The increasing prevalence of carbapenem-resistant Klebsiella pneumoniae (CRKP) is a healthcare crisis in China. Bloodstream infection (BSI) caused by CRKP is a more serious situation due to ineffective antibacterials and high mortality.1 Therapeutic options against these infections are limited; “second line” agents include colistin, tigecycline, aminoglycosides, and carbapenems.2 The best available treatment against CRKP infections is still under study owing to different chemoresistance mechanisms and limited effectiveness. Rather than monotherapy, clinicians are increasingly resorting to combination therapies, such as dual carbapenems, carbapenems combined with polymyxin B or tigecycline.3–5 However, clinical outcomes are not confirmed in the absence of evidence-based trials.

Regarded as one of the last resorts, polymyxin B has been used alternatively in China, especially following the surge of CRKP only susceptible to colistin. Thus, researchers are paying more attention to polymyxin B options as monotherapy or combination therapy, medication doses, and adverse effects.2 Combination therapy is probably better than monotherapy for serious CRKP bacteremia, but the timing clinicians should implement such therapy is still unclear.2,5,6 Our retrospective observational study aimed to estimate the impact of early initiation of polymyxin B on the outcome of patients with CRKP BSI.

A total of 69 patients who had CRKP bacteremia and received polymyxin B between Oct 1, 2015, and Mar 31, 2018 were retrieved. Forty cases were ultimately analyzed, and 29 cases were excluded. Refractory mixed infections occurred in 15 cases, including seven CRAB and four CRPA infections, three cases with MRSA, three cases with serious intracranial CRKP infections, and one case of invasive aspergillosis. More details can be seen in the flow chart (Fig. 1).

Fig. 1.

Flow chart of patients with bloodstream infections due to carbapenem-resistant Klebsiella pneumoniae treated with polymyxin B.

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Table 1 reports the characteristics of patients with bacteremia due to CRKP and the variables associated with the timing of polymyxin B between early and delayed administration. The early use and delayed use groups had similar characteristics and great homogeneity. As a trauma center, complicated multiple injuries, as common primary diseases leading to ICU admission, accounted for 37.5%, the same as infectious diseases in our study. Age, sex and source of infection were similar in the two groups, and types of primary diseases were not significantly different. Broncho-pulmonary infection was considered the source of bacteremia in 16 patients and the gastrointestinal tract in five cases. Primary bloodstream infections, without clearly CRKP infectious or colonized sites, accounted for a large proportion (42.5%).

In terms of clinical characteristics, APACHE II scores (18.83 versus 22.06, p=0.103) and Charlson comorbidity indexes (2.39 versus 2.52, p=0.808) on admission into ICU were similar in both early and delayed use groups. Likewise, similar SOFA scores (15.43 versus 14.47, p=0.293) and Pitt bacteremia scores (4.17 versus 3.41, p=0.679) indicate that the patients had the same clinical condition when bloodstream infections were diagnosed. Laboratory parameters, including white blood cell count, blood platelet count (PLT), C-reactive protein (CRP), procalcitonin (PCT), and serum bilirubin were also similar in the two groups. Other conditions that may affect prognosis, such as acute kidney injury (AKI), invasive procedures, immunosuppression, and septic shock were not significantly different in the two groups, indicating homogeneity in the severity of infection.

All isolates were resistant to meropenem and imipenem and sensitive to colistin. Nearly 27.5% of isolates were resistant to tigecycline. Although we used the most sensitive antibiotic, the overall lethality rate of CRKP bloodstream infections were still high. Twenty-four (60%) patients died, 10 (43.48%) patients with early administration of polymyxin B and 14 (82.35%) with delayed administration (p=0.022, OR=0.321; CI: 0.110–0.940). All patients accepted polymyxin B-based combination therapies. However, there was no difference between the three combinations with tigecycline, carbapenems, and amikacin. Compared with the delayed application, early use of polymyxin B showed greater bacterial clearance rate (65.22% versus 29.41%, p=0.025; OR=0.533; CI: 0.295–0.965) and reduced 30-day mortality (39.13% versus 70.59%, p=0.045; OR=0.461; CI: 0.199–0.989) and the overall mortality (43.48% versus 82.35%, p=0.022; OR=0.321; CI: 0.110–0.940). Fig. 2 shows the Kaplan–Meier curves of patients treated with early and delayed administration of polymyxin B (p=0.042). It should be pointed out that polymyxin B duration and total dosages in the two groups were similar (11.57 days versus 11.76 days, p=0.919; 1306.52mg versus 1247.06mg, p=0.711, respectively). Therefore, mortality was not correlated with longer treatment duration or higher dosage of polymyxin B. During the treatment, there were neither cases with detectable renal toxicity nor neurovirulence related to polymyxin B.

Fig. 2.

Kaplan–Meier curves of patients treated with early and delayed administration of polymyxin B.

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In our study, preemptive use of polymyxin B before blood culture results had better bacterial clearance and more favorable outcome in patients with BSI due to CRKP than delayed use of the drug.

Polymyxin B is an undisputed effective antibiotic choice for treating patients with CRKP bloodstream infections according to culture results. However, the limitations of traditional microbiological techniques in identifying bloodstream pathogens will delay treatment initiation of serious infections such as CRKP BSI. Furthermore, polymyxin B was only recently approved for entry into the Chinese market, and the price is exceedingly expensive. As a result, clinicians regard it as the last resort, preferring tigecycline or carbapenems, postponing the use of polymyxin B and unavoidably affecting prognosis. Gutiérrez-Gutiérrez et al. observed that appropriate therapy starting up to five days after infection was associated with decreased mortality (OR=0.44) in patients with BSIs due to CPE.5

Early appropriate therapy (starting up to two days after infection) can also reduce mortality (OR=0.84). We defined early use of polymyxin B as administering it before blood culture results, which is analogous to empirical antibiotic treatment. In contrast, the delayed group can be considered as having received targeted antibiotic therapy.10 However, there is some difference between early use in our study and empirical treatment, as half of the patients (57.5%) had primary infection sites, such as the broncho-pulmonary and gastrointestinal tract. Once the infectious symptoms occurred, BSI due to CRKP prompted early targeted therapies first. Nonetheless, most patients with primary BSIs had high risk factors, including invasive procedures, immunosuppression and history of carbapenems use.11,12 Patients in the delayed use group also had high risk of CRKP infections, but other antibiotic regimens were chose owing to the refusal of the patients’ relatives and the availability of alternative regimens. The total treatment duration and dosages of polymyxin B were similar in the two groups. Therefore, the advantages of early administration cannot be attributed to these factors. We speculate that early application of polymyxin B can reach an effective blood concentration as quickly as possible and truncating the duration of bacteremia, eventually reducing the death rate.

The impact of the underlying conditions in mortality of critical patients presenting with CRKP bacteremia are vital and could outweight the influence of antibiotic therapy. We tried our best to balance the characteristics of patients to avoid confounding primary diseases by employing strict eligibility criteria, such as excluding patients with terminal disease, intracranial CRKP infections, and high APACHE II scores (>30 points).

Although an optimal regimen is yet to be defined, most studies have recommended polymyxin B-based combinations in instead of monotherapy to reduce mortality.2,4,5,13 In a recent randomized controlled trial (RCT) by Mical Paul et al. polymyxin B combined with a carbapenem was not more effective than monotherapy in carbapenem-resistant Gram-negative bacterial infections. However, the main bacterium was CRAB rather than CRKP, and pneumonia and infections of other sites were included in this RCT, leading to great heterogeneity.14 In the study by Gutiérrez-Gutiérrez et al. polymyxin B was administered to 154 patients, half of them on monotherapy had a 30-day mortality of 54% (40/74), whereas those patients on polymyxin B-containing regimens had a 30-day mortality of 38% (28/74).5 Different combinations have been recommended as there are many possible treatment regimens. Carbapenem-containing regimens, as Daikos et al. reported, is among the most effective combinations.6 The survival rate was 52% with polymyxin B with carbapenems in our report, which was similar to the 50% synergy seen in vitro.15 In our study, polymyxin B was frequently combined with either a carbapenem, or tigecycline, or aminoglycosides. Two-thirds of patients received the combination of polymyxin B and a carbapenem, with a high mortality rate (61.11%). However, we cannot be able to draw any definitive conclusions because of the small sample sizes and nonsignificant statistical results. Our study has some limitations, such as the impacts of unmeasured variables and confounding factors due to the observational nature of the study.

We recommend early administration of polymyxin B-based combination therapy before blood culture results for patients with bloodstream infections due to CRKP. Irrespective of drug dosage and treatment duration, early use can effectively eliminate bacteria, improving 30-day and overall mortality.

Qiqiang Liang collected and analyzed the data and wrote the first draft of the manuscript. Zhijiang Xu assisted with the statistical analyses of the microorganisms. Man Huang reviewed and modified the draft of the manuscript.

No funding.

The authors declare no conflicts of interest.