Clinical and Epidemiological Characteristics of Carbapenem-Resistant Klebsiella pneumoniae Infections in a Tertiary Hospital in China

Abstract

Purpose:

Infections caused by carbapenem-resistant Klebsiella pneumoniae (CR-KP) are an important public health problem. This study aimed to evaluate the clinical characteristics of patients with CR-KP.

Methods:

A retrospective cohort study was conducted of all patients with CR-KP infection. A total of 615 patients with CR-KP infection were identified and 135 patients who did not meet the eligibility criteria were excluded. Clinical characteristics, antimicrobial regimens, and patient outcomes were analyzed.

Results:

The overall mortality rate of CR-KP infections was 37.3% and the mortality rate in patients with bloodstream infections was 66.2%. Survival analysis revealed that there were statistically significant differences between patients with bloodstream infections and those with pulmonary and drainage fluid infections. Logistics regression analysis showed that hemopathy, age >60 years, solid tumors, diabetes, septic shock, acute kidney injury, and stroke were independent predictors of 30-day mortality rate. The chi-square test showed that treatment with a combination of carbapenems, tigecycline, and polymyxin B was superior to treatment with carbapenems with polymyxin B, without tigecycline.

Conclusions:

CR-KP infections, especially bloodstream infections, have a high mortality rate. The outcome is strongly dependent on patients' clinical conditions. Antimicrobial regimens combining carbapenems, tigecycline, and polymyxin B might be a better choice.

Introduction

Carbapenem-resistant Klebsiella pneumoniae (CR-KP) infection is a health threat worldwide.^1–3 Infections caused by CR-KP are associated with a high mortality rate, ranging from 18% to 48% overall, and from 51% to72% in bloodstream infections, depending on the type of antimicrobial therapy administered and patient characteristics.^4–7

The first CR-KP strain was identified in 1993, and since then, CR-KP strains have become endemic in many countries.⁸ The 2016 Annual Report of the European Antibiotic Surveillance Network reported a mean prevalence of carbapenems resistance of 6.1%. In 2018, the prevalence of K. pneumoniae resistance in China was 15.4% to imipenem and 17.9% to meropenem.⁹

Although several studies have shown the effectiveness of combination regimens for reducing mortality, choosing an effective treatment regimen remains a challenge for clinicians.^10–13

This study evaluated the clinical characteristics of CR-KP infections in a tertiary hospital in China.

Methods

Patients

All patients with CR-KP infections at the First Affiliated Hospital of Zhengzhou University between January 2018 and December 2019 were identified from the hospital database. The study was approved by the human ethics committee of the First Affiliated Hospital of Zhengzhou University. The patients included in the database were followed by reviewing their medical records and contacting them directly. The requirement for informed consent was waived owing to the retrospective study design. Ethics approval number: 2020-KY-1468.

All patients included in this study were required to meet the following inclusion criteria: (1) age between 18 and 80 years and (2) diagnosis of CR-KP infection base on at least one positive culture. All sputum specimens were bronchoalveolar lavage fluid. Patients who died or were discharged within 48 hours after the initiation of adjusted therapy regimens and those with incomplete or missing data were excluded.

Sample collection

Patient variables include age, gender, presence of acute or chronic comorbidities, Acute Physiology and Chronic Health Evaluation (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores, absolute lymphocyte count (LYM, within 2 days of culture collection), previous surgery (≤30 days before the positive culture), any invasive procedures (≤72 hours before the positive culture), steroid or immunosuppressive therapy (≤30 days before the positive culture), previous antimicrobial therapy regimens (≤30 days before the positive culture), survival days, and adjusted therapy regimens after the positive culture. Rectal swabs were collected from some patients and screened for the presence of carbapenem-resistant enteric bacteria.

The primary outcome was death within 30 days of the first positive culture. Survivor and nonsurvivor subgroups were compared to identify the predictors of mortality.

Antimicrobial therapies

Once the culture and susceptibility results were known, the attending physician determined the appropriateness of the initial antimicrobial therapy. Antimicrobial therapy administered within 5 days after the onset of infection was defined as empirical therapy. Appropriate definitive antibiotic therapy was defined as that matching the in vitro susceptibility results according to the Clinical and Laboratory Standards Institute criteria.

Definitions

Septic shock was defined as sepsis with persistent hypotension, requiring vasopressors to maintain a mean arterial pressure ≥65 mmHg and serum lactate levels >2 mmol/L, despite adequate fluid resuscitation.¹⁴

Acute kidney injury was defined as follows: (1) increase in serum creatinine by ≥0.3 mg/dL within 48 hours, (2) increase in serum creatinine by ≥1.5 times baseline, and (3) urine volume <0.5 mL/kg per hour for ≥6 hours.¹⁵

Samples were routinely collected for microbial culture patients had fever and there was evidence or clinical suspicion of infection. Bloodstream infection was defined as hospital acquired if the index blood culture was collected >48 hours after hospital admission.

Statistical analysis

Statistical analysis was performed using SPSS version 22.0 (IBM Corp., Armonk, NY). Categorical variables reported as frequencies were compared using the χ² test or Fisher's exact test. Multivariable logistic regression analysis was used to identify independent risk factors for mortality. Kaplan–Meier curves were plotted to compare the 30-day survival rate in patients with blood stream infection, bronchoalveolar lavage fluid infection, and drainage infection. Continuous variables were evaluated using multiple linear regression analysis. Receiver-operating characteristic (ROC) curves were constructed for the LYM, and the APACHE II and SOFA scores. p-Value <0.05 was considered statistically significant.

Results

Baseline characteristics

We collected clinical data from 615 patients diagnosed with CR-KP infections between January 2018 and December 2019. A total of 135 patients who did not meet the eligibility criteria were excluded, and the remaining 480 patients were enrolled in the study. The baseline characteristics of the study cohort are given in Table 1.

Table 1.

Demographic and Clinical Characteristics of the Study Cohort According to the 30-Day Outcome

Variable	All, N = 480	30-Day outcome		χ²	p
Variable	All, N = 480	Death, N = 179	Survival, N = 301	χ²	p
Gender
Female	191	70	121	0.06	0.813
Male	289	109	180
Age (years)
≤60	209	53	166	29.51	<0.001
>60	271	126	135
Ward
Respiratory ICU	104	34	70	1.2	0.273
General ICU	110	47	63	1.8	0.18
Surgical ICU	119	48	71	0.63	0.428
Neurological ICU	111	34	77	2.74	0.098
Emergency ICU	36	16	20	0.85	0.356
Specimen type
BALF	379	120	259	24.41	<0.001
Blood or catheter tip	68	45	23	28.27	<0.001
Drainage liquid	21	7	14
Urine	9	1	8
Cerebrospinal fluid	3	3	0
Comorbidity
COPD	85	33	52	0.04	0.84
Solid tumors	81	46	35	4.01	0.045
Hematopathy	20	16	4	16.27	<0.001
Chronic liver disease	42	24	18	6.85	0.009
Organ transplantation	20	11	9	2.06	0.15
Coronary heart disease	169	72	97	2.81	0.094
Hypertension	229	91	138	0.93	0.335
Diabetes	97	49	48	8.4	0.004
Infectious disease	87	36	51	0.56	0.454
Tuberculosis	15	5	10	0.10	0.747
CNS sequelae	105	35	70	0.70	0.404
Complications
Septic shock	108	83	25	91.09	<0.001
Acute kidney injury	117	86	31	84.72	<0.001
Stroke	188	45	143	22.64	<0.001
Acute heart failure	39	17	22	0.72	0.396
Preinfection variables
Central venous catheter	387	159	228	12.29	<0.001
Intubation or tracheotomy	430	165	265	2.06	0.151
CRRT	58	36	22	17.32	<0.001
Steroid therapy	93	40	53	1.61	0.200
Immunosuppressive	23	14	9	5.74	0.017
Chemoradiotherapy	19	13	6	8.20	0.004

BALF, bronchoalveolar lavage fluid; CNS, central nervous system; COPD, chronic obstructive pulmonary disease; CRRT, continuous renal replacement therapy; ICU, intensive care unit.

The 30-day mortality rate in patients with CR-KP was 37.3%. The majority of patients (289, 60.2%) were male, and 191 (39.8%) were female. Of the 480 patients, 379 patients (78.9%) had pulmonary infection and 68 patients (14.2%) had bloodstream infection. Hypertension, coronary heart disease, and neurological diseases were the most common underlying diseases (47.7%, 35.2%, and 21.9%, respectively). Stroke (188, 39.2%) was the most common acute complication, followed by acute kidney injury (117, 24.4%) and septic shock (108, 22.5%). Septic shock was significantly more frequent among nonsurvivors than among survivors (46.3% vs. 8.3%, p < 0.001).

Most patients (430, 89.6%) underwent intubation or tracheotomy, and 387 patients (80.6%) underwent central venous catheter insertion. A proportion of patients received steroid therapy (93, 19.4%) or continuous renal replacement therapy (58, 12.1%). Rectal swabs were collected from 116 patients and screened for the presence of carbapenem-resistant enteric bacteria, of whom 35 (30.2%) were positive.

Antibiotic therapy

The empirical and definitive antibiotic therapies administered to patients with CR-KP in the survivor and nonsurvivor groups are summarized in Table 2. The most frequently used antibiotic regimens for both empirical and definitive therapies were carbapenems in both groups. The survival according to the antibiotic regimen is given in Table 3.

Table 2.

Antibiotic Therapy According to the 30-Day Outcome

Variable	All	30-Day outcome
Variable	All	Death	Survival
Empirical antibiotic therapy
Penicillins and cephalosporins	158	109	166
Carbapenems	184	69	115
Tigecycline	69	20	49
Quinolones	153	60	93
Others	63	35	28
Definitive therapy
Carbapenems	339	150	189
Tigecycline	327	143	184
Polymyxin B	40	27	13
Ceftazidime avibactam	23	14	9
Other cephalosporins	124	36	88
Fosfomycin	60	43	17

Table 3.

Combination Antibiotic Regimens According to the 30-Day Outcome

Antibiotic regimen		30-Day outcome		Survival rate
Antibiotic regimen	All	Death	Survival	Survival rate
A: Ceftazidime avibactam and tigecycline	24	7	17	70.8%
B: Carbapenems, tigecycline, and polymyxin B	28	9	19	67.9%
C: Carbapenems and polymyxin B	33	19	14	42.4%
D: Carbapenems and tigecycline	198	87	111	56.1%
E: Carbapenems, tigecycline, and fosfomycin	44	18	26	59.1%

The chi-square test showed that both regimen A (ceftazidime avibactam and tigecycline, χ² = 4.52, p = 0.033) and regimen B (carbapenems, tigecycline, and polymyxin B, χ² = 3.96, p = 0.04) were associated with significantly better survival than regimen C (carbapenems and polymyxin B alone) (Fig. 1). However, there was no statistically significant difference in survival among patients treated with antibiotic regimens D (carbapenems and tigecycline), C (carbapenems and polymyxin B), and E (carbapenems, tigecycline, and fosfomycin). Polymyxin B and tigecycline appeared to have a synergistic effect and were more effective than a regimen of carbapenems plus polymyxin B alone. Ceftazidime avibactam-based antimicrobial regimens had no advantage over other antibiotic regimens.

FIG. 1.

(A) Ceftazidime avibactam and tigecycline. (B) Carbapenems and tigecycline and polymyxin B. (C) Carbapenems and polymyxin B.

In addition, we investigated the effectiveness of tigecycline in combination with other antibiotic regimens for the treatment of CR-KP. The different antibiotic regimens used are listed in Table 4.

Table 4.

Outcomes in Patients Who Received Tigecycline in Combination with Other Antibiotic Regimens

Other antibiotic regimens	Total	30-Day outcome		Survival rate
Other antibiotic regimens	Total	Death	Survival	Survival rate
Imipenem	97	45	52	53.6%
Meropenem	39	12	27	69.2%
Biapenem	62	30	32	51.6%
Ceftazidime avibactam	24	7	17	70.8%
Third- or Fourth-generation cephalosporins	39	16	21	56.8%

Chi-square test showed that there were no statistically significant differences among the different antibiotic regimens (χ² = 5.432, p = 0.246). Considering the price of antibiotic regimens, we recommend the use of biapenem combined with tigecycline as a therapeutic regimen.

Prognostic factors

In the multivariate logistic regression analysis, hemopathy, age (>60 years), solid tumors, diabetes, septic shock, acute kidney injury, and stroke were independent predictors associated with the 30-day mortality rate (Table 5).

Table 5.

Multivariable Logistic Regression Analysis of Risk Factors for Mortality

Variable	OR (95% CI)	p
Hemopathy	9.19 (2.56–33.05)	0.001
Age >60 years	2.70 (1.58–4.59)	<0.001
Solid tumors	2.31 (1.17–4.55)	0.016
Diabetes	1.97 (1.15–3.36)	0.013
Septic shock	6.02 (3.03–11.99)	<0.001
Acute kidney injury	3.38 (1.78–6.41)	<0.001
Stroke	0.56 (0.33–0.97)	0.037

CI, confidence interval; OR, odds ratio.

Correlation analysis and ROC curves

Multivariate linear regression was performed to assess the correlation between APACHE II and SOFA scores, lymphocyte absolute value, and survival time. Survival time was negatively correlated with APACHE II and SOFA scores, and positively correlated with lymphocyte absolute value (Fig. 2). The areas under the ROC curves for the APACHE II score, SOFA score, and lymphocyte absolute value were 0.825, 0.876, and 0.797, respectively, with cutoff values of 17, 6, and 0.775, respectively.

FIG. 2.

Linear regression analyses of the survival time in relation to the absolute lymphocyte count, SOFA and APACHE II scores. (A) Survival in relation to the absolute lymphocyte count. (B) Survival time in relation to the SOFA (green circles) and APACHE II (orange triangles) scores. APACHE II, Acute Physiology and Chronic Health Evaluation; SOFA, Sequential Organ Failure Assessment.

Survival analysis

Survival analysis showed that patients with bloodstream infections had significantly worse survival than patients with pulmonary or drainage fluid infections (Fig. 3).

FIG. 3.

Kaplan–Meier survival curves of survival in relation to the site of infection. BALF, bronchoalveolar lavage fluid.

Discussion

In this study we evaluated 30-day mortality rate in patients with CR-KP infection. The total mortality rate of patients with CR-KP infection was 37.3% and was higher in patients with bloodstream infection (66.2%) as in previous studies.^2,3,16 Mortality was associated with patient characteristics, antibiotic therapeutic regimens, and the immune status of the patients.

The relatively high mortality rate compared with previous studies might be attributable to several factors. First, our hospital is a tertiary referral hospital, and many patients had severe disease on admission to our hospital. The state of the patients was directly related to mortality, as shown in previous studies.^4,5 Second, administering appropriate empirical antibiotic therapy and definitive therapy are important predictors of patients' outcome.^6,17 Therefore, it is very important to administer appropriate antibiotic regimen before patients are admitted to the intensive care unit.

Clinical departments, especially surgery departments, should pay more attention to the rational use of antibiotic regimens. Finally, it is important to detect pathogens and adjust the therapeutic regimen to treat CR-KP infection.¹⁸ However, the positive rate of bacterial culture was low. The positive rate of rectal swabs for the carbapenem-resistant enteric bacteria was only 30.2% in our study. In recent years, next-generation sequencing has emerged as a tool to help diagnose infections with organisms that are difficult to culture. Its role in diagnosing CR-KP infections warrants further study.¹⁹

Independent risk factors associated with mortality included hemopathy, age >60 years, solid tumors, diabetes, septic shock, acute kidney injury, and stroke. Correlation analysis showed that survival time was positively correlated with LYM. Lymphocytes are involved in innate and adaptive immunity, and a low is directly associated with poorer prognosis.^20–22

We investigated the effectiveness of tigecycline in combination with different antibiotic regimens (meropenem, imipenem, biapenem, ceftazidime avibactam, and third- or fourth-generation ephalosporins) in the treatment of CR-KP, and the differences were not statistically significant. Considering the price of antibiotic regimens, we recommend the use of biapenem combined with tigecycline as a therapeutic regimen. The combination of tigecycline with meropenem or ceftazidime avibactam was associated with a higher survival rate. As there were many neurosurgical patients, meropenem was used frequently.

Antibiotic regimens A (ceftazidime avibactam and tigecycline) and B (carbapenems, tigecycline, and polymyxin B) were superior to antibiotic regimen C (carbapenems and polymyxin B). This may be because polymyxin B is a narrow-spectrum antibiotic and some patients have multiple drug-resistant bacterial infections. In addition, polymyxin B and tigecycline may have synergistic effect in treating CR-KP infection. Finally, ceftazidime avibactam-based antimicrobial regimens had no advantage over other therapeutic regimens; however, the sample size was small, and the effectiveness of ceftazidime avibactam-based antimicrobial regimens warrants further study.

Our study has some limitations. The sample size was too small to allow detection of subtle differences in the treatment outcome. As our data were obtained from a single center, a multicenter prospective cohort study with a more extensive collection of data on potential confounders is required.

Conclusion

Our study confirmed a high mortality rate in patients hospitalized with CR-KP infections, especially for bloodstream infections. The outcome was strongly associated with patients' clinical conditions. A combination of carbapenems, tigecycline, and polymyxin B might be a good choice for treating patients with CR-KP infections. Ceftazidime avibactam-based antimicrobial regimens had no advantage over other therapeutic regimens. Further research is required to confirm this finding, especially in light of the introduction of new antimicrobial agents.

Footnotes

Authors' Contributions

Z.C. contributed to methodology, software, collecting data, and writing the original draft. L.W. was involved in investigation, methodology, data curation, and validation. M.F. took care of review and editing.

Availability of Data and Materials

Data will be made available upon reasonable request.

Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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