Fecal Carriage of Extended-Spectrum β-Lactamase and Carbapenemase-Producing Enterobacterales Strains in Patients with Colorectal Cancer in the Oncology Unit of Amizour Hospital,Algeria: A Prospective Cohort Study

Abstract

Background:

The prevalence of extended-spectrum β-lactamase (ESBL)-producing Enterobacterales (ESBL-E) and carbapenemase-producing Enterobacterales (CPE) is now disseminated worldwide. This study aims to describe the prevalence of ESBL and CPE fecal carriage in colorectal cancer patients.

Methods:

All patients admitted to the oncology service of Amizour hospital (Algeria) for colorectal cancer chemotherapy from March to May 2019 were screened for ESBL-E or CPE fecal carriage. After culturing on chromogenic media, the presumptive colonies were identified by mass spectroscopy. Antibiotic susceptibility testing was performed according to the European Committee on Antimicrobial Susceptibility Testing. The β-lactamases encoding genes and plasmid-mediated quinolone-resistant genes were screened by PCR and sequencing.

Results:

ESBL-E strains were recovered from rectal swabs in 6 patients (14.3%) and only 1 patient (2.4%) was found a carrier for OXA-48-producing Klebsiella pneumoniae. The most frequently encountered species among ESBL-E was Escherichia coli (n = 5), followed by K. pneumoniae (n = 1). PCR and sequencing showed that four isolates harbored the bla_CTX-M-15 gene and two strains harbored the bla_CTX-M-14 gene. Also, one strain of K. pneumoniae was found to harbor both qepA and qnrS genes.

Conclusion:

This study highlighted the fecal carriage of ESBL-E and OXA-48-producing Enterobacterales strains in colorectal cancer patients.

Introduction

In 2018, 18,078,957 new cases of cancer were recorded in the world, in which 1,849,518 (10.2%) were represented by colorectal cancer.¹ In Algeria, 53,076 new cases were recorded in 2018 and colorectal cancer represents the second cancer type after breast cancer with 5,537 (10.4%) recorded new cases. In the same report, 9,555,027 deaths were attributed to cancer in which 880,792 (9.2%) were caused by colorectal cancer.¹

Among the multidrug-resistant (MDR) pathogens, extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) or carbapenemase-producing Enterobacterales (CPE) are actually widespread and constitute a great challenge for physicians for their treatment.² Thus, for example, bacteremia caused by ESBL-E has been associated with higher mortality compared with non-ESBL-producing Enterobacterales bacteremia.^3,4 Colistin alone, or in combination with other antibiotics, were used in managing carbapenem-resistant infections before the emergence of colistin resistance. However, the emergence of colistin resistance, particularly in carbapenem-resistant strains, is compromising this combination regimen.⁵

Colonization with ESBL-E, most commonly of the gastrointestinal tract, has been linked to subsequent infection with these MDR pathogens.⁶ This is particularly concerning in the cancer patients since chemotherapy treatment of cancer has several side effects and among them, the destruction of the mucosal barrier.⁷ This gut permeability facilitates the microbial translocation from the digestive tract to the bloodstream.⁸

Therefore, given the scarcity of studies on the fecal carriage in patients with cancer, and especially those with colorectal cancer, we performed this study that aimed to describe the prevalence of the fecal carriage of MDR Enterobacterales in colorectal cancer patients.

Methods

Study setting

The hospital of Amizour is a public general hospital with a capacity of 200 beds and has a catchment area of 160.000 inhabitants. The oncology service has a capacity of 12 beds and hosts about twenty cancer patients per day requiring chemotherapy.

Design of the study

From March to May 2019, we conducted a prospective cohort study of adult patients, with colorectal cancer who came to the oncology service of Amizour hospital (Algeria) for receiving cancer chemotherapy.

These patients were not hospitalized in this ward and they have their chemotherapy cure periodically every 3 weeks on average. This study protocol was approved by the local ethics committee and conformed to the ethical guidelines of the Declaration of Helsinki. Written informed consent was obtained from each participant enrolled in the study.

At the oncology service, a total of 42 patients have agreed and 27 have refused to participate in this study. The patients who agreed were screened for ESBL-E, CPE, and colistin resistance through a rectal swabbing. To ascertain the persistence of the fecal carriage, a second rectal swabbing was made at the next chemotherapy. The patients were asked again for their agreement before sampling them. Thus, from the initial 42 patients who agreed for the first time, only 25 patients agreed again to be sampled from the second time (17 patients did not accept to be sampled). The inclusion criteria were all adult patients having colorectal cancer and agreed to participate in the study. The exclusion criteria included all patients who did not agree to participate in the study.

To assess possible risk factors for MDR fecal carriage, we have collected data from the interview of the patient and its medical record. Data collected included the following: gender, age, diabetes mellitus, high blood pressure, surgery in the last 3 months before admission, antibiotic use and radiotherapy within 3 months, the number of prior cancer chemotherapy, and neutropenia. In addition, we systematically recorded the presence of any infection episode at the moment of sampling.

Microbiological procedures

The rectal swab was obtained per each patient. The swab containing the sample was transferred into 1 mL phosphate-buffered saline buffer. An inoculum volume of 200 μL was plated onto each of four chromogenic media: ChromID^® ESBL medium (bioMérieux, Marcy l'Etoile, France), ChromID OXA-48 (bioMérieux), ChromID CARBA (bioMérieux), and ChromID Colistin R (bioMérieux) for screening respectively for ESBL-producing, OXA-48-producing, carbapenemase-producing, and colistin-resistant Enterobacterales. Suspected colonies were subcultured from respective screening agar plates onto MacConkey plates and identified using the Vitek^® MS system (bioMérieux, Marcy l'Etoile, France).

Antibiotic susceptibility testing

Susceptibility to antimicrobial agents was tested by the disk diffusion method (BioRad, Marnes La Coquette, France) on Mueller-Hinton agar according to the European Committee on Antimicrobial Susceptibility Testing recommendations.⁹ The MICs of carbapenems (ertapenem, imipenem, and meropenem) and colistin were determined by E-test method (bioMérieux) and micro-broth dilution (Umic^®, Biocentric, Bandol, France), respectively.

Molecular characterization of the antibiotic resistance genes

Total DNA was extracted using the EZ1 DNA Tissue Kit on the BioRobot EZ1 extraction platform (Qiagen, Courtaboeuf, France). Genes encoding the most clinically prevalent carbapenemases (bla_KPC, bla_OXA-48-like, bla_VIM, bla_IMP, and bla_NDM) and ESBLs (bla_TEM, bla_SHV, and bla_CTX-M) were detected by PCR using specific primers and confirmed by sequencing the PCR products, as described previously.^10,11 The plasmid-mediated quinolone resistance encoding genes (qnrA, qnrB, qnrS, qepA, oqxAB, and aac[6′]-Ib-cr) were screened for strains resistant to quinolones by PCR as previously described.^12–14

Statistical analysis

The prevalence of fecal carriage of ESBL-E was calculated as the percentage of carriers among the total number of patients included. Carriers and non-carriers patients were compared for their fecal carriage prevalence using univariate analysis with the chi-square test for qualitative variables and Student's t-test for continuous variables. Statistical analyses were performed using GraphPad Prism 6 (GraphPad Software, La Jolla, CA). p < 0.05 was considered a statistically significant difference.

Results

Participants

The main characteristics of these patients are indicated in Table 1. The mean age of study participants was 60.2 ± 13.3 years, the sex ratio (male/female) was 1.0 (21/21), 14.3% (n = 6) were diabetic, and 14.3% (n = 6) had high blood pressure. The common colorectal cancer diagnoses were as follows: colon cancer (n = 22), sigmoid cancer (n = 8), rectum cancer (n = 6), cecum cancer (n = 3), rectosigmoid junction cancer (n = 2), and anal canal cancer (n = 1) (Table 2).

Table 2.

Main Characteristics of Patients with Colorectal Cancer Carrying or not an Extended-Spectrum β-Lactamase-Producing Enterobacterales

	ESBL carriers (n = 6)	No ESBL carriers (n = 36)	Total (n = 42)	p
Age median, years	59.7 ± 17.2	60.4 ± 13.1	60.2 ± 13.3	NS
Sex M/F no. (%)	4/2	17/19	21 (50)/21 (50)	0.377
Localization of cancer
Colon n (%)	3 (50)	19 (52.8)	22 (52.4)	NS
Sigmoid n (%)	1 (16.7)	7 (19.4)	8 (19.0)	NS
Rectum n (%)	0 (0)	6 (16.7)	6 (14.3)	NS
Cecum n (%)	2 (33.3)	1 (2.8)	3 (7.1)	0.05
Recto-sigmoid junction n (%)	0 (0)	2 (5.5)	2 (4.8)	NS
Anal canal n (%)	0 (0)	1 (2.8)	1 (2.4)	NS
Other comorbidities
Neutropenia n (%)	1 (16.7)	9 (25)	10 (23.8)	NS
Diabetes mellitus n (%)	3 (50)	3 (8.3)	6 (14.3)	0.006
High blood pressure n (%)	1 (16.7)	5 (13.9)	6 (14.3)	NS
Antecedents (3 months)
Previous antibiotic use n (%)	1 (16.7)	5 (13.9)	6 (14.3)	NS
Previous surgery n (%)	2 (33.3)	4 (11.1)	6 (14.3)	NS
Previous chemotherapy n (%)	3 (50)	31 (86.1)	34 (81)	NS
Number of chemotherapy cure	1.5 ± 1.8	2.8 ± 1.6	2.6 ± 1.7	0.037

ESBL, extended-spectrum β-lactamase; NS, not significant.

Table 1.

Characteristics of the Studied Population

Patient's code	Fecal carriage in the first sampling period	Fecal carriage in the second sampling period	Age (years)	The time interval between the date of first and second sampling periods	Sex	Chemotherapy^a	Surgery^a	Neutropenia	Antibiotic treatment^a	Diabetes	Presence of an infection
C1	No	No	52	21 days	F	No	No	No	No	No	No
C2	No	No	66	13 days	F	Yes	No	No	No	No	No
C3	Yes	Yes	39	41 days	M	No	No	No	Yes	No	SSI
C4	No	Undone	55	Undone	M	No	Yes	No	Yes	Yes	No
C5	Yes	No	71	20 days	M	No	No	ND	No	Yes	No
C6	No	No	71	20 days	F	Yes	No	No	No	No	No
C10	No	No	61	20 days	F	Yes	No	Yes	Yes	No	No
C7	No	No	60	49 days	M	Yes	No	ND	No	No	No
C8	Yes	Yes	48	20 days	M	Yes	No	No	No	No	No
C9	No	No	54	20 days	F	Yes	No	Yes	No	No	No
C11	Yes	No	63	20 days	M	Yes	Yes	Yes	No	Yes	No
C12	No	No	51	24 days	M	Yes	Yes	Yes	No	No	No
C13	No	Undone	83	Undone	F	Yes	No	No	No	No	No
C14	No	Undone	73	Undone	M	Yes	No	No	No	No	No
C15	No	No	75	27 days	M	Yes	No	ND	Yes	No	No
C16	No	No	64	20 days	F	Yes	Yes	No	Yes	No	No
C17	No	Undone	85	Undone	M	Yes	No	No	No	No	No
C18	No	No	78	21 days	M	Yes	No	Yes	No	Yes	No
C19	No	No	69	21 days	M	Yes	No	Yes	No	No	No
C20	No	No	53	21 days	F	Yes	No	No	No	Yes	No
C21	No	No	37	22 days	F	Yes	No	No	No	No	No
C22	No	No	48	21 days	M	Yes	No	No	No	No	No
C24	No	No	55	21 days	M	No	No	ND	No	No	No
C25	No	No	56	21 days	M	Yes	No	Yes	No	No	No
C26	No	No	57	21 days	M	Yes	No	No	No	No	No
C27	No	Undone	52	Undone	F	Yes	No	No	No	No	No
C28	No	Undone	42	Undone	F	Yes	Yes	Yes	No	No	No
C44	No	Undone	47	Undone	M	Yes	No	No	No	No	No
C29	No	No	85	21 days	F	Yes	No	No	No	No	No
C30	No	No	49	24 days	M	Yes	No	No	No	No	No
C32	No	Undone	61	Undone	F	Yes	No	Yes	No	No	No
C33	No	No	56	18 days	F	Yes	No	No	No	No	UTI
C34	No	Undone	37	Undone	M	Yes	No	No	Yes	No	No
C35	No	No	80	20 days	M	No	Yes	No	No	No	No
C36	No	Undone	50	Undone	F	No	Yes	No	No	No	No
C37	No	Undone	56	Undone	F	Yes	No	Yes	No	No	No
C38	No	Undone	64	Undone	M	Yes	No	No	No	No	No
C39	No	Undone	78	Undone	F	Yes	Yes	ND	No	No	No
C40	No	Undone	59	Undone	F	Yes	No	No	No	No	No
C41	No	Undone	54	Undone	F	Yes	No	No	No	No	No
C42	Yes	Undone	86	Undone	F	Yes	No	No	No	Yes	No
C43	Yes	Undone	51	Undone	F	No	Yes	No	No	No	No

Chemotherapy, surgery, and antibiotic treatment within 3 months.

SSI, surgical site infections; UTI, urinary tract infection.

At sampling, 14.3% (n = 6) of patients had recently been exposed to antimicrobials, 14.3% (n = 6) had a surgical intervention within the previous 3 months, and 81% (n = 34) of patients had at least one chemotherapy cure. No patients had radiotherapy within the 3 months preceding sampling (Table 2).

Fecal carriage, bacterial isolates, and antibiotic susceptibility

ESBL-E and CPE were recovered from rectal swabs in 6 (14.3%) and 1 (2.4%) patients, respectively. None of the patients carried colistin-resistant Enterobacterales isolates.

When comparing the prevalence of ESBL-E in colonized group and noncolonized group with respect to risk factors, no significances were observed for age (p = 0.849), sex-ratio M/F (p = 0.377), antibiotic treatment for the last 3 months before admission (p = 0.857), and surgery in the last 3 months before admission (p = 0.442). However, two variables showed statistical significance for ESBL-E fecal carriage including chemotherapy within the 3 last months (p = 0.037) and diabetes mellitus (p = 0.006) (Table 2).

The OXA-48-producing Klebsiella pneumoniae isolate was recovered from a female patient, aged 71 years, diagnosed with colon cancer, and having high blood pressure. This patient neither received antibiotic treatment nor had surgery within the last 3 months before sampling.

The most frequently encountered species among ESBL-E was Escherichia coli (n = 5), followed by K. pneumoniae (n = 1). All these isolates were resistant to ampicillin, ticarcillin, piperacillin, cefepime, aztreonam, cefotaxime, while 83.3% (n = 5) were resistant to ceftazidime and cotrimoxazole and 33.3% (n = 2) were resistant to nalidixic acid. The isolates were susceptible to amoxicillin-clavulanic acid, piperacillin-tazobactam, ticarcillin-clavulanic acid, cefoxitin, ertapenem, imipenem, aminoglycosides (gentamicin, amikacin, netilmicin, and tobramycin), colistin, and ciprofloxacin.

Molecular characteristics and follow-up

Concerning the ESBL isolates, PCR and sequencing showed that the E. coli isolates harbored the bla_CTX-M-15 gene (n = 3) and the bla_CTX-M-14 gene (n = 2) (Table 3). The K. pneumoniae isolate recovered from patientC8 harbored the bla_CTX-M-15 gene. Moreover, this isolate had both the qepA and qnrS genes (Table 3).

Table 3.

Characteristics of Enterobacterales and OXA-48-Producing Enterobacterales Isolates

Patient's code	Date	Identification	Origin, period	β-lactamases	Antibiotic resistance pattern	PMQR
C3	March 24	Escherichia coli	Fecal, first sampling	CTX-M-14	AMP TIC PIL FEP CZD FIX ATM COX CXM SXT	NT
	May 5	E. coli	Fecal, second sampling	CTX-M-14	AMP TIC PIL FEP CZD FIX ATM COX CXM SXT	NT
	March 24	E. coli	Wound	CTX-M-14	AMP TIC PIL FEP CZD FIX ATM COX CXM SXT	NT
C5	March 24	E. coli	Fecal, first sampling	CTX-M-14	AMP TIC PIL FEP CZD FIX ATM COX CXM SXT	NT
C5	April 14	Negative	Fecal, second sampling	—	—	—
C6	March 25	Negative	Fecal, first sampling	—	—	None
C6	April 15	Klebsiella pneumoniae	Fecal, second sampling	OXA-48	AMP TIC PIL AMC PTZ TCC TEM ETP NAL NXN OFX CIP	—
C8	March 26	K. pneumoniae	Fecal, first sampling	CTX-M-15	AMP TIC PIL FEP CZD FIX ATM COX CXM NAL OFX SXT	QnrS+QepA
C8	April 16	K. pneumoniae	Fecal, second sampling	CTX-M-15	AMP TIC PIL FEP CZD FIX ATM COX CXM NAL OFX SXT	QnrS+QepA
C11	March 27	E. coli	Fecal, First sampling	CTX-M-15	AMP TIC PIL FEP FIX ATM COX CXM SXT	None
C11	April 17	Negative	Fecal, second sampling	—	—	—
C42	April 30	E. coli	Fecal, First sampling	CTX-M-15	AMP TIC PIL FEP CZD FIX ATM COX CXM SXT	NT
C42	Undone	—	—	—	—	—
C43	April 30^`	E. coli	Fecal, First sampling	CTX-M-15	AMP TIC PIL FEP CZD FIX ATM COX CXM SXT	NT
C43	Undone	—	—	—	—	—

AMP, ampicillin; ATM, aztreonam; CIP, ciprofloxacin; COX, cefotaxime; CXM, cefuroxime; CZD, ceftazidime; ETP, ertapenem; FEP, cefepim; FIX, cefixime; NAL, nalidixic acid; NT, non-tested; NXN, norfloxacin; OFX, ofloxacin; PIL, piperacillin; PMQR, plasmid-mediated-quinolone resistant; PTZ, piperacillin+tazobactam; SXT, cotrimoxazole; TCC, ticarcillin+clavulanic acid; TEM, temocillin; TIC, ticarcillin.

In the second sampling period, 2 patients (C3 and C8) were found to be still carriers of ESBL-E respectively after 41 and 20 days after the first sampling time (Table 1). Thus, from patient C3, we have isolated respectively on March 24 and May 5, two CTX-M-14-producing E. coli isolates with the same antibiotic resistance pattern (Table 3). Concerning patient C8, we have isolated respectively on March 26 and April 16, two CTX-M-15-producing K. pneumoniae isolates with the same antibiotic resistance pattern and harboring qnrS and qepA genes (Table 3). Furthermore, from the patient C3, we have also isolated an E. coli strain producing CTX-M-14 and showing the same antibiotic resistance patterns with the two E. coli strains isolated from the fecal carriage of this patient. This patient had surgery (for colon) 1 year ago and he did not still get cured from his surgical site infection.

Concerning the CPE isolate, PCR and sequencing showed that the K. pneumoniae isolate harbored bla_OXA-48 gene. This strain was resistant to ampicillin, ticarcillin, piperacillin, amoxicillin-clavulanic acid, piperacillin-tazobactam, ticarcillin-clavulanic acid, ertapenem, nalidixic acid, and ciprofloxacin. The isolate was susceptible to cefepime, cefotaxime, ceftazidime, aztreonam, imipenem, aminoglycosides, cotrimoxazole, and colistin (Table 3).

Discussion

The main finding reported in our study was that the prevalence of ESBL-E and CPE fecal carriage in patients with colorectal patients was respectively 14.3% and 2.4%.

Patients with cancer are more likely to suffer from an infection due to pathogenic bacteria in comparison to patients without cancer,¹⁵ involving frequent use of antibiotics. Oncological treatment frequently needs the use of surgery and chemotherapy or radiotherapy that increase the risk of hospital-acquired infections especially due to MDR bacteria. ESBL-producing Enterobacterales are known to be implicated in the colonization and infection of several sites, both in immunocompetent and immunocompromised patients. Cancer patients are frequently exposed to cytotoxic treatments that contribute to the weakening of their immune system and the gut inflammation promoting the microbial translocation.¹⁶ It was reported that ESBL-producing E. coli was commonly found in a gastrointestinal cancer patient group compared to patients under other types of cancer.¹⁵

In this study, we have highlighted a fecal carriage prevalence of 16.7%. A previous study from Algeria reported that of the 171 children with different cancers studied, 93 (54.4%) were ESBL carriers.¹⁷ Important variations have been observed in the fecal carriage of ESBL-E in cancer patients. In Germany, Liss et al. and Vehreschild et al. have reported a colonization rate of 17.5% and 11.1%, respectively among adults with solid or hematologic malignancies.^18,19 Similar rate (11.3%) was reported from the Czech Republic.²⁰ In Spain, the prevalence of ESBL-producing E. coli fecal carriage in neutropenic cancer patients varied between 29%²¹ to 31.8%.²² In Asia, colonization rates of 10.3% in Japan,²³ 50% in Malaysia,²⁴ and 58.4% in India²⁵ were reported. In North America, Reddy et al. reported that the rate of ESBL-E colonization doubled during the 6-year study period, increasing from 1.33% in 2000 to 3.21% in 2005.²⁶

Golzarri et al. concluded in their study that colonization of ESBL-E in cancer patients duplicated the risk of surgical site infections by the same strain and, by a factor of 4, the risk of bloodstream infections.²⁷ In our study, we reported 1 patient (C3) harboring a CTX-M-14-producing E. coli isolate in a fecal carriage (from first and second sampling) and from surgical wound infection.

In our study, we have observed that diabetes mellitus and chemotherapy during the previous 3 months were associated characteristics with ESBL colonization. However, Golzarri et al. reported no significance for diabetes mellitus (p = 0.379) and chemotherapy within the previous 3 months (p = 0.219).²⁷

In addition to ESBL-E fecal carriage, we have also reported a fecal carriage rate of CPE of 2.4%. Only a few studies have reported the colonization of cancer patients with CPE.^28–30 Thus, Rock et al. have reported two K. pneumoniae strains producing KPC-2, CTX-M-15, TEM-1B, SHV-28, and OXA-1 isolated from the fecal carriage in 2 patients admitted into large academic medical facility cancer center in Baltimore, Maryland.²⁹ A Klebsiella michiganensis strain co-producing OXA-181 and NDM-1 carbapenemases have been isolated from a cancer patient in uMgungundlovu District, KwaZulu-Natal Province, South Africa.²⁸ In a nationwide Italian pediatric hematology-oncology survey, Caselli et al. reported that of the 15 centers, 4 (27%) reported no isolation of CPE, while 8 reported BSI by CPE, and 3 reported episodes of colonization only.³⁰

Our study presents some limitations including the size of the population sampled and the short time period of the follow-up. Despite these limitations, our results increase our knowledge of the epidemiology of MDR bacteria in Algeria, a country in which the epidemiology data of MDR bacteria are rare. It is to highlight that in Amizour hospital and in many Algerian hospitals, no control measures (routine screening for MDR bacteria at admission, contact precautions, isolation of patients, decolonization of MDR bacteria, etc.) were applied. In addition, this study has allowed us to educate the patients and increase awareness of the medical staff on the antibiotic resistance dangers encountered.

Conclusion

In conclusion, this study describes the low prevalence of ESBL-E and CPE fecal carriage, respectively 14.3% and 2.4%, in a prospective cohort of colorectal cancer patients and the detailed risk factors for their carriage. It is important to adopt a local plan for the control of MDR bacteria to avoid the proliferation of these microorganisms that may have a direct impact on the patient's health, already weakened by disease.

Footnotes

Acknowledgments

J.P.L. belongs to the FHU InCh (Federation HospitaloUniversitaire Infections Chroniques, Université Montpellier, Aviesan). We thank the Nîmes University Hospital for its structural, human, and financial support through the award obtained by our team during the internal call for tenders “Thématiques phares.”

We thank the “Direction Générale de la Recherche Scientifique et du développement technologique (DGRSDT) of Algerian Ministry of Higher Education and Scientific Research.”

Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received.

References

The Global Cancer Observatory. 2018. https://gco.iarc.fr/today.

Catho

, and Huttner

B.D.

. 2019. Strategies for the eradication of extended-spectrum beta-lactamase or carbapenemase-producing Enterobacteriaceae intestinal carriage. Expert Rev. Anti. Infect. Ther. 17:557–569.

Rottier

W.C.

, Ammerlaan

H.S.M

, and Bonten

M.J.M

. 2012. Effects of confounders and intermediates on the association of bacteraemia caused by extended-spectrum β-lactamase-producing Enterobacteriaceae and patient outcome: a meta-analysis. J. Antimicrob. Chemother. 67:1311–1320.

Schwaber

M.J.

, and Carmeli

. 2007. Mortality and delay in effective therapy associated with extended-spectrum beta-lactamase production in Enterobacteriaceae bacteraemia: a systematic review and meta-analysis. J. Antimicrob. Chemother. 60:913–920.

Osei Sekyere

2019. Mcr colistin resistance gene: a systematic review of current diagnostics and detection methods. Microbiologyopen, 8:e00682.

Alevizakos

, Karanika

, Detsis

, and Mylonakis

. 2016. Colonisation with extended-spectrum β-lactamase-producing Enterobacteriaceae and risk for infection among patients with solid or haematological malignancy: a systematic review and meta-analysis. Int. J. Antimicrob. Agents, 48:647–654.

Montassier

, Gastinne

, Vangay

, Al-Ghalith

G.A

, Bruley des Varannes

, Massart

, Moreau

, Potel

, de La Cochetière

M.F

, Batard

, and Knights

. 2015. Chemotherapy-driven dysbiosis in the intestinal microbiome. Aliment. Pharmacol. Ther. 42:515–528.

van der Velden, W.J.F.M., Herbers

A.H.E

, Netea

M.G

, and Blijlevens

N.M.A

. 2014. Mucosal barrier injury, fever and infection in neutropenic patients with cancer: introducing the paradigm febrile mucositis. Br. J. Haematol. 167:441–452.

The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. (Version 8.0); 2018. http://www.eucast.org.

10.

Pitout

J.D.D.

, Hanson

N.D

, Church

D.L

, and Laupland

K.B.

. 2004. Population-based laboratory surveillance for Escherichia coli-producing extended-spectrum beta-lactamases: importance of community isolates with blaCTX-M genes. Clin. Infect. Dis. 38:1736–1741.

11.

Poirel

, Bonnin

R.A

, and Nordmann

. 2012. Genetic features of the widespread plasmid coding for the carbapenemase OXA-48. Antimicrob. Agents Chemother. 56:559–562.

12.

Cattoir

, Poirel

, Rotimi

, Soussy

C.-J

, and Nordmann

. 2007. Multiplex PCR for detection of plasmid-mediated quinolone resistance qnr genes in ESBL-producing enterobacterial isolates. J. Antimicrob. Chemother. 60:394–397.

13.

Kim

H.B.

, Wang

, Park

C.H

, Kim

E.-C

, Jacoby

G.A

, and Hooper

D.C.

. 2009. oqxAB encoding a multidrug efflux pump in human clinical isolates of Enterobacteriaceae. Antimicrob. Agents Chemother. 53:3582–3584.

14.

Park

C.H.

, Robicsek

, Jacoby

G.A

, Sahm

, and Hooper

D.C.

. 2006. Prevalence in the United States of aac(6’)-Ib-cr encoding a ciprofloxacin-modifying enzyme. Antimicrob. Agents Chemother. 50:3953–3955.

15.

Lin

, Jia

, Fu

, Zhao

, Huang

, Tang

, Meng

, Zhao

, and Liang

. 2019. A comparative analysis of infection in patients with malignant cancer: a clinical pharmacist consultation study. J Infect Public Health. 12:789–793.

16.

Biehl

L.M.

, Schmidt-Hieber

, Liss

, Cornely

O.A

, and M. Vehreschild

J.G.T

. 2016. Colonization and infection with extended spectrum beta-lactamase producing Enterobacteriaceae in high-risk patients – Review of the literature from a clinical perspective. Crit. Rev. Microbiol. 42:1–16.

17.

Medboua-Benbalagh

, Touati

, Kermas

, Gharout-Sait

, Brasme

, Mezhoud

, Touati

, Guillard

, and de Champs

. 2017. Fecal carriage of extended-spectrum β-lactamase-producing Enterobacteriaceae strains is Associated with worse outcome in patients hospitalized in the Pediatric Oncology Unit of Beni-Messous Hospital in Algiers, Algeria. Microb. Drug Resist. 23:757–763.

18.

Liss

B.J.

, Vehreschild

J.J

, Cornely

O.A

, Hallek

, Fätkenheuer

, Wisplinghoff

, Seifert

, and M. Vehreschild

J.G.T

. 2012. Intestinal colonisation and blood stream infections due to vancomycin-resistant enterococci (VRE) and extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBLE) in patients with haematological and oncological malignancies. Infection, 40:613–619.

19.

Vehreschild, M.J.G.T., Hamprecht

, Peterson

, Schubert

, Häntschel

, Peter

, Schafhausen

, Rohde

, Lilienfeld-Toal

M.V

, Bekeredjian-Ding

, Libam

, Hellmich

, Vehreschild

J.J

, Cornely

O.A

, and Seifert

. 2014. A multicentre cohort study on colonization and infection with ESBL-producing Enterobacteriaceae in high-risk patients with haematological malignancies. J. Antimicrob. Chemother. 69:3387–3392.

20.

Kolar

, Htoutou Sedlakova

, Pudova

, Roderova

, Novosad

, Senkyrikova

, Szotkowska

, and Indrak

. 2015. Incidence of fecal Enterobacteriaceae producing broad-spectrum beta-lactamases in patients with hematological malignancies. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub. 159:100–103.

21.

Arnan

, Gudiol

, Calatayud

, Liñares

, M.Á. Dominguez, Batlle

, Ribera

J.M

, Carratalà

, and Gudiol

. 2011. Risk factors for, and clinical relevance of, faecal extended-spectrum β-lactamase producing Escherichia coli (ESBL-EC) carriage in neutropenic patients with haematological malignancies. Eur. J. Clin. Microbiol. Infect. Dis. 30:355–360.

22.

Calatayud

, Arnan

, Liñares

, Dominguez

M.A

, Gudiol

, Carratalà

, Batlle

, Ribera

J.M

, and Gudiol

. 2008. Prospective study of fecal colonization by extended-spectrum-beta-lactamase-producing Escherichia coli in neutropenic patients with cancer. Antimicrob. Agents Chemother. 52:4187–4190.

23.

Chong

, Shimoda

, Yakushiji

, Ito

, Aoki

, Miyamoto

, Kamimura

, Shimono

, and Akashi

. 2014. Clinical impact of fluoroquinolone-resistant Escherichia coli in the fecal flora of hematological patients with neutropenia and levofloxacin prophylaxis. PLoS One, 9:e85210.

24.

Nurul Atifah

M.A.

, Loo

H.K.C

, Subramaniam

, Wong

E.H

, Selvi

, Ho

S.E

, Kamarulzaman

, and Parasakthi

. 2005. Faecal prevalence of extended-spectrum beta-lactamase (ESBL)-producing coliforms in a geriatric population and among haematology patients. Malays. J. Pathol. 27:75–81.

25.

Thacker

, Pereira

, Banavali

S.D

, Narula

, Vora

, Chinnaswamy

, Prasad

, Kelkar

, Biswas

, and Arora

. 2014. Alarming prevalence of community-acquired multidrug-resistant organisms colonization in children with cancer and implications for therapy: a prospective study. Indian J. Cancer, 51:442–446.

26.

Reddy

, Malczynski

, Obias

, Reiner

, Jin

, Huang

, Noskin

G.A

, and Zembower

. 2007. Screening for extended-spectrum beta-lactamase-producing Enterobacteriaceae among high-risk patients and rates of subsequent bacteremia. Clin. Infect. Dis. 45:846–852.

27.

Golzarri

M.F.

, Silva-Sánchez

, Cornejo-Juárez

, Barrios-Camacho

, Chora-Hernández

L.D

, Velázquez-Acosta

, and Vilar-Compte

. 2019. Colonization by fecal extended-spectrum β-lactamase-producing Enterobacteriaceae and surgical site infections in patients with cancer undergoing gastrointestinal and gynecologic surgery. Am J Infect Control. 47:916–921.

28.

Founou

R.C.

, Founou

L.L

, Allam

, Ismail

, and Essack

S.Y.

. 2018. Genomic characterisation of Klebsiella michiganensis co-producing OXA-181 and NDM-1 carbapenemases isolated from a cancer patient in uMgungundlovu District, KwaZulu-Natal Province, South Africa. S. Afr. Med. J. 109:7–8.

29.

Rock

, Curless

M.S

, Cantara

, Mehta

, Marrone

K.A

, Carroll

K.C

, Simner

, and Maragakis

L.L.

. 2017. Resolution of carbapenemase-producing Klebsiella pneumoniae outbreak in a Tertiary Cancer Center; the Role of Active Surveillance. Infect Control Hosp Epidemiol, 38:1117–1119.

30.

Caselli

, Cesaro

, Fagioli

, Carraro

, Ziino

, Zanazzo

, Meazza

, Colombini

, Castagnola

, and Infectious Diseases Study Group of the Italian Association of Pediatric Hematology and Oncology (AIEOP). 2016. Incidence of colonization and bloodstream infection with carbapenem-resistant Enterobacteriaceae in children receiving antineoplastic chemotherapy in Italy. Infect Dis (Lond), 48:152–155.