Clinical Management of a Pandrug-Resistant OXA-48 Klebsiella pneumoniae Infection in the Pediatric Intensive Care Unit

Abstract

Background:

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is one of the serious forms of health care-associated infection. Pan-drug resistant (PDR) CRKP infections can cause severe infections. Mortality and treatment costs in the pediatric intensive care unit (PICU) are high. This study aims to share our experience regarding the treatment of oxacillinase (OXA)-48-positive PDR-CRKP infection in our 20-bed tertiary PICU with isolated rooms and 1 nurse for every 2–3 patients.

Methods:

Patient demographic characteristics, underlying diseases, previous infections, source of infection PDR-CRKP, treatment modalities, measures used, and outcomes were recorded.

Findings:

Eleven patients (eight men and three women) were found to have PDR OXA-48-positive CRKP. Because of the simultaneous detection of PDR-CRKP in three patients and the rapid spread of the disease, it was classified as a clinical outbreak, and strict infection control measures were taken. Combination therapy with double carbapenemase (meropenem and imipenem), amikacin, colistin, and tigecycline was used for treatment. The mean duration of treatment and isolation was 15.7 and 65.4 days, respectively. No treatment-related complication was observed, only one patient died, and the mortality rate was 9%.

Conclusions:

This severe clinical outbreak can be successfully treated with effective treatment with combined antibiotics and strict adherence to infection control measures. ClinicalTrial.gov ID: 28/01/2022 - 1/5

Introduction

Broad-spectrum antibiotics are commonly used for life-threatening sepsis, especially in intensive care units and health care facilities. Following the widespread use of these drugs, the incidence of resistant Gram-negative bacterial infections, such as extensive beta-lactamase-positive germs, carbapenem resistance, multidrug resistance, and pan-drug resistance (PDR), has increased in health care centers.^1–3 Over the past two decades, this condition has become a major health concern for all health care providers worldwide.

The frequent use of carbapenems increases the use of beta-lactamases. In the 1980s, the Ambler classification divided beta-lactamases into four major groups. In Enterobacteriaceae species, beta-lactamases are divided into three distinct groups: class A, B, and D. Class A includes the most common type called Klebsiella pneumoniae carbapenemase (KPC), class B is metallo-beta-lactamases, the most commonly detected being New Delhi Metallo-beta-lactamase, and class D are oxacillinases (OXA) such as OXA-48, which was first detected in Turkey in 2001.⁴

In pediatric intensive care units (PICUs), the increasing use of invasive devices, prolonged length of stay, inadequate or delayed therapy, comorbid conditions, and severity of illness are associated with an increase in infections caused by antimicrobial-resistant pathogens.⁵ In the past decade, carbapenem-resistant Enterobacteriaceae (CRE) have become a common problem in hospital-acquired infections and can cause outbreaks in intensive care units.^5,6 These strains are usually resistant to other classes of antibiotics and commonly become PDR in the ICU. There are insufficient data in the literature on the treatment of infections caused by PDR Enterobacteriaceae in children. In this study, we report a sudden increase in OXA-48-positive carbapenem-resistant K. pneumoniae (CRKP) infections in our PICU and believe we can contribute to the literature by detailing the treatment methods we use and the measures we take.

Materials and Methods

Study setting, patient population, and design

Our PICU is a 20-bed tertiary care unit in a 260-bed academic Children's Hospital. It is divided into 2 sections with 10 beds each, and there are 4 isolated rooms. A nurse is usually responsible for two, rarely three patients, and for hemodynamically unstable patients receiving complex therapy such as ECMO, the nurse-patient ratio is adjusted to 1:1. Each physician is responsible for 2 patients, and the intensive care specialists and their instructors follow each patient regularly.

On average, 60 patients 28 days to 18 years of age are seen monthly. The outbreak of OXA-48-positive PDR-CRKP was retrospectively evaluated over 8 months. The following variables were collected for the study: sex, age, underlying diseases, presence of comorbidities, indication for admission to the PICU, length of stay, antibiotic use, invasive and surgical procedures, source of infection, measures taken (Table 1), and outcomes (colonization, bed occupancy, antibiotic use, mortality, etc.). Diagnosis of infection and isolation of PDR-CRKP was based on the Centers for Disease Control and Prevention criteria.⁵

Table 1.

Preventive and Control Bundles

1. All infected patients must be isolated.

2. PICU must be divided into two departments as the infected and noninfected areas with a strict, unopenable barrier.

3. Infected and uninfected areas must have separated medical teams (doctors, nurses, and cleaning staff), and all the team members should not contact other health care providers and equipment.

4. All the working team members have to pay attention to hand hygiene, the hands should be washed carefully with water or hand disinfectant when entering the PICU, before touching each patient, and when exiting from PICU.

5. The medical team must wear gloves before touching patients.

6. Specific isolation clothes must be worn before entering the infected area and these clothes must be disrobed before exit.

7. Personnel cannot wear a white gown or jacket before entering the infected area.

8. Medical team clothes must be washed at the end of each day.

9. No patient can be hospitalized in the PICU from outside until the outbreak is completely be eradicated.

10. All the patients must be washed twice a day with chlorhexidine under the supervision of the responsible nurse.

11. Maximum sterilization rules will be followed before any invasive procedure can be performed in the intensive care.

12. Swab and environment cultures were taken from all patients weekly and patients with positive culture results were isolated to the infected area.

13. Infected patients must be isolated in a separate unit in the hospital after discharge from the PICU and the infected patients should not apply to other hospitals after their discharge from the hospital, and they will have to be received in a separate area in the hospital.

PICU, pediatric intensive care unit.

A clinical case was defined as patients with symptoms of infection such as fever, tachycardia, respiratory distress, or sepsis during follow-up in the PICU and microbiologically confirmed to be OXA-48-positive pan-drug resistance carbapenem-resistant Klebsiella pneumonia infection (PDR-CRKP) in any culture obtained (tracheal aspirate, blood, urine, wound, and stool). The outbreak was defined as a sudden increase in the number of OXA-48-positive-PDR-CRKP infection cases in the PICU population. The study used treatment protocols officially established by the Infection Control Committee. The local ethics committee approved the study. Written informed consent was obtained from the patient's parents.

Microbiological evaluation

Samples were collected from all patients included in the study at multiple sites. Blood, urine, wound, skin, and stool cultures were collected in the microbiology laboratory of the university hospital and for detailed identification in the main microbiology laboratory in the academic campus. Blood cultures were filled into pediatric bottles and incubated for 5 days in the Bactec FX automated blood culture system (Becton Dickinson, USA). Tracheal aspirates from the patients were quantitatively inoculated onto 5% sheep blood agar (Oxoid, England), eosin methylene blue agar (Oxoid), and Sabouraud dextrose agar (Becton Dickinson, USA), and chocolate agar (Oxoid) plates. Urine and wound swab samples were inoculated onto sheep blood agar and eosin methylene blue agar bi plates.

Identification and antimicrobial susceptibility testing were performed using conventional and automated systems (Phoenix 100™ System; Becton Dickinson, USA DCC). Antimicrobial susceptibility testing of K. pneumoniae isolates was also performed and interpreted according to EUCAST criteria.⁵ The Kirby-Bauer disk diffusion method was performed using Bioanalysis AST disks (Bioanalysis, Turkey), and the minimum inhibitory concentrations (MICs) of carbapenems were determined using gradient strips (bioMérieux, France), and colistin susceptibility was determined using the broth microdilution method.^7,8

All strains were subjected to phenotypic and genotypic screening for carbapenemase production. Phenotypic identification of carbapenemase production was performed using the combination disk method (Mastdiscscombi; Mastdiagnostics, United Kingdom). DNA was extracted using the DNeasy Blood and Tissue Kit (Qiagen, USA) according to the manufacturer's instructions. The presence of 11 carbapenemase genes (bla_IMP, bla_VIM, bla_SPM, bla_KPC, bland_M, bla_OXA-48, bla_GIM, bla_SIM, bla_AIM, bla_DIM_, and bla_BIC) was determined by performing three consecutive multiplex PCR reactions according to the protocol of Poirel et al.⁹

Preventive bundle protocol

When the infection was detected, all patients were isolated, and the PICU was divided into two zones, infected and uninfected areas. A separate medical team worked in the infected area. All the measures mentioned in Table 1 were strictly enforced by the team. It was recommended by the infection control committee not to admit patients from outside until the outbreak was completely eradicated. However, still, a limited number of patients were admitted to the uninfected area during the isolation period.

Antibiotic treatment protocol

We administered combined antibiotic therapy to all patients who were found to be infected. In patients with severe comorbidities such as septic shock, immunodeficiency, and multiple organ dysfunction, double carbapenem combination (DCC) infusion therapy (meropenem and imipenem) was administered. In the treatment of DCC, meropenem was administered 120 mg/[kg·day] three times daily and imipenem was administered 100 mg/[kg·day] four times daily. Each meropenem dose was infused for 4 hours, and imipenem for 3 hours, consecutively. Thus, patients were treated with carbapenem for 24 hours.

Amikacin and colistin were administered to all infected patients. Tigecycline was administered at a dose of 1 mg/[kg·dose] every 12 hours in patients younger than 11 years and 50 mg/dose every 12 hours in patients older than 12 years. Tigecycline was not used in patients younger than two years of age, except in one patient with immunodeficiency. Colistin and amikacin were administered at 5 and 15 mg/[kg·day], respectively, divided into two doses. The patients were followed closely for acute kidney injury. All doses of antibiotics were adjusted according to creatinine clearance. The estimated glomerular filtration rate (eGFR) was calculated daily using the Schwartz formula, and the daily dose of each nephrotoxic antibiotic was updated according to the eGFR grade.¹⁰

Results

During the study period, 11 patients were found to have PDR-CRKP. Seven of these patients had severe infections, while the other four patients were asymptomatic. Initially, seven patients (six male and one female) were consecutively found to have PDR-CRKP. Their average age was 6 years. The average time between the patient's admission to the PICU and the onset of infection was 45 days. Two patients had ventilator-associated pneumonia (VAP), two had central line-associated bloodstream infection (CLABSI), two had surgical site infections, and one had catheter-associated urinary tract infection (CAUTI). All cases from PDR-CRKP were only moderately sensitive to tigecycline, and all were OXA-48 positive. At the time of infection onset, 17 patients were in the intensive care unit. Infection occurred almost simultaneously in three patients, and seven patients became infected within 1 week.

After seven patients became infected during the first week, OXA-48-positive PDR-CRKP was detected in the stool cultures of four patients. PDR-CRKP was detected in the urine culture of two of these patients and the tracheal aspirate cultures of the other two. These four patients were determined by the Infectious Disease Committee to have no active infection. They had been previously treated with broad-spectrum antibiotics for various infections and had been in the PICU for an average of 26 days. They were isolated only and received no treatment for the infection. All infected patients were isolated, and the PICU staff strictly followed the rules recommended by the Infection Control Committee. PDR-CRKP was not detected in cultures taken from PICU staff and surfaces during the study.

Extended-spectrum beta-lactamase CRKP was detected in all isolates. All showed intermediate resistance to tigecycline (MIC = 2 mg/L), whereas all were resistant to ampicillin, cefazolin, aztreonam, cefepime, piperacillin-tazobactam, colistin (MIC = 8 mg/L), levofloxacin, fosfomycin, ertapenem (MIC = 32 mg/L), imipenem (MIC = 32 mg/L), and meropenem (MIC = 32 mg/L). The blaOXA-48 gene was detected in all isolates.

Demographic data, clinical conditions, and treatments of the seven patients in whom clinical onset first occurred are shown in Table 2. These patients had refractory fevers and an increase in acute-phase reactants. Four patients had septic shock (patients 1, 2, 3, and 4), and three patients had sepsis (patients 5, 6, and 7).

Table 2.

Patient's Demographic Data, Clinical Features, and Infection Sources

No.	Gender	Age	Primary disease	Presence of comorbidities	Invasive procedures in PICU	Surgery	Infections before PDR-CRKP	Antibiotic treatment before PDR-CRKP	Date of admission PICU-first PDR-CRKP Detected (days)	Infection type with PDR-CRKP
1	F	1 Year	SCID	Atypical HUS chronic renal failure	Intubated, CVC, Peritoneal dialysis catheter	Abdominal laparoscopy	Pseudomonas aeruginosa, Aspergillus fumigatus	Cefepime, Voriconazole	49	VAP
2	M	15 Years	Dilated CMP	Total artificial heart	Intubated CVC	VA-ECMO Total artificial heart operation Tracheostomy, Colostomy	—	Piperacillin-tazobactam	67	Wound culture from decubitus
3	M	15 Years	TBI	Frontal craniotomy	Intubated CVC, Chest tube ICC	Craniotomy, Tracheostomy	Acinetobacter baumannii	Meropenem, Colistin, SAM	54	CLABSI
4	M	8 Years	CLD, Pneumonia	Tracheostomy, Gastrostomy, PHT	Tracheostomy CVC Gastrostomy	Bronchoscopy	—	Piperacillin-tazobactam	12	VAP
5	M	4 Months	MSUD	—	Intubated CVC	—	Klebsiella pneumoniae, Pseudomonas aeruginosa	Meropenem, Colistin	44	CAUTI
6	M	15 Months	TBI	Seizures, SAH, subgaleal hematoma	Intubated CVC ICC	Craniotomy	Acinetobacter baumannii	Meropenem, Colistin	50	Surgical site
7	M	15 Months	Leigh syndrome	Respiratory failure, resistant epilepsy	Intubated CVC	Tracheostomy, Gastrostomy	—	SAM	38	CLABSI

F, female; M, male; CAUTI, catheter-associated urinary tract infection; CLABSI, central line-associated bloodstream infection; CLD, chronic lung disease; CMP, cardiomyopathy; CRKP, carbapenem-resistant Klebsiella pneumoniae; CVC, central venous catheter; HUS, hemolytic uremic syndrome; ICC, intracranial catheter; MSUD, maple syrup urine disease; PDR-CRKP, pan-drug resistant carbapenem-resistant Klebsiella pneumoniae; PICU, pediatric intensive care unit; SAH, subarachnoid hemorrhage; SAM, sulbactam-ampicillin; SCID, severe combined immune deficiency; TBI, traumatic brain injury; VAP, ventilator-associated pneumonia.

We administered combined antibiotic therapy to patients who had severe infections. DCC infusion therapy (meropenem and imipenem) was administered to patients with severe concomitant diseases such as septic shock, immunodeficiency, and multiple organ dysfunction syndrome. In the study, four patients received DCC, and all seven patients received combined antibiotic therapy. No complication related to combined antibiotic therapy occurred during or after treatment. Only in patient 2, sensorineural hearing loss was observed, but the patient's neurological condition was not good before the treatment initiation, we do not know whether this condition was related to the treatment. Only one patient died, and this occurred without documented infection after 21 days of treatment and 87 days of isolation. The mean duration of treatment and isolation was 15.7 and 65.4 days, respectively.

In Figure 1, the detection times of PDR-CRKP infection, treatment times, and isolation times after the onset of the outbreak are shown in each patient individually. The mortality rate of the study was 14.2% when only symptomatic patients were evaluated, whereas the mortality rate was 9% when all cases were included. In addition, only one patient (patient 5) was readmitted to the PICU for urinary tract infection with OXA-48-positive CRKP after discharge. The duration of isolation of the PDR-CRKP outbreak, treatment methods, and survival of seven patients are summarized in Table 3. Isolation lasted 153 days (patient 2). Colonization of the skin and gastrointestinal tract was observed in all infected patients, whereas no colonization was observed in uninfected patients who were in the PICU at the same time.

FIG. 1.

The detection times of PDR-CRKP, treatment times, and isolation times after the onset of the outbreak are shown in each patient individually (PICU). PDR-CRKP, pan-drug resistant carbapenem-resistant Klebsiella pneumonia infection; PICU, pediatric intensive care units.

Table 3.

The Antibiotics Used for Pan-Drug Resistant Carbapenem-Resistant Klebsiella pneumoniae, Isolation Times, and Outcome

Patients	Infection type	Treatment of PDR-CRKP	Duration of treatment (days)	Isolation time in PICU(days)	Result
1	Septic shock	DCC, tigecycline, colistin	21	87	Not survived
2	Septic shock	DCC, tigecycline, colistin	21 Days (Imipenem, amikacin, and colistin) 30 Days (meropenem tigecycline)	153	Survived
3	Septic shock	DCC, tigecycline, colistin	30	52	Survived
4	Septic shock	DCC, colistin	7	58	Survived
5	Sepsis	Meropenem, amikacin, colistin	10	11	Survived
6	Sepsis	Meropenem, amikacin, colistin	10	41	Survived
7	Sepsis	Meropenem, amikacin, colistin	10	56	Survived

DCC, double carbapenem combination.

Discussion

A PDR-CRKP infection is a serious form of nosocomial infection in intensive care units. The mortality rate of CRKP infections is reported to be ∼50% in adults.¹¹ In one meta-analysis, the mortality rate of CRE infections was 26–44%; in another study, the mortality rate of OXA-48-positive CRKP infections was 58.3%.^12,13 There are insufficient data in the literature on the mortality of PDR-CRKP in children, and our mortality rate is significantly lower than in other adult studies.

When drug-resistant infection is detected in intensive care units, it is important to take infection control measures to prevent the spread of infection. Because PDR-CRKP was detected in three patients and spread rapidly in our PICU, we considered it a clinical outbreak and took all prevention and control measures. We formed a separate health care team to treat the infected area. Our PICU environment was physically suitable for this separation process, and it was our advantage that the number of physicians and nurses working in the clinic was sufficient. PDR-CRKP was not determined by the staff or environmental cultures.

In this clinical outbreak of OXA-48-positive infection, CRKP was detected in the initial cases as septic shock. All of these patients had severe underlying diseases, several different invasive procedures, surgeries, and long hospital stays. All the above risk factors are consistent with previous studies.¹⁴ Most patients were treated with a broad spectrum of antibiotics before the onset of the disease. While previous antibiotic use has been reported in the literature to be an independent risk factor for CRKP, some studies have specifically defined carbapenem use as a risk factor for CRKP.^9,13–15 Our patients were treated with meropenem before CRKP, but because of the small number of cases in our study, no association between the use of meropenem and CRKP can be established.

Our goal was to eliminate the infection in the PICU by providing adequate antibiotic support in the initial phase. Therefore, we used a wide range of combined antibiotic therapies because our patients were critically ill, had severe underlying diseases, and stayed longer in the PICU. In patients who had severe infections, we used combined antibiotic therapy. The literature indicates that appropriate treatment is the only variable that independently predicts survival.¹¹ The use of combined antibiotics has been shown to reduce mortality, but there is no clear information on which antibiotic combinations should be used.^11,16–18 Ceftazidime-avibactam is a successful treatment for PDR-CRKP infections.^19,20 Unfortunately, we could not use ceftazidime-avibactam during the study period because there was no drug available in our country and foreign approval was required.

OXA-48 CRKP exhibits varying degrees of carbapenem resistance, possibly due to differences in gene expression.²¹ Carbapenems do not reduce mortality and may even be harmful because of their side effects, and they can be used when the in vitro MIC is in the range of 4–8 mg/dL.^22,23 Combination treatments of carbapenems are associated with lower mortality when MIC levels are high.²⁴ DCC has been used as a combination of meropenem and ertapenem for CRKP infections, and successful results have been obtained.^25,26 Although the rationale for this combination has not been studied in detail, it is believed that one of the carbapenem compounds deflects the carbapenemase enzyme, which acts as a self-moderating inhibitor, allowing and maintaining the activity of the other carbapenem.^27,28

A meta-analysis of 22 studies describing CRE infections found a significantly higher risk of all-cause mortality in patients treated with monotherapy (odds ratio, 2.19; 95% confidence interval 1.00–4.80), with large heterogeneity (I² = 84.2%; QP = 0.003).²⁹ In some studies in adults, double- or triple-combination therapies with colistin, tigecycline, aminoglycosides, and carbapenems have been used to treat CRKP infections, and mortality rates have been reported to range from 23.6% to 32.5%.^24,30 The mortality rate of combination therapy with tigecycline, colistin, and meropenem was reported to be 12.5%, and successful results were shown with the addition of tigecycline to combination therapy.^18,31 In our study, we used colistin and tigecycline together with DCC. We used this treatment on four patients because they were in septic shock. We used colistin to increase the intracellular activity of DCC,²⁵ and we obtained good results using imipenem instead of ertapenem.

The main limitation of the study is the small sample size, the absence of ceftazidime-avibactam in our country during the study period, and the fact that no molecular genotyping of OXA-48 PDR-CRKP was performed during the study period. Pulsed-field gel electrophoresis could not be performed. From a microbiological point of view, we cannot speak of an outbreak, but we accepted this situation as a clinical outbreak because it occurs as a severe infection in three patients simultaneously and then spreads rapidly to other patients.

Conclusions

PDR-CRKP can cause serious infectious diseases such as CLABSI, VAP, CAUTI, and surgical wound infections in PICUs. If an infected or colonized patient is discovered, isolation and infection control measures should be implemented immediately. PICU architecture and design (presence of isolated rooms) and adequate health care workers are important factors in reducing the spread of outbreaks. Successful treatment outcomes can be achieved with appropriate treatment, good follow-up, and full adherence to infection control measures. Experience in children is very limited, and further studies with this approach are needed to demonstrate treatment efficacy. Our study has had successful results with a small group of patients. Treatment of this severe infection should be planned according to the patient's clinical condition. Combined antibiotic therapy can be used in patients who have severe infections, and stay in PICU.

Footnotes

Acknowledgments

In this research report, all individuals who contributed to this article are listed as authors. We would like to thank everyone who contributed to this study as mentioned above.

Authors' Contributions

M.H. and T.K.: review and editing (equal) and writing—original draft (lead). Ö.T.P.: writing—original draft (supporting). S.Ö., A.Y., and T.E.: conceptualization (supporting). Z.C.K., H.G., and D.Ö.: contributed to microbiological diagnosis, genetic evaluation, and writing material and method part. H.Ö. and E.Ç.: contributed to infection control, treatment plans, data evaluation, and execution. E.İ.: methodology (lead); writing—review and editing (equal); and conceptualization (lead). All authors approved the final version of the article.

Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

References

Magiorakos

, Srinivasan

, Carey

, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: An International Expert Proposal for Interim Standard Definitions for Acquired Resistance. Clin Microbiol Infect, 2012; 18(3):268–281; doi: 10.1111/j.1469-0691.2011.03570.x

Ripabelli

, Tamburro

, Guerrizio

, et al. Tracking multidrug-resistant Klebsiella pneumoniae from an Italian Hospital: Molecular epidemiology and surveillance by PFGE, RAPD and PCR-based resistance genes prevalence. Curr Microbiol, 2018; 75(8):977–987; doi: 10.1007/s00284-018-1475-3

Ripabelli

, Sammarco

, Scutella

, et al. Carbapenem-resistant KPC- and TEM-producing Escherichia coli ST131 isolated from a hospitalized patient with urinary tract infection: First isolation in Molise Region, Central Italy, July 2018. Microb Drug Resist, 2020; 26(1):38–45; doi: 10.1089/mdr.2019.0085

Poirel

, Heritier

, Tolun

, et al. Emergence of oxacillinase-mediated resistance to imipenem in Klebsiella pneumoniae. Antimicrob Agents Chemother, 2004; 48(1):15–22; doi: 10.1128/AAC.48.1.15-22.2004

McGrath

, Asmar

. Nosocomial infections and multidrug-resistant bacterial organisms in the pediatric intensive care unit. Indian J Pediatr, 2011; 78(2):176–184; doi: 10.1007/s12098-010-0253-4

Glupczynski

, Huang

, Bouchahrouf

, et al. Rapid emergence and spread of OXA-48-producing carbapenem-resistant Enterobacteriaceae isolates in Belgian hospitals. Int J Antimicrob Agents, 2012; 39(2):168–172; doi: 10.1016/j.ijantimicag.2011.10.005

The European Committee on Antimicrobial Susceptibility Testing. Breakpoint Tables for Interpretation of MICs and Zone Diameters. Version 6.0; 2016. Available from: https://www.eucast.org [Last accessed: June, 2022].

Recommendations for MIC Determination of Colistin (Polymyxin E) as Recommended by the Joint CLSI-EUCAST Polymyxin Breakpoints Working Group. Available from: https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/General_documents/Recommendations_for_MIC_determination_of_colistin_March_2016.pdf [Last accessed: June, 2022].

Poirel

, Walsh

, Cuvillier

, et al. Multiplex PCR for detection of acquired carbapenemase genes. Diagn Microbiol Infect Dis, 2011; 70(1):119–123; doi: 10.1016/j.diagmicrobio.2010.12.00

10.

Taketomo

, Hodding

, Kraus DM. Pediatric & Neonatal Dosage Handbook with International Trade Names Index, Lexicomp 20th Edition. Wolters Kluwer, Lexicomp, Inc.: Ohio; 2013–2014.

11.

Zarkotou

, Pournaras

, Tselioti

, et al. Predictors of mortality in patients with bloodstream infections caused by KPC-producing Klebsiella pneumoniae and impact of appropriate antimicrobial treatment. Clin Microbiol Infect, 2011; 17(12):1798–1803; doi: 10.1111/j.1469-0691.2011.03514.x

12.

Falagas

, Tansarli

, Karageorgopoulos

, et al. Deaths attributable to carbapenem-resistant Enterobacteriaceae infections. Emerg Infect Dis, 2014; 20(7):1170–1175; doi: 10.3201/eid2007.121004

13.

Balkan

, Aygun

, Aydin

, et al. Bloodstream infections due to OXA-48-like carbapenemase-producing Enterobacteriaceae: Treatment and survival. Int J Infec Dis, 2014; 26:51–56; doi: 10.1016/j.ijid.2014.05.012

14.

Mantzarlis

, Makris

, Manoulakas

, et al. Risk factors for the first episode of Klebsiella pneumoniae resistant to carbapenems infection in critically ill patients: A prospective study. Biomed Res Internat, 2013; 2013:850547; doi: 10.1155/2013/850547

15.

Schwaber

, Klarfeld-Lidji

, Navon-Venezia

, et al. Predictors of carbapenem-resistant Klebsiella pneumoniae acquisition among hospitalized adults and effect of the acquisition on mortality. Antimicrob Agents Chemother, 2008; 52(3):1028–1033; doi: 10.1128/AAC.01020-07

16.

Qureshi

, Paterson

, Potoski

, et al. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: Superiority of combination antimicrobial regimens. Antimicrob Agents Chemother, 2012; 56(4):2108–2113; doi: 10.1128/AAC.06268-11

17.

Lee

, Burgess

. Treatment of Klebsiella pneumoniae carbapenemase (KPC) infections: A review of published case series and case reports. Ann Clin Microbiol Antimicrob, 2012; 11:32; doi: 10.1186/1476-0711-11-32

18.

Tumbarello

, Viale

, Viscoli

, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: The importance of combination therapy. Clin Infect Dis, 2012; 55(7):943–950; doi: 10.1093/cid/cis588

19.

Stewart

, Harris

, Henderson

, et al. Treatment of infections by OXA-48-producing Enterobacteriaceae. Antimicrob Agents Chemother, 2018; 62(11):e01195-18; doi: 10.1128/AAC.01195-18

20.

Soriano

, Carmeli

, Omrani et al

. Ceftazidime-avibactam for the treatment of serious gram-negative infections with limited treatment options: A systematic literature review. Infect Dis Ther, 2021; 10(4):1989–2034; doi: 10.1007/s40121-021-00507-6

21.

Walsh TR. Clinically significant carbapenemases: An update. Curr Opin Infect Dis, 2008; 21(4):367–371; doi: 10.1097/QCO.0b013e328303670b

22.

Carrilho

, Oliveira

, Gaudereto

, et al. A prospective study of treatment of carbapenem-resistant Enterobacteriaceae infections and risk factors associated with outcome. BMC Infect Dis, 2016; 16(1):629; doi: 10.1186/s12879-016-1979-z

23.

Paul

, Carmeli

, Durante-Mangoni

. Combination therapy for carbapenem-resistant Gram-negative bacteria. J Antimicrob Chemother, 2014; 69(9):2305–2309; doi: 10.1093/jac/dku168

24.

Daikos

, Tsaousi

, Tzouvelekis

, et al. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: Lowering mortality by antibiotic combination schemes the role of carbapenems. Antimicrob Agents Chemother, 2014; 58(4):2322–2328; doi: 10.1128/AAC.02166-13

25.

Oliva

, Gizzi

, Marcellino

, et al. Bactericidal and synergistic activity of the double-carbapenem regimen for infections caused by carbapenemase-producing Klebsiella pneumoniae. Clin Microbiol Infect, 2016; 22(2):147–153; doi: 10.1016/j.cmi.2015.09.014

26.

Oliva

, Scorzolini

, Castaldi

, et al. Double-carbapenem regimen, alone or in combination with colistin, in the treatment of infections caused by carbapenem-resistant Klebsiella pneumoniae (CR-Kp). J Infect, 2016; 74(1):103–106; doi: 10.1016/j.jinf.2016.10.002

27.

Camargo

, Simkins

, Beduschi

, et al. Successful treatment of carbapenemase-producing pan drug-resistant Klebsiella pneumoniae bacteremia. Antimicrob Agents Chemother, 2015; 59(10): 5903–5908; doi: 10.1128/AAC.00655-15

28.

Cui

, Zhang H and H

. Carbapenemases in Enterobacteriaceae: Detection and antimicrobial therapy. Front Microbiol, 2019; 10:1823; doi: 10.3389/fmicb.2019.01823

29.

Martin

, Fahrbach

, Zhao

, et al. Association between carbapenem resistance and mortality among adult, hospitalized patients with serious infections due to Enterobacteriaceae: Results of a systematic literature review and meta-analysis. Open Forum Infect Dis, 2018; 5(7):ofy150; doi: 10.1093/ofid/ofy150

30.

Tumbarello

, Viale

, Bassetti

, et al. Infections caused by KPC-producing Klebsiella pneumoniae: Differences in therapy and mortality in a multicenter study authors' response. J Antimicrob Chemother, 2015; 70(10):2922; doi: 10.1093/jac/dkv200

31.

Dan

, Mendler

, Hemming

, et al. High-dose tigecycline and colistin for successful treatment of disseminated carbapenem-resistant Klebsiella pneumoniae infection in a liver transplant recipient. BMJ Case Rep, 2014; 2014:bcr2014205865; doi: 10.1136/bcr-2014-205865