Clinical Characteristics of Carbapenem-Resistant Klebsiella Pneumoniaee Infections In A Tertiary Hospital In China

doi:10.21203/rs.3.rs-636758/v1

Background：The infections due to carbapenem-resistant Klebsiella pneumoniae (CR-KP) have become an important problem. The aim of the study is to evaluate the clinical characteristics of CR-KP.

Methods: A retrospective cohort study has been made on all patients presenting with CR-KP infections. 615 patients with CR-KP humor infections diagnosed were identified. 135 patients who did not meet the requirements were excluded. Clinical characteristics, antimicrobial regimens, and outcomes of patients have been analyzed.

Results: The CR-KP infections overall mortality was 37.3%, and bloodstream infections mortality was 66.2%. Survival analysis revealed that there were statistically significant differences between bloodstream infection and pulmonary and drainage fluid infection. Logistics regression analysis showed that hemopathy, age (>60 years), solid tumors, diabetes, septic shock, acute kidney injury and stroke were independent predictors associated with the 30-day mortality. Multivariate linear regression was performed in APACHE II score, SOFA score, lymphocyte absolute value (LYM) and survival time. Survival time was negatively correlated with APACHE II score and SOFA score, while positively correlated with LYM. Finally, we investigated different antimicrobial regimens for CR-KP infections. Chi-square test showed that antimicrobial regimen combined carbapenems, tigecycline with polymyxin B was superior the one combined carbapenems with polymyxin B. Ceftazidime avibactam-based antimicrobial regimens also had no advantage over other therapeutic regimens.

Conclusions: Our study confirmed there is a high mortality rate in CR-KP infections, especially in the bloodstream infections. The outcome is greatly influenced by the patients’ clinical conditions. Antimicrobial regimen combined carbapenems, tigecycline with polymyxin B might be a better choice.

Infectious Diseases

Carbapenem-resistant Klebsiella pneumoniae

Bloodstream infection

Antimicrobial regimen

Clinical characteristics

The carbapenem-resistant Klebsiella pneumoniae (CR-KP) infection is a current health threat worldwide [1–3]. Infections caused by CR-KP isolated are associated with a high mortality rate, ranging from 18–48%, up to 51%-72% in bloodstream infections, depending on the type of therapy administered and different characteristics [4–7].

The first CR-KP was identified in 1993, and since then the CR-KP strains are endemic in many countries [8]. The Annual Report of the European Antibiotic Surveillance Network was published in 2016, reporting a mean percentage of carbapenems resistance equal to 6.1%. In 2018 in China, Klebsiella pneumoniae had a resistance rate of 15.4% to imipenem and 17.9% to meropenem [9].

Although several studies have demonstrated the efficacy of combination regimens in terms of decreased mortality, an effective treatment is still a challenge for clinicians [10–13].

The aim of our study was to evaluate the clinical characteristics of CR-KP infections in a tertiary hospital in China.

All patients with CR-KP infection at the First Affiliated Hospital of Zhengzhou University between January 2018 and December 2019 had been identified from the 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 information and directly contacting the patients.

All patients included in this study have to meet the following criteria: (1) Age between 18 and 80 years; (2) Diagnosis of CR-KP infection was documented by either one or more positive culture; (3) All sputum specimens were bronchial alveolar lavage fluid. Besides, patients who died or discharged within 48h after adjusted therapy regimens and patients with incomplete or missing data were excluded.

Patient characteristics

Patient variables include age, gender, presence of acute or chronic comorbidities, APACHE II score, SOFA score, lymphocyte absolute value (LYM, within 2 days of culture collection), previous surgery (≤ 30 days before culture positive), any invasive procedures (≤ 72h before culture positive), steroid therapy or immunosuppressive taken over previous 30days, previous antimicrobial therapy regimens (≤ 30 days), survival days and adjusted therapy regimens after culture positive. Rectal swabs from some patients were collected and screened for the presence of carbapenem-resistant enteric bacteria.

The outcome measured was death within 30 days since the first positive culture. Survivor and non-survivor subgroups have been compared to identify predictors of mortality.

Antimicrobial therapies

The attending physician determined the appropriate initial antimicrobial therapy. Antimicrobial therapy was administered within 5days after infection onset 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 (CLSI) criteria.

Definitions

Septic shock is defined as sepsis plus persistent hypotension, requiring vasopressor to maintain mean arterial pressure ≥ 65 mmHg, and serum lactate levels > 2 mmol/L despite adequate fluid resuscitation.

Acute kidney injury is defined as follows: (1) Increase in serum creatinine by ≥ 0.3mg/dl within 48 hours; (2) Increase in serum creatinine by ≥ 1.5 times baseline; (3) Urine volume < 0.5 ml/kg/hour for six hours [16].

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

Statistical analysis

Statistical analysis was performed by using SPSS 22.0 (IBM, Armonk, USA). Categorical variables were recorded as absolute numbers and their relative frequencies, and they were compared by the χ² or Fisher exact test. Categorical variables were analyzed by multivariate logistic regression analysis to identify independent risk factors for mortality. Kaplan-Meier curves were drawn to compare 30-day survival rate in patients with blood stream infection, patients with bronchial alveolar lavage fluid infection and patients with drainage infection. Continuous variables were evaluated by the multiple linear regression analysis. ROC curves were also drawn for APACHE II score, SOFA score and LYM. P value < 0.05 was considered statistically significant.

Baseline characteristics

We collected 615 patients’ clinical data with CR-KP humor infections diagnosed between January 2018 and December 2019. 135 patients who did not meet the requirements were excluded, and the remaining 480 patients were enrolled in the study. Baseline characteristics of study cohort are reported in Table 1(At the end of the artical).

Table 1 Demographic and clinical characteristics of the study cohort

Variables	30-days outcome
Variables	Total, 480		Death, 179	Survival, 301	χ²	p-value
Gender
▪ Female	191		70	121	0.06	0.813
▪ Male	289		109	180
Age
▪ ≤60	209		53	166	29.51	<0.001
▪ >60	271		126	135
Wards
▪ 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
Specimens
▪ BALF		379	120	259	24.41	<0.001
▪ Blood and catheter tips		68	45	23	28.27	<0.001
▪ Drainage liquid		21	7	14
▪ Urine		9	1	8
▪ Cerebrospinal fluid		3	3	0
Comorbidities
▪ 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
Acute comorbidities
▪ Septic shock		108	83	25	91.09	<0.001
▪ Acute kidney injure		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
Pre-infection 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	0.2
▪ Immunosuppressive		23	14	9	5.74	0.017
▪ Chemoradiotherapy		19	13	6	8.20	0.004

The total 30-day mortality of patients with CR-KP was 37.3%. Of all patients, the majority were male (289, 60.2%) and the female were 191 (39.8%). 379 patients (78.9%) were pulmonary infection and 68 patients (14.2%) were 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 in acute complications, followed by AKI (117, 24.4%) and septic shock (108, 22.5%), and septic shock was significantly more frequent among patients in the death group than those in the survival group (46.3% vs. 8.3%, p < 0.001). Most of patients (430, 89.6%) were intubation or tracheotomy and 387 patients (80.6%) carried a central venous catheter. A proportion of patients got steroid therapy (93, 19.4%) and continuous renal replacement therapy (CRRT, 58, 12.1%). Finally, 116 patients’ rectal swabs were collected and screened for the presence of carbapenem-resistant enteric bacteria, but only 35 patients were detected positive (30.2%).

Table 2 Therapies in the death and survive groups

Variables	30-days outcome
Variables	Total	Death	Survive
Previous antibiotic therapy
▪Penicillins &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

Therapies

The empirical and definitive therapies for patients with CR-KP in the survivor and death group are summarized in Table 2. The most frequently used antibiotics for both empirical and definitive therapy were carbapenems in two groups. Then, we did a statistical analysis for the different antibiotic therapeutic regimens and the results were listed in Table 3.

Table 3

Different antibiotic therapeutic regimens
Antibiotic therapeutic regimens	30-days outcome
Antibiotic therapeutic regimens	Total	Death	Survive	survival rate
A: Ceftazidime avibactam & Tigecycline	24	7	17	70.8%
B: Carbapenems & Tigecycline & Polymyxin B	28	9	19	67.9%
C: Carbapenems & Polymyxin B	33	19	14	42.4%
D: Carbapenems & Tigecycline	198	87	111	56.1%
E: Carbapenems & Tigecycline & Fosfomycin	44	18	26	59.1%

Chi-square test showed that both antibiotic regimen B (carbapenems plus tigecycline and polymyxin B, χ² = 3.96, p = 0.04) and antibiotic regimen A (ceftazidime avibactam plus tigecycline, χ² = 4.52, p = 0.033) were superior to antibiotic regimen C (carbapenems combined with polymyxin B) and the differences were of statistical significance. However, there was no statistically significant difference among antibiotic regimen D (carbapenems plus tigecycline), antibiotic regimen C (carbapenems plus polymyxin B) and regimen E (carbapenems plus tigecycline plus fosfomycin). It seemed that polymyxin B and tigecycline have synergistic effect and carbapenems plus polymyxin B was not a recommended therapeutic regimen (Fig. 1). Ceftazidime avibactam-based antimicrobial regimens also had no advantage over other therapeutic regimens.

In addition, we investigated the efficacy of tigecycline combination with other different antibiotics in the treatment of CR-KP. The different antibiotic therapeutic regimens were listed in Table 4.

Table 4

Tigecycline combination with other different antibiotics
Tigecycline and other antibiotics	30-days outcome
Tigecycline and other antibiotics	Total	Death	Survive	Survive rate	χ²	p-value
Imipenem	97	45	52	53.6%	5.432	0.246
Meropenem	39	12	27	69.2%
Biapenem	62	30	32	51.6%
Ceftazidime avibactam	24	7	17	70.8%
3rd or 4th ephalosporins	39	16	21	56.8%

Chi-square test showed that there was no statistically significant difference among different antibiotic regimens. Considering the price of antibiotics, we recommend 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 (Table 5).

Table 5

Multivariate analysis of risk factors for mortality
Variables	B	OR (95% CI)	p-value
Hemopathy	2.218	9.191 (2.555–33.053)	0.001
Age(> 60 years)	0.992	2.696 (1.584–4.590)	< .001
Solid tumors	0.835	2.305 (1.169–4.546)	0.016
Diabetes	0.677	1.968 (1.152–3.361)	0.013
Septic shock	1.796	6.024 (3.027–11.989)	< 0.001
AKI	1.218	3.381 (1.784–6.406)	< 0.001
Stroke	-0.573	0.564 (0.329–0.966)	.037

Correlation analysis and ROC curves

Multivariate linear regression was performed in APACHE II score, SOFA score, lymphocyte absolute value (LYM) and survival time. Survival time was negatively correlated with APACHE II score and SOFA score, and positively correlated with LYM (Figs. 2 and 3). In addition, ROC curves were also drawn for APACHE II score, SOFA score and LYM, with AUC of 0.825, 0.876 and 0.797, and with cut-off value of 17, 6 and 0.775 respectively.

Survival analysis

Survival analysis showed that pulmonary and drainage fluid infections were statistically significance differences from bloodstream infection with CR-KP (Fig.4).

In this study we evaluated 30-day mortality in patients with CR-KP infection. The total mortality of patients with CR-KP infection was 37.3%, while with bloodstream infection mortality was 66.2% [2, 3, 5]. It was patients’ characteristics, antibiotic therapeutic regimens as well as immune status of the patients made mortality so high.

The relatively higher mortality compared with previous studies might be attributable to several factors. First, our hospital is a tertiary referral hospital, and many patients had been very serious when they were admitted to our hospital. The states of the patients were directly related to mortality and had repeatedly reported in previous studies [4, 5]. Second, a previous study has reported that administering the appropriated empirical antibiotic therapy and definitive therapy was an important predictor of patients’ outcome [6, 17, 18]. Therefore, it is very important to take the antibiotics reasonably before patients transferred to ICU. Clinical departments, especially surgery, should pay more attention to the rational use of antibiotics. Finally, it is important to detect pathogen and adjust the therapeutic regimen to treat CR-KP infection [19]. But 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, which had emerged to help to diagnose CR-KP infection, demand a further study [20].

Independent risk factors associated with mortality were 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 were involved in the patient's innate immunity and adaptive immunity, and low immune status was directly related to patient prognosis [21–23].

We investigated the efficacy of tigecycline combination with different antibiotics (meropenem, imipenem, biapenem, ceftazidime avibactam, and 3rd or 4th ephalosporins) in the treatment of CR-KP, and the differences had not statistically significant. Considering the price of antibiotics, we recommend biapenem combined with tigecycline as a therapeutic regimen. Tigecycline combination with meropenem or ceftazidime avibactam had a higher survival rate. Because there were more neurosurgical patients, meropenem was used more frequently.

Chi-square test showed that both antibiotic regimen 1 (carbapenems plus tigecycline and polymyxin B) and antibiotic regimen 2 (ceftazidime avibactam plus tigecycline) were superior to antibiotic regimen 3 (carbapenems combined with polymyxin B). The reasons may be that polymyxin B was a narrow-spectrum antibiotic, and some patients often had multiple drug-resistant bacterial infections. Beside, polymyxin B and tigecycline may have synergistic effect in treating CR-KP infection. Finally, ceftazidime avibactam-based antimicrobial regimens also had no advantage over other therapeutic regimens, but the sample size is too small and it needs further study.

There are some limits in our study. The size of some samples is too small to allow us to detect subtle differences in treatment outcome. Since our data come from a single center, a multi-centers prospective study with more extensive collection of potential confounders is required.

Our study confirmed a high mortality rate of CR-KP, especially in the bloodstream infections. The outcome is heavily influenced by the patients’ clinical conditions. Carbapenems, tigecycline and polymyxin B combined antimicrobial regimen might be a better choice. Ceftazidime avibactam-based antimicrobial regimens had no advantage over other therapeutic regimens. Additional data needs to further elucidate this finding especially in light of the introduction of the new agents.

CR-KP: carbapenem-resistant Klebsiella pneumoniae

LYM: lymphocyte absolute value

Ethics approval and consent to participate: The study was performed in accordance with the Declaration of Helsinki. It was approved by the Human Ethics Committee of the First Affiliated Hospital of Zhengzhou University, and the reference number was med-2018-113. Written informed consents were obtained from all patients.

Consent for publication: All authors consent for publication.

Availability of data and materials: The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. (The datasets was saved in https://figshare.com/s/152a28cea445230e10b9)

Competing interests: The authors declare that they have no competing interests.

Funding: Not applicable.

Authors' contributions: ZW C collected data and wrote the initial draft of the manuscript. LR W searched the literatures. W C also collected data and expanded the discussion. MH L was responsible for design and revision of the manuscript. YX L and M F revised the manuscript critically for intellectual content. All authors read and approved the final manuscript.

Acknowledgements: Not applicable.

Authors' information: Intensive Care Unit, the First Affiliated Hospital of Zhengzhou University, Henan, China

Nordmann P, Naas T, Poirel L. Global spread of Carbapenemase-producing Enterobacteriaceae. Emerg Infect Dis. 2011; 17(10):1791–8.
Tumbarello M, Trecarichi EM, De Rosa FG, et al. Infections caused by KPC-producing Klebsiella pneumoniaee: differences in therapy and mortality in a multicentre study. J Antimicrob Chemother. 2015; 70(7):2133–43.
Munoz-Price LS, Poirel L, Bonomo RA, et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniaee carbapenemases. Lancet Infect Dis. 2013; 13(9):785–96.
Tumbarello M, Viale P, Viscoli C, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniaee carbapenemase-producing K. pneumoniaee: importance of combination therapy. Clin Infect Dis. 2012; 55(7):943–50.
Daikos GL, Tsaousi S, Tzouvelekis LS, et al. Carbapenemase-producing Klebsiella pneumoniaee bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother. 2014; 58(4):2322–8.
Qureshi ZA, Paterson DL, Potoski BA, et al. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniaee: superiority of combination antimicrobial regimens. Antimicrob Agents Chemother. 2012; 56 (4):2108–13.
Fraenkel-Wandel Y, Raveh-Brawer D, Wiener-Well Y, Yinnon AM, Assous MV. Mortality due to blaKPC Klebsiella pneumoniaee bacteraemia. J Antimicrob Chemother. 2016; 71(4):1083–7.
Falcone M, Russo A, Iacovelli A, et al. Predictors of outcome in ICU patients with septic shock caused by Klebsiella pneumoniaee carbapenemase-producing K. pneumoniaee. Clin Microbiol Infect. 2016; 22(5):444–50.
Hu F, Guo Y, Yang Y, et al. Resistance reported from China antimicrobial surveillance network (CHINET) in 2018. Eur J Clin Microbiol Infect Dis. 2019; 38(12):2275–81.
Giacobbe DR, Del Bono V, Trecarichi EM, et al. Risk factors for bloodstream infections due to colistin-resistant KPC-producing Klebsiella pneumoniaee: results from a multicenter case-control-control study. Clin Microbiol Infect. 2015; 21(12):1106.e1-8.
Vardakas KZ, Matthaiou DK, Falagas ME, Antypa E, Koteli A, Antoniadou E. Characteristics, risk factors and outcomes of carbapenem-resistant Klebsiella pneumoniaee infections in the intensive care unit. J Infect. 2015; 70(6):592–9.
Wu HS, Wang FD, Tseng CP, Wu TH, Lin YT, Fung CP. Characteristics of healthcare-associated and community-acquired Klebsiella pneumoniaee bacteremia in Taiwan. J Infect. 2012; 64(2):162–8.
Machuca I, Gutiérrez-Gutiérrez B, Pérez Cortés S, et al. Oral decontamination with aminoglycosides is associated with lower risk of mortality and infections in high-risk patients colonized with colistin-resistant, KPC-producing Klebsiella pneumoniaee. J Antimicrob Chemother. 2016; 71(11):3242–9.
Seymour CW, Liu VX, Iwashyna TJ, et al. Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315(8):762–74.
Ronco C, Bellomo R, Kellum JA. Acute kidney injury. Lancet. 2019; 394(10212):1949–64.
Brescini L, Morroni G, Valeriani C, et al. Clinical and epidemiological characteristics of KPC-producing Klebsiella pneumoniaee from bloodstream infections in a tertiary referral center in Italy. BMC Infect Dis. 2019; 19(1):611.
Qureshi ZA, Paterson DL, Potoski BA, et al. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniaee: superiority of combination antimicrobial regimens. Antimicrob Agents Chemother. 2012; 56(4):2108–13.
Schechner V, Kotlovsky T, Kazma M, et al. Asymptomatic rectal carriage of blaKPC producing carbapenem-resistant Enterobacteriaceae: who is prone to become clinically infected? Clin Microbiol Infect. 2013; 19(5):451–6.
Mendes RE, Jones RN, Woosley LN, Cattoir V, Castanheira M. Application of Next-Generation Sequencing for Characterization of Surveillance and Clinical Trial Isolates: Analysis of the Distribution of β-lactamase Resistance Genes and Lineage Background in the United States. Open Forum Infect Dis. 2019; 6(Suppl 1):S69-78.
Xiong H, Keith JW, Samilo DW, Carter RA, Leiner IM, Pamer EG. Innate Lymphocyte/Ly6C(hi) Monocyte Crosstalk Promotes Klebsiella Pneumoniaee Clearance. Cell. 2016; 165(3):679–89.
Bengoechea JA, Sa Pessoa J. Klebsiella pneumoniaee infection biology: living to counteract host defences. FEMS Microbiol Rev. 2019; 43(2):123–44.
Kumar P, Chen K, Kolls JK. Th17 cell based vaccines in mucosal immunity. Curr Opin Immunol. 2013; 25(3):373–80.
Guo K, Gong W, Zheng T, et al. Clinical parameters and outcomes of necrotizing soft tissue infections secondary to gastrointestinal fistulas. BMC Infect Dis. 2019; 19(1):597.

No competing interests reported.

Clinical Characteristics of Carbapenem-Resistant Klebsiella Pneumoniaee Infections In A Tertiary Hospital In China

Status:

Version 1

Abstract

Figures

Background

Methods

Patient characteristics

Antimicrobial therapies

Definitions

Statistical analysis

Results

Baseline characteristics

Therapies

Prognostic factors

Correlation analysis and ROC curves

Survival analysis

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1