Skip to main content

Clinical outcomes and safety of polymyxin B in the treatment of carbapenem-resistant Gram-negative bacterial infections: a real-world multicenter study

Abstract

Background

High morbidity and mortality due to carbapenem-resistant Gram-negative bacilli (CR-GNB) has led to the resurgence of polymyxin B (PMB) use in the last decade. The aim of our multicenter, real-world study was to evaluate the effectiveness and safety of PMB in the treatment of CR-GNB infections.

Methods

The real-world study included patients treated with intravenous PMB for at least 7 days during the period of October 2018 through June 2019. Associations between these clinical features and 28-day mortality or all-cause hospital mortality were explored through univariate analyses and multivariable logistic regression.

Results

The study included 100 patients. Many patients presented with combined chronic conditions, septic shock, mechanical ventilation, and the presence of Klebsiella pneumoniae. The mean duration of PMB therapy was 11 days (range 7–38 days). Temperature (38 °C vs 37.1 °C), white blood cells (14.13 × 109/l vs 9.28 × 109/l), C-reactive protein (103.55 ug/l vs 47.60 ug/l), procalcitonin (3.89 ng/ml vs 1.70 ng/ml) and APACHE II levels (17.75 ± 7.69 vs 15.98 ± 7.95) were significantly decreased after PMB treatment. The bacteria eradication rate was 77.65%. The overall mortality at discharge was 15%, and 28-day mortality was 40%. Major adverse reactions occurred in 16 patients. Nephrotoxicity was observed in 7 patients (7%).

Conclusions

Our results provide positive clinical and safety outcomes for PMB in the treatment of CR-GNB. Timely and appropriate use of PMB may be particularly useful in treating patients with sepsis in CR-GNB infections.

Introduction

In recent years, infections due to carbapenem-resistant Gram-negative bacilli (CR-GNB) have become an increasingly important cause of mortality and morbidity around the world [1]. The organisms most commonly identified in CR-GNB infections are Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa [2,3,4]. These bacteria can lead to bloodstream, respiratory tract, skin and soft tissue, urinary tract, intra-abdominal, and surgical infections [3, 5,6,7]. They are responsible for nosocomial infections, particularly among critically ill patients hospitalized in intensive care units (ICUs) [8].

Mortality rates of greater than 47% have been reported for CR-GNB infections [5, 9,10,11,12,13]. The decline in the development of newer antibiotics has created a challenge for clinicians treating CR-GNB infections [2, 14]. As a result, physicians have sought solutions in the arsenal of older therapeutics. This has led to the re-introduction of polymyxins in the treatment of infections caused by CR-GNB, as polymyxins are one of the few antibiotics that remain effective against these organisms [3]. Two polymyxins in clinical use, polymyxin B (PMB) and colistin, had fallen out of favor due to nephrotoxicity and neurotoxicity reported during 1960s. However, due to multiple drug resistance among Gram-negative bacilli, physicians have been increasingly forced to rely on polymyxins for the treatment of infections caused by these pathogens. It has not been determined which of these agents is superior in terms of the cure rate or microbiological resolution [15, 16]. A systematic review and meta-analysis summarized findings that included no significant difference in mortality between patients treated with these two polymyxins; this study also found a lower nephrotoxicity profile for PMB [15]. Additionally, recently published research demonstrated that PMB, unlike colistin, is not cleared renally and therefore, dosing of PMB should not be adjusted based on renal function [17]. However, the simulated values for AUC across 24 h at steady state for patients with creatinine clearance ≥ 80 ml/min were higher than those for patients with creatinine clearance < 80 ml/min [18].

The international consensus guidelines for the optimal use of polymyxins recommend that patients intravenous PMB should receive a dose of 1.25–1.5 mg/kg (equivalent to 12,500–15,000 IU/kg) PMB every 12 h infused over 1 h [16]. In one study, clinicians found that combination therapy with at least two in vitro active agents was associated with higher efficacy in treating bloodstream infections caused by CR-GNB [6, 19]. Carbapenem was the agent combined most commonly with PMB, followed by tigecycline, and cefoperazone–sulbactam [20].

Currently, there is a lack of data available on the efficacy, 28-day mortality, and adverse events for PMB in the treatment of CR-GNB infections. Here, we report on a multicenter, real-world study of patients receiving intravenous PMB to investigate the clinical outcomes of antimicrobial therapy in patients infected with CR-GNB.

Methods

Study design and patients

This multicenter, real-world study was conducted at 14 hospitals in Henan province during the period of October 2018 through June 2019. The institutional research ethics committee of the First Affiliated Hospital of Zhengzhou University approved the retrospective study (SS-2019-015).

Inclusion criteria

Patients aged > 14 years with CR-GNB infection who received PMB therapy for at least 7 days were included in the study. Patients with positive culture of CR-GNB, or patients were highly suspected infection of CR-GNB would receive intravenous PMB. The organisms identified in CR-GNB infections are Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, and Stenotrophomonas maltophilia.

Exclusion criteria were < 14 years old, received intravenous PMB for fewer than 7 days, previous enrolment in the trial, pregnancy, breast feeding during the study period, or on renal replacement therapy.

Data collection

Data was collected from electronic patient registration and follow-up. The database was generated by the clinician through a query of the electronic medical records. The following variables were recorded: age, gender, underlying disease, hospitalization date, dates of admission to and discharge from ICU, vital signs, Acute Physiology and Chronic Health Evaluation II (APACHEII) score, Sequential Organ Failure Assessment (SOFA) score, any major surgeries performed, ventilator care, site of isolation of organisms, exposure to antimicrobial therapies, clinical features, biochemical indices, and microbiological data on admission and on the day of introduction of PMB.

The dose and duration of PMB therapy, renal function, clinical and microbiological outcomes, and adverse reactions to PMB were noted. Patients were followed up until the end of treatment at 28 days.

Patient screening procedure

Diagnoses of infections were based on clinical features and the isolation of bacteria from areas that are normally sterile. The microbiologically documented infection was defined as positive cultures in sterile of localized, and absence of any bacterial pollution or colonization. Severe sepsis was defined as sepsis associated with organ dysfunction or hypoperfusion. Septic shock was defined as sepsis 3.0 [21]. Pulmonary infection included hospital-associated pneumonia (HAP) and ventilator-associated pneumonia (VAP). HAP was defined as a pneumonia occurring 48 h or more after admission. VAP was defined as a pneumonia developing 48 h or more after tracheal intubation. Chronic diseases included heart disease, hypertension, stroke, cancer, diabetes mellitus, and chronic obstructive pulmonary disease.

Microbiology

The CR-GNB include Enterobacteriaceae, Acinetobacter spp., Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Burkholderia cepacia. But, the most common CR-GNB found were Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, and Stenotrophomonas maltophilia. All CR-GNB infections were identified in the microbiology laboratory. The biological samples included blood, vein catheter samples, urine, sputum, tracheal secretions, bronchial‐alveolar lavage fluid, intraperitoneal fluid, and pleural drainage fluid. Bacterial identification and drug sensitivity tests were performed using a Vitek® 2 automated system (France Biomerieux). Susceptibility was interpreted according to Clinical and Laboratory Standards Institute criteria [22]. Enterobacteriaceae with a minimal inhibitory concentration (MIC) ≥ 4 µg/ml were considered resistance to carbapenem [22]. Pseudomonas aeruginosa and Acinetobacter spp. with a minimal inhibitory concentration (MIC) ≥ 8 µg/ml were considered resistance to carbapenem [22]. Burkholderia cepacia with a MIC ≥ 16 µg/ml were considered resistance to meropenem [22]. Isolates with a MIC ≤ 2 µg/ml were considered susceptible to PMB (colistin breakpoint for Enterobacteriaceae) [23]. The treating clinicians evaluated whether pathogens were the pathogenic bacteria according to the characteristics of pathogen distribution in the institution and their own experience.

Treatment regimen

All patients were treated with intravenous PMB, most in combination with other anti-CR-GNB agents, to which all strains remained sensitive. The international consensus guidelines for the optimal use of polymyxins recommend that patients who require intravenous PMB receive a loading dose of 2.0–2.5 mg/kg, and then a dose of 1.25–1.5 mg/kg (equivalent to 12,500–15,000 IU/kg) PMB every 12 h infused over 1 h [16]. Upon isolation of strains of CR-GNB that were resistant to carbapenem, an intravenous antibiotic regimen was initiated at the discretion of the attending physician.

Outcomes

The primary outcome of this analysis was 28-day mortality; the secondary outcomes included all-cause hospital mortality, ICU mortality, and the occurrence of adverse events during PMB therapy. The clinical outcomes of this study were based on the recovery of patients following PMB therapy. The measure of 28‐day mortality refers to patient deaths occurring within 28 days from the start of intravenous PMB, even if the death was related to other comorbidities that were not the infection.

Clinical cure was defined as a combined outcome of survival and the complete disappearance or improvement of signs and symptoms of infection after day 7 of PMB therapy. Failure of treatment was defined as maintenance or worsening of signs and symptoms of disease or radiologic deterioration. Bacteria eradication rate, the rate that the bacteria were eliminated during the course of PMB treatment.

Common adverse events included nephrotoxicity, neurotoxicity, skin hyperpigmentation, and eosinophil increase. The major adverse reaction was nephrotoxicity. Nephrotoxicity was defined as increase in serum creatinine (SCr) by ≥ 26.5 umol/l within 48 h, or increase in SCr to ≥ 1.5 times baseline within 7 days, or urine volume < 0.5 ml/kg/h for 6 h [24]. Skin hyperpigmentation was evaluated based on changes of the skin of the face and neck during PMB therapy or 4 weeks after treatment completion. Neurotoxicity included any of the following: apnea, encephalopathy, paresthesia, or seizures.

Statistical analysis

Statistical analyses were carried out using the statistical software package IBM SPSS Statistics 21.0 (SPSS, Chicago, IL). Descriptive analysis was performed to describe the distribution of the variables of interest. Categorical variables were presented as counts and percentages and were compared between survivors and non-survivors using Chi-squared test or Fisher’s exact test. Continuous variables of each group were presented as the mean ± SD or median with interquartile range (IQR) and were compared between survivors and non-survivors using Student’s t-test or Mann–Whitney U test, as appropriate. Paired t-test or Wilcoxon signed rank test was used to compare the continuous variables before and after therapy and categorical variables were compared using the McNemar test. Associations between these covariates and 28-day mortality or all-cause hospital mortality were explored through multivariable logistic regression. Kaplan–Meier curves were conducted to demonstrate the survival probability within 28 days and were compared using log-rank test between groups. A P-value < 0.05 was considered statistically significant.

Results

Demographic and clinical features

A total of 106 patients were enrolled in the study between October 1, 2018 and June 30, 2019. Follow-up studies were completed for 100 patients (94.3%). The mean length of hospitalization was 41.6 ± 26.42 days (range 7–130 days), and the mean residence time in the ICU was 26 days. There were 23 patients without chronic disease and 37 patients with one chronic illness; the remainder of patients had a combination of multiple chronic diseases. There were 39 patients who had septic shock at the beginning of therapy; an additional 10 patients later progressed to shock. The demographic and clinical features of patients who received intravenous PMB are summarized in Table 1.

Table 1 Clinical features and details of patients receiving intravenous PMB

Treatment regime

For 85 patients, the pathogen culture was positive; 21 patients of these were infected with two bacteria species. In 35 cases, the patient had multi-site infection. 97 patients received between 2 and 4 antimicrobials daily, and 3 patients treated with intravenous PMB as a single agent. The most common combinations were PMB + Carbapenem (30%), PMB + Carbapenem + Tigecycline (26%) and PMB + Tigecycline (11%). The other (13%) combination therapy were PMB and fosfomycin combined with carbapenem or tigecycline or cephalosporin.

Overall, the condition of patients improved after the PMB treatment. Temperature, white blood cells, C-reactive protein (CRP), procalcitonin, and APACHEII levels were significantly decreased among patients. Platelets were significantly increased (P < 0.001). The number of patients with mechanical ventilation or shock significantly decreased after PMB treatment (Table 2).

Table 2 Comparison of patient conditions before and after therapy

Microbiological eradication occurred in 66 (77.65%) out of 85 patients with electropositive germiculture. Serious adverse reactions occurred in 16 patients (16%). The rates of adverse reactions of 100, 150, 200 mg/day PMB were 15.09%, 11.76%, 20% (P = 0.735). Seven patients experienced at least two adverse reactions. No patients had treatment discontinued because of an adverse reaction. Nephrotoxicity was manifested by transient creatinine and urea nitrogen elevations, and no patient required hemodialysis. Among 6 patients demonstrating neurotoxicity, 4 patients showed persistent drowsiness, transient irritability, paresthesia, fatigue, dizziness, or drowsiness, and the other 2 patients underwent invasive mechanical ventilation due to adverse reactions of respiratory depression.

Outcomes

The outcomes of patients receiving intravenous PMB are shown in Table 3. The 28-day mortality was 40%. More than 60% deaths occurred 7–14 days after enrollment, as shown in the Kaplan–Meier survival curve (Fig. 1). The survivors and nonsurvivors had similar characteristics (Table 4). However, the platelet count in the nonsurvivors group was lower than in the survivor group (P = 0.001). In terms of clinical characteristics, SOFA scores (6.77 ± 4.07 vs 9.25 ± 4.25, P = 0.004), APACHE II scores (16.17 ± 7.80 vs 19.7 8 ± 6.80, P = 0.016) and the number of patients on mechanical ventilation (21% vs 30%, P < 0.001) or having septic shock (17% vs 32%, P < 0.001) were lower in the survivor group than in the nonsurvivor group. There were no different therapeutic outcomes among the different anti-infection therapeutic regimen.

Table 3 Outcomes of patients receiving intravenous PMB
Fig. 1
figure1

Survival analysis at 28 days: Kaplan–Meier curve. Survival rate from the receiving intravenous PMB to 28 days

Table 4 Characteristics associated with 28-day mortality among patients who received intravenous PMB

Prior to intravenous PMB, empirically anti-infective treatment by intravenous carbapenem or tigecycline 10.4 ± 8.3 days (range 2–28 days) showed no clinical improvement. Efforts to improve salvage treatment were urgently required. The mortality among the 85 patients with identified pathogens was 38.82%, while the mortality among patients with negative pathogen culture results was 46.67% (P = 0.58). During treatment, similar adverse reactions related to PMB were observed in the two groups. There were no significant differences in characteristic and therapeutic effect of patients with intravenous PMB among centers (Table 5).

Table 5 Characteristic and therapeutic effect of patients receiving intravenous PMB among centers

The factors demonstrating statistically significant differences in univariate analysis in Table 4 were analyzed by logistic regression (Table 6). The 28-day mortality was 58.82% for patients on mechanical ventilation compared to 20.41% for patients who were not on mechanical ventilation. The 28-day mortality was 65.31% in patients with septic shock compared to 15.69% in patients who did not have septic shock. Survival of patients is shown in Fig. 2.

Table 6 Multivariate analysis of factors associated with 28-day mortality
Fig. 2
figure2

Kaplan–Meier 28-day survival curve comparing patients on mechanical ventilation or with septic shock. A 28-day mortality rate was 59% and 20% in patients with mechanical ventilation and not on mechanical ventilation, respectively (log-rank, P < 0.01). B 28-day mortality rate was 65% and 16% in patients with septic shock and without septic shock, respectively (log-rank, P < 0.01)

Discussion

In this study, patients with CR-GNB infection treated with PMB had a bacteria eradication rate of 77.65%, ICU-related mortality of 12%, hospital mortality of 15%, and 28-day mortality of 40%. These results are favorable compared with those reported for studies of patients receiving different treatments for CR-GNB infections [25]. For example, in patients infected with carbapenem-resistant Acinetobacter baumannii who did not receive appropriate empirical antimicrobial therapy, the overall mortality rate was 86.1% [26]. In one retrospective study, the overall ICU mortality rate was 45.2% for critically ill patients infected with CR-GNB who received tigecycline therapy [27]. In another retrospective study, the in-hospital mortality rate for patients receiving tigecycline for the treatment of carbapenem-resistant Klebsiella pneumoniae bloodstream infections was 62.5% [28]. In a retrospective cohort study of the treatment of infections due to carbapenem-resistant Enterobacteriaceae, the 30-day mortality was 50% after ceftazidime–avibactam treatment [29]. Our results suggest that treatment with PMB may reduce the mortality of patients with CR-GNB.

Our study found that after 7 days of PMB treatment, the temperature of patients with CR-GNB infection returned to normal, and the number of patients with septic shock or mechanical ventilation decreased. Moreover, the infection indicators of white blood cell, procalcitonin, and CRP were all significantly reduced. The symptoms of thrombocytopenia in patients with CR-GNB infection improved. APACHE II scores were also lower than the initial sepsis. The mortality of PMB target therapy was 38.82%, while the mortality of patients with empiric therapy was 46.67% (P = 0.580). Our results suggest that PMB may be a clinically effective treatment for patients infected with CR-GNB. The survival was no difference in 28-day mortality in patients that received 100, 150, 200 mg/day PMB. Some studies found that there was no difference in PMB daily dose between survivors and nonsurvivors [20, 30]. But other studies suggested that the daily dose of PMB treatment failure in CR-GNB infections among critically ill patients was lower than success [9]. Randomized controlled trials with large data are required to determine the optimal therapeutic dose.

Our results suggest that PMB therapy is safe for the treatment of infections caused by CR-GNB, as intravenous PMB was well tolerated in most patients. Serious adverse reactions occurred in 16 patients (16%), 7 patients had at least two adverse reactions, eight of whom had transient adverse reactions.

In our study, adverse effects related to nephrotoxicity occurred in 7 patients (7%) and were mild and reversible; none required renal replacement therapy. While the prevalence of nephrotoxicity was not lower in our study than in other observational studies (4.2% to 40.5%) [11, 18, 20, 31,32,33,34], it was at the lower end of these reported ranges. Assessment of the contribution of PMB to renal impairment may be complicated by other factors such as infection, septic shock, multiple organ dysfunction syndrome (MODS), and concomitant use of other nephrotoxic drugs. One study found that malignancy, co-infection with other microorganisms, and PMB daily dose were risk factors for polymyxin B-associated nephrotoxicity [35]. Their results also indicated daily dose differed between patients with and without nephrotoxicity (131 mg vs 150 mg, P = 0.005) during PMB administration [35]. Our results showed that PMB daily dose was not marked relation with adverse effects.

Neurotoxicity of PMB is less common than nephrotoxicity, and it is usually mild and resolves after prompt discontinuation of therapy [11, 20, 31]. In another study, however, no cases of neurotoxicity complications occurred among 247 patients who were given PMB therapy [31]. In a previous study, intravenous PMB was associated with neurotoxicity (7%), manifestations of seizures and neuromuscular weakness [11]. In our study, among the 6 patients with neurotoxicity, 2 patients underwent invasive mechanical ventilation due to the adverse effects of respiratory depression. Neither patient used sedative analgesics. PMB therapy was not stopped in the patients with respiratory depression and the endotracheal tube was removed before the end of PMB treatment.

In the present study, three cases (3%) developed skin hyperpigmentation in the face and neck. This incidence is lower than previous studies [20, 31]. During treatment, there were no other adverse reactions such as rashes, itching, dermatitis, or fever. While our results support the use of PMB, the safety of polymyxin therapy requires further study.

Mechanical ventilation and septic shock were associated with higher 28-day mortality in the present study. Similarly, the other study showed mechanical ventilation, septic shock, multiple-site infection, and total PMB cumulative dose to be independently associated with treatment efficacy [20]. A previous study of a large US cohort found that most patients with culture-positive community onset sepsis did not have resistant bacteria [36], while a study of the epidemiology of sepsis in Chinese ICUs found that only 12% of culture-positive were multi-drug resistant organisms [37]. In our study, the mortality of patients with empiric PMB therapy was higher. This underscores the need for rapid identification of CR-GNB infection and an increased of judicious use of PMB for the treatment of sepsis, to avoid progression to mechanical ventilation or septic shock. In this regard, the optimization and validation of PMB-based combinations may have considerable clinical benefits. Our combination therapy was similar to that of most other research [9, 20]. It has been reported that the development of resistance was observed over a course of 72 h with PMB monotherapy against CRAB isolates [38]. Several clinical trials demonstrated that the increased use of colistin has led to the development of colistin resistance. It is suggested that intravenous of colistin, carbapenem, quinolone in the past three months prior to hospitalization and the length of hospital stay were risk factors contributing to colistin-resistant against microorganisms infection [39].Therefore, rational use of the colistins will be essential.

The present study has several limitations, including its retrospective, real-world design and lack of a control group or direct basis of comparison with other treatments. Another limitation was the relatively small number of patients included in the study. Serum PMB concentrations were not determined in the study. The decision to use additional antibiotics was made by individual clinicians, which may have introduced bias. Additionally, the concomitant use of other antibiotics with PMB makes it impossible to attribute treatment efficacy solely to PMB. Further, it was difficult to properly evaluate adverse effects attributable to PMB in view of the use of other drugs in seriously ill patients. Despite these limitations, our study represents a multicenter study evaluating a range of CR-GNB infections treated with PMB combination therapy.

Conclusions

In summary, the findings from our study suggest that timely and appropriate use of PMB may have a positive impact on clinical outcomes in the treatment of CR-GNB infections. These results underscore the need to more quickly identify patients with CR-GNB who may benefit from judicious use of PMB, in particular, patients with septic shock or on mechanical ventilation who may be at higher risk of mortality. Clinicians should apply strict protocols when using this antimicrobial agent to prevent the occurrence and spread of polymyxin resistance.

Availability of data and materials

The datasets used and/or analyzed in this study are not publicly available due to privacy issues but are available from the corresponding author upon reasonable request.

Abbreviations

CR-GNB:

Carbapenem-resistant Gram-negative bacilli

PMB:

Polymyxin B

ICU:

Intensive care unit

APACHEII:

Acute Physiology and Chronic Health Evaluation II

SOFA:

Sequential Organ Failure Assessment

HAP:

Hospital-associated pneumonia

VAP:

Ventilator-associated pneumonia

PCT:

Procalcitonin

CRP:

C-reactive protein

PLT:

Platelet count

MODS:

Multiple organ dysfunction syndrome

References

  1. 1.

    Patel G, Bonomo RA. “Stormy waters ahead”: global emergence of carbapenemases. Front Microbiol. 2013;4:48.

    Article  Google Scholar 

  2. 2.

    Velkov T, Roberts KD, Nation RL, Thompson PE, Li J. Pharmacology of polymyxins: new insights into an “old” class of antibiotics. Future Microbiol. 2013;8(6):711–24.

    CAS  Article  Google Scholar 

  3. 3.

    Gales AC, Jones RN, Sader HS. Contemporary activity of colistin and polymyxin B against a worldwide collection of Gram-negative pathogens: results from the SENTRY Antimicrobial Surveillance Program (2006–09). J Antimicrob Chemother. 2011;66(9):2070–4.

    CAS  Article  Google Scholar 

  4. 4.

    Paul M, Daikos GL, Durante-Mangoni E, Yahav D, Carmeli Y, Benattar YD, Skiada A, Andini R, Eliakim-Raz N, Nutman A, et al. Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial. Lancet Infect Dis. 2018;18(4):391–400.

    CAS  Article  Google Scholar 

  5. 5.

    Rigatto MH, Falci DR, Lopes NT, Zavascki AP. Clinical features and mortality of patients on renal replacement therapy receiving polymyxin B. Int J Antimicrob Agents. 2016;47(2):146–50.

    CAS  Article  Google Scholar 

  6. 6.

    Medeiros GS, Rigatto MH, Falci DR, Zavascki AP. Combination therapy with polymyxin B for carbapenemase-producing Klebsiella pneumoniae bloodstream infection. Int J Antimicrob Agents. 2019;53(2):152–7.

    CAS  Article  Google Scholar 

  7. 7.

    Maniara BP, Healy LE, Doan TL. Risk of nephrotoxicity associated with nonrenally adjusted intravenous polymyxin B compared to traditional dosing. J Pharm Pract. 2020;33(3):287–92.

    Article  Google Scholar 

  8. 8.

    Fridkin SK, Steward CD, Edwards JR, Pryor ER, Mcgowan JJ, Archibald LK, Gaynes RP, Tenover FC. Surveillance of antimicrobial use and antimicrobial resistance in United States hospitals: project ICARE phase. 2 Project Intensive Care Antimicrobial Resistance Epidemiology (ICARE) hospitals. Clin Infect Dis. 1999;29(2):245–52.

    CAS  Article  Google Scholar 

  9. 9.

    Ismail B, Shafei MN, Harun A, Ali S, Omar M, Deris ZZ. Predictors of polymyxin B treatment failure in Gram-negative healthcare-associated infections among critically ill patients. J Microbiol Immunol Infect. 2018;51(6):763–9.

    CAS  Article  Google Scholar 

  10. 10.

    Bratu S, Landman D, Haag R, Recco R, Eramo A, Alam M, Quale J. Rapid spread of carbapenem-resistant Klebsiella pneumoniae in New York City: a new threat to our antibiotic armamentarium. Arch Intern Med. 2005;165(12):1430–5.

    CAS  Article  Google Scholar 

  11. 11.

    Sobieszczyk ME, Furuya EY, Hay CM, Pancholi P, Della-Latta P, Hammer SM, Kubin CJ. Combination therapy with polymyxin B for the treatment of multidrug-resistant Gram-negative respiratory tract infections. J Antimicrob Chemother. 2004;54(2):566–9.

    CAS  Article  Google Scholar 

  12. 12.

    Liang Q, Huang M, Xu Z. Early use of polymyxin B reduces the mortality of carbapenem-resistant Klebsiella pneumoniae bloodstream infection. Braz J Infect Dis. 2019;23(1):60–5.

    Article  Google Scholar 

  13. 13.

    Rigatto MH, Vieira FJ, Antochevis LC, Behle TF, Lopes NT, Zavascki AP. Polymyxin B in combination with antimicrobials lacking in vitro activity versus polymyxin B in monotherapy in critically ill patients with Acinetobacter baumannii or Pseudomonas aeruginosa infections. Antimicrob Agents Chemother. 2015;59(10):6575–80.

    Article  Google Scholar 

  14. 14.

    Karaiskos I, Giamarellou H. Multidrug-resistant and extensively drug-resistant Gram-negative pathogens: current and emerging therapeutic approaches. Expert Opin Pharmacother. 2014;15(10):1351–70.

    CAS  Article  Google Scholar 

  15. 15.

    Vardakas KZ, Falagas ME. Colistin versus polymyxin B for the treatment of patients with multidrug-resistant Gram-negative infections: a systematic review and meta-analysis. Int J Antimicrob Agents. 2017;49(2):233–8.

    CAS  Article  Google Scholar 

  16. 16.

    Tsuji BT, Pogue JM, Zavascki AP, Paul M, Daikos GL, Forrest A, Giacobbe DR, Viscoli C, Giamarellou H, Karaiskos I, et al. International consensus guidelines for the optimal use of the polymyxins: endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). Pharmacotherapy. 2019;39(1):10–39.

    Article  Google Scholar 

  17. 17.

    Sandri AM, Landersdorfer CB, Jacob J, Boniatti MM, Dalarosa MG, Falci DR, Behle TF, Bordinhao RC, Wang J, Forrest A, et al. Population pharmacokinetics of intravenous polymyxin B in critically ill patients: implications for selection of dosage regimens. Clin Infect Dis. 2013;57(4):524–31.

    CAS  Article  Google Scholar 

  18. 18.

    Wang P, Zhang Q, Zhu Z, Pei H, Feng M, Sun T, Yang J, Zhang X. Comparing the population pharmacokinetics of and acute kidney injury due to polymyxin B in chinese patients with or without renal insufficiency. Antimicrob Agents Chemother. 2021;65(2):e01900-20.

    Article  Google Scholar 

  19. 19.

    Tan J, Yu W, Wu G, Shen J, Fang Y, Zhu H, Xiao Q, Peng W, Lan Y, Gong Y. A real-world study comparing various antimicrobial regimens for bloodstream infections caused by carbapenem-resistant Gram-Negative Bacilli in a Tertiary Hospital, Shanghai, China, from 2010 to 2017. Infect Drug Resist. 2020;13:2453–63.

    CAS  Article  Google Scholar 

  20. 20.

    Lu Q, Li G, Qu Q, Zhu H, Luo Y, Yan H, Yuan H, Qu J. Clinical efficacy of polymyxin B in patients infected with carbapenem-resistant organisms. Infect Drug Resist. 2021;14:1979–88.

    Article  Google Scholar 

  21. 21.

    Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801–10.

    CAS  Article  Google Scholar 

  22. 22.

    M100-S11, Performance standards for antimicrobial susceptibility testing. Clin Microbiol Newsl. 2001; 23(6):49.

  23. 23.

    Testing ECOA. Breakpoint table for interpretation of MICs and zone diameters, version 9.0. edition; 2019.

  24. 24.

    Kellum JA, Lameire N. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit Care. 2013;17(1):204.

    Article  Google Scholar 

  25. 25.

    Ngamprasertchai T, Boonyasiri A, Charoenpong L, Nimitvilai S, Lorchirachoonkul N, Wattanamongkonsil L, Thamlikitkul V. Effectiveness and safety of polymyxin B for the treatment of infections caused by extensively drug-resistant Gram-negative bacteria in Thailand. Infect Drug Resist. 2018;11:1219–24.

    CAS  Article  Google Scholar 

  26. 26.

    Du X, Xu X, Yao J, Deng K, Chen S, Shen Z, Yang L, Feng G. Predictors of mortality in patients infected with carbapenem-resistant Acinetobacter baumannii: a systematic review and meta-analysis. Am J Infect Control. 2019;47(9):1140–5.

    Article  Google Scholar 

  27. 27.

    Wu X, Zhu Y, Chen Q, Gong L, Lin J, Lv D, Feng J. Tigecycline therapy for nosocomial pneumonia due to carbapenem-resistant gram-negative bacteria in critically ill patients who received inappropriate initial antibiotic treatment: a retrospective case study. Biomed Res Int. 2016;2016:8395268.

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Geng TT, Xu X, Huang M. High-dose tigecycline for the treatment of nosocomial carbapenem-resistant Klebsiella pneumoniae bloodstream infections: a retrospective cohort study. Medicine (Baltimore). 2018;97(8):e9961.

    CAS  Article  Google Scholar 

  29. 29.

    Alraddadi BM, Saeedi M, Qutub M, Alshukairi A, Hassanien A, Wali G. Efficacy of ceftazidime-avibactam in the treatment of infections due to Carbapenem-resistant Enterobacteriaceae. BMC Infect Dis. 2019;19(1):772.

    Article  Google Scholar 

  30. 30.

    Peyko V, Cohen H. A comparison of adjusted versus unadjusted doses of polymyxin B based on renal function and incidence of acute kidney injury. J Pharm Pract. 2020;33(3):255–61.

    Article  Google Scholar 

  31. 31.

    Mattos K, Gouvea IR, Quintanilha J, Cursino MA, Vasconcelos P, Moriel P. Polymyxin B clinical outcomes: a prospective study of patients undergoing intravenous treatment. J Clin Pharm Ther. 2019;44(3):415–9.

    CAS  Article  Google Scholar 

  32. 32.

    Ouderkirk JP, Nord JA, Turett GS, Kislak JW. Polymyxin B nephrotoxicity and efficacy against nosocomial infections caused by multiresistant gram-negative bacteria. Antimicrob Agents Chemother. 2003;47(8):2659–62.

    CAS  Article  Google Scholar 

  33. 33.

    Nelson BC, Eiras DP, Gomez-Simmonds A, Loo AS, Satlin MJ, Jenkins SG, Whittier S, Calfee DP, Furuya EY, Kubin CJ. Clinical outcomes associated with polymyxin B dose in patients with bloodstream infections due to carbapenem-resistant Gram-negative rods. Antimicrob Agents Chemother. 2015;59(11):7000–6.

    CAS  Article  Google Scholar 

  34. 34.

    Cai Y, Leck H, Tan RW, Teo JQ, Lim TP, Lee W, Chlebicki MP, Kwa AL. Clinical experience with high-dose polymyxin B against carbapenem-resistant gram-negative bacterial infections-a cohort study. Antibiotics (Basel). 2020;9(8):451.

    CAS  Article  Google Scholar 

  35. 35.

    Zhang J, Hu Y, Shen X, Zhu X, Chen J, Dai H. Risk factors for nephrotoxicity associated with polymyxin B therapy in Chinese patients. Int J Clin Pharm-Net. 2021;43(4):1109–15.

    CAS  Article  Google Scholar 

  36. 36.

    Rhee C, Kadri SS, Dekker JP, Danner RL, Chen HC, Fram D, Zhang F, Wang R, Klompas M. Prevalence of antibiotic-resistant pathogens in culture-proven sepsis and outcomes associated with inadequate and broad-spectrum empiric antibiotic use. JAMA Netw Open. 2020;3(4):e202899.

    Article  Google Scholar 

  37. 37.

    Xie J, Wang H, Kang Y, Zhou L, Liu Z, Qin B, Ma X, Cao X, Chen D, Lu W, et al. The epidemiology of sepsis in Chinese ICUs: a national cross-sectional survey. Crit Care Med. 2020;48(3):e209–18.

    Article  Google Scholar 

  38. 38.

    Beganovic M, Daffinee KE, Luther MK, Laplante KL. Minocycline alone and in combination with polymyxin B, meropenem, and sulbactam against carbapenem-susceptible and -resistant Acinetobacter baumannii in an in vitro pharmacodynamic model. Antimicrob Agents Chemother. 2021;65(3):e0168020.

    Article  Google Scholar 

  39. 39.

    Yilmaz GR, Dizbay M, Guven T, Pullukcu H, Tasbakan M, Guzel OT, Tekce YT, Ozden M, Turhan O, Guner R, et al. Risk factors for infection with colistin-resistant gram-negative microorganisms: a multicenter study. Ann Saudi Med. 2016;36(3):216–22.

    Article  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Chao Qin (The Fifth Affiliated Hospital of Zhengzhou University), Changyu Zhang (The Second Affiliated Hospital of Zhengzhou University), Xianrong Song (Henan Provincial Chest hospital), Ping Lou (The Medical Group of Zhengzhou First People’s Hospital), Yanqiu Gao (Zhengzhou Central Hospital), Ying Cai (Jinshui District General Hospital of Zhengzhou), Tiancai Wang (Nanshi Hospital of Nanyang), Xianfa Jiao (People’s Hospital of Zhengzhou), Yongmei Zhang (First Affiliated Hospital, Henan University of Science and Technology), Lin Guo (The Seventh People’s Hospital of Zhengzhou), Jing Feng (Zhengzhou Yihe Hospital), Fengling Ju (Nanyang Second General Hospital), Hong Liu (The First People’s Hospital of Pingdingshan) for their support with data collection.

Funding

This study was supported by the United Fund of National Natural Science Foundation of China (Grant No. U2004110), Leading Talents Fund in Science and Technology Innovation in Henan Province (Grant No.194200510017); Science and Technology people-benefit project of Zhengzhou (2019KJHM0001); The special fund for young and middle-aged medical research of China International Medical Exchange Foundation (Grant No. Z-2018-35); The integrated thinking research foundation of the China foundation for International Medical Exchange (Grant No. Z-2016-23-2001); and the Overseas Training Program of Health Science and Technology Talents in Henan Province (HWYX2019008).

Author information

Affiliations

Authors

Contributions

All authors were involved in the research concept and design. XJZ, SYQ, and XGD contributed to the data acquisition. XJZ and TWS have reviewed and take responsibility for all of the data. XJZ, BH, SGZ, SHL, and HXW performed the analysis and interpretation of the data. XJZ contributed to the writing of the first draft. TWS and HBZ reviewed this article and made necessary changes to improve it. All authors reviewed the final manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Haibo Zhang or Tongwen Sun.

Ethics declarations

Ethics approval and consent to participate

The study was approved by the institutional research ethics committee of The First Affiliated Hospital of Zhengzhou University, and waived informed consent based on the real-world design and anonymization of patient identifiers before analysis.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zhang, X., Qi, S., Duan, X. et al. Clinical outcomes and safety of polymyxin B in the treatment of carbapenem-resistant Gram-negative bacterial infections: a real-world multicenter study. J Transl Med 19, 431 (2021). https://doi.org/10.1186/s12967-021-03111-x

Download citation

Keywords

  • Carbapenem-resistant Gram-negative bacilli
  • Infections
  • Polymyxin B
  • Adverse effects
  • 28-day mortality