on the epidemiology of CRAB infection among solid organ transplant recipients and on its impact on the survival of these patients [5–9]. The objective of the present study was to analyze the possible influence of carbapenem resistance and other potential risk factors on mortality among solid organ transplant recipients with A. baumannii infection.

A total of 19 (39%) patients died: 18 within 30 days, and one on the 52^nd day after the diagnosis of the infection. This was the case of a liver transplant recipient who was reoperated on the first postoperative week because of a biliary fistula that was successfully repaired with a choledochojejunostomy. On the 28^th postoperative day, she was reoperated due to an abdominal abscess caused by Stenotrophomonas maltophilia. On the 50^th postoperative day she was reoperated again to drain another abdominal abscess. CRAB was isolated in the clinical specimen collected during this surgery. Despite prolonged treatment with polymyxin B combined with meropenem, she underwent laparotomy in two other occasions due to the persistence of the abdominal infection. CRAB was still isolated from the abscess secretion collected during the last reoperation, which took place one week before her death.

In 17 cases (35%), deaths were defined as associated with A. baumannii infection, including the one occurring 52 days after the infection. Most A. baumannii-associated deaths (15 cases, 88%) occurred within 14 days of the diagnosis. The median time from the diagnosis of infection to death tended to be shorter among patients who did not receive appropriate empiric antimicrobial therapy (one day) than in other patients (8 days, p = 0.07).

The emergence of infections caused by CRAB and other multi-drug resistant bacteria among transplant patients poses a difficult therapeutic challenge. In CRAB infections, therapeutic options are frequently restricted to drugs such as polymyxins and amikacin, which are associated with a higher risk of toxicity. Tigecycline has a better toxicity profile, however, its use as a monotherapy for the treatment of severe infections caused by CRAB, such as bacteremia and hospital-acquired pneumonia, is considered clinically unreliable [1, 12]. Such therapeutic limitations justify the hypothesis that CRAB infection might be associated with a poorer prognosis especially in immunocompromised hosts.

Most studies that addressed the impact of A. baumannii infection on mortality defined overall 14 or 30-day mortality as their primary outcome. However, it has been observed both in transplant recipients [8] and in other critically ill patients [13] that CRAB infection may have a prolonged course that may ultimately result in death after several weeks of continued antimicrobial therapy [8]. Thus, the analysis of overall 14-day mortality might underestimate the impact of CRAB on mortality. On the other hand, overall 30-day mortality is more likely to be influenced by factors other than CRAB infection, like those related to the underlying clinical severity of the affected patients. Therefore, death associated with A. baumannii was defined as the primary outcome of this study. As expected, most A. baumannii-associated deaths occurred within 14 days. However, some patients had more prolonged course of the disease, and in one of these cases A. baumannii-associated death occurred 52 days after the diagnosis of infection.

There was no significant association between carbapenem resistance and mortality. It might be argued that this study was underpowered to detect a moderate increase in CRAB associated mortality. In fact, there was a non-significant increase in mortality among patients with CRAB infection in the univariate analyses. However, in the final multivariable model for death associated with A. baumannii infection, the estimated odds ratio for carbapenem resistance was lower than one. This finding suggests that the lack of association between carbapenem resistance and mortality in this report is unlikely to be related to inadequate statistical power. Conflicting results have been reported regarding the possible influence of carbapenem resistance on mortality among critically ill patients [14–19]. The reasons for this inconsistency are not clear, but it is probable that it comes from methodological differences among these studies, especially in the approach to minimize confounding by baseline clinical severity and to assess the effect of early appropriate therapy [19].

Acquisition of infection in the ICU and being on mechanical ventilation at the time of infection diagnosis were both strongly related to A. baumannii-associated death. These factors are probably surrogate markers of clinical severity and its association with mortality is in line with the results of other studies that pointed out the influence of factors related to baseline clinical severity on the outcome of A. baumannii infections [13, 14, 17, 20, 21].

The beneficial impact of early start of effective therapy on the outcome A. baumannii infection has been suggested by the results of other studies [6, 18–22]. Indeed, Kwon at al. observed that carbapenem resistance was related to mortality in patients with A. baumannii bacteremia only if the use of effective therapy was not taken into account in the analysis [19]. Accordingly, in this series of abdominal organ transplant recipients, the use of appropriate empiric antimicrobial therapy was related to a significantly better outcome. Similar results have been reported by Kim and cols. [6] in a small case series of living-donor liver transplant recipients. However, that study also included subjects infected with Acinetobacter lwoffii, a species that has been associated with low mortality in immunocompromised patients [23]. It is plausible that the impact of delaying appropriate antimicrobial therapy for these infections may be higher in immunocompromised hosts than in immunocompetent patients. However, this issue was not addressed in the present study. Similarly to what has been described elsewhere [6, 18, 19, 21, 22], the proportion of patients who received inappropriate empirical antibiotic therapy was high in this series. Our findings underscore the importance of finely adjusting the selection of empiric antimicrobial therapy to the local epidemiological conditions.

The epidemiology and outcome of A. baumannii infection among KT recipients is largely unknown. We found that the overall cumulative incidence of A. baumannii infection was significantly lower in KT recipients than in LT patients. The prevalence of carbapenem resistance was not significantly different between isolates from both groups of patients, but clinical severity at the time of infection diagnosis was lower among KT patients as indicated by significantly lower frequency of ICU-acquired infection, use of central venous catheter, mechanical ventilation and extra-urinary site infection. As expected, the diagnosis of acute graft rejection was more frequent among KT recipients, but this factor was not independently related to A. baumannii-associated mortality in our analyses. The lower baseline clinical severity was probably responsible for the better outcome of KT patients that was observed only in the unadjusted statistical analysis. Unfortunately, because of the relatively small number of cases included in the study, we could not address specific prognostic factors for KT and LT recipients infected with CRAB.

The present study has some limitations. The sample size was relatively small and, thus, it is possible that the influence of some of the studied variables on mortality was missed in the multivariable analyses. Due to a retrospective design, we were not able to categorize patients according to any validated severity of illness score. Although other surrogate markers were used, we cannot rule out the possibility of residual confounding related to differences in baseline clinical severity. Similarly, it is not possible to preclude confounding by aspects related to antimicrobial therapy that were not addressed in the present study, such as the specific drug or combination of drugs used, doses and the exact number of hours elapsed between the clinical diagnosis of infection and the start of antibiotic treatment. One additional limitation of the study was the identification of Acinetobacter isolates by Vitek-1 system. However, most of the isolates would be classified as A. baumannii by the current, more accurate methods, and most human infections are caused by this species. Therefore, it is likely that this limitation did not have a major impact in the final results. Finally, because this is a single center study, the external validity of findings is uncertain. Larger, multicenter, prospective studies would help to provide a better definition of the factors that influence the outcome of A. baumannii infections in transplant recipients.

These results suggest that A. baumannii-associated mortality among liver and kidney transplant recipients is influenced by baseline clinical severity and by the early start of appropriate therapy, but not by carbapenem resistance.