Prevalance of Carbapenem-Resistant Enterobacteriaceae in patients of tertiary

care hospital in Pakistan and their clinical characteristics: A descriptive study

Dr Kashif Aziz

Resident

Internal Medicine AKUH Karachi

Supervisor

Dr Om Pakash

Consultant Gastroenterologist AKUH Karachi

Introduction

Multidrug-resistant organisms (MDROs) are serious challenges on clinical treatment, infection

control and public health.1 Enterobacteriaceae are inhabitants of the intestinal flora and
important pathogens in both nosocomial and community settings. Bacteria belonging
to Enterobacteriaceae, such as Escherichia coli, Klebsiella
pneumoniae, Enterobacterspp., Citrobacter spp, Serratia spp, Proteus spp, and Morganella, are
all important human pathogens. They cause a wide array of diseases including urinary tract,
respiratory tract, bloodstream, intra-abdominal, and skin and soft tissue infections.2 Treatment
of infections caused by these bacteria has become challenging particularly those with increasing
resistance to extended spectrum -lactams due to expression of extended-spectrum -
lactamase (ESBL) and/or AmpC -lactamase. Therefore, carbapenems have been the major last
agent of choice for treating infections caused by these multidrug-resistant isolates 3,4
carbapenem resistance among Enterobacteriaceae has increased gradually over the
years in different regions. The emergence of carbapenem-resistant Enterobacteriaceae (CRE) is
worrisome because treatment options are very limited. The mechanisms of carbapenem
resistance among Enterobacteriaceae include production of ESBL and/or AmpC enzymes in
combination with loss of outer membrane protein or up-regulation of efflux pump, and
secretion of carbapenemases. Among the carbapenemases found
in Enterobacteriaceae, K. pneumoniae carbapenemase (KPC) and New-Delhi metallo--
lactamase1 (NDM-1) have been most noteworthy.5
In Asian countries the rates of resistance to imipenem vary from 0.1% (95% CI, 0.1-1.2%)
to 5.8% (95% CI, 2.2-11.0%). The top three countries with the highest resistance rates to
imipenem are Indonesia (5.8%), Vietnam (3.0%) and Philippines (3.7%). Singapore (0.1%),
Kuwait (0.1%) and Japan (0.2%) show the lowest resistance rates. Rate of resistance to
imipenem in China is 1.4% (95% CI, 1.0-1.6%), higher than the average rate (0.7%). As to
meropenem resistance in Enterobacteriaceae, only six countries contribute available data. The
average rate of resistance to meropenem is 0.9% (95% CI, 0.7-1.2%). Turkey (2.9%) and India
(2.6%) show higher resistance rates than others. In China, the prevalence of meropenem
resistance rate among Enterobacteriaceae is 1.4% (95% CI, 1.0-1.9%).6
Among the three most common Enterobacteriaceae genera, Klebsiella spp. has the
highest resistance rates to imipenem and meropenem. In 2000-2004, its resistance rates are
0.5% (95% CI, 0.2-0.8%) and 0.3% (95% CI, 0.-0.8%), and they keep stably escalating trends
during the later years. In 2009-2011, they has risen to 1.9% (95% CI, 1.3-2.7%) and 2.4% (95%
CI, 1.5-3.5%), over three times higher than the first period. E. coli exhibits the lowest
carbapenems resistance rates among all the Enterobacteriaceae genera.6
In a study the prevalence of CRE was found to be 6% done in a tertiary care centre in
Pakistan.7 Very few studies have been done in our country that also study the clinical characteristics.
The complexity and recurrent features of CRE pose a threat to affected patients worldwide and
frequently lead to poorer outcomes such as longer hospital stays, increased mortality, and
higher hospitalization cost . It is important for us to explore the characteristics of prevalence
and clinical distribution of CRE. Then we can take effective prevention and control measures to
avoid the outbreak of CRE in hospitals. Therefore we devised this study to see the CRE
prevalence in our hospital and to see their clinical characteristics.

Objective

1. Find the prevalence of CRE in a tertiary care hospital

2. Find the sensitivity pattern of CRE in our hospital patients
3. Find the clinical characteristics of CRE patients in our hospital

Operational Definitions

Carbapenum Resistant Enterobacteriacie

Germs of class enetrobacteriacie that are resistant to carabapenum imepenum and/or carabapenum on
culture and sensitivity test. Isolates showing inhibition zone size (Meropenem and/or Imipenem
<21mm) were identified as carbapenem resistant strains.

CRE Patient

Patient whose blood culture will grow CRE

Invasive lines

Peripheral and central catheters and any other medical device which are in direct contact with blood
stream of patient.

Susceptibility of bacteria

Sensitivities will be determined by microbiology lab accrording to Clinical & Laboratory

Standards Institute guidelines. This will be done by agar impregnated with various types of
antibiotics onto the bacterial culture. The bacteria are allowed to incubate for a five days, and
then the plate is examined to see whether the bacterial growth is inhibited (or not) by the
antibiotics on each disk. Sensitivities will be labeled into 3 categories
1. Sensitive if bacterial isolate produce sufficient zone of inhibition according to CLSI
criteria
2. resistant if bacterial isolate did not produce suffiecient zone of inhibition according to
CLSI criteria
3. Indeterminate if bacterial isolate produce zone inhibition that is does not fall into
category of sensitive or resistant according to CLSI criteria
Primary team

Medicine department team comprising of Consultant and resident who is responsible for care
of an inpatient
Material and methods
Study design

Descriptive cross sectional study

Setting

Aga khan university hospital, Department of Medicine.

Duration of study: 6 month after approval of synopsis.

Sample size: The sample size for frequency in a population is calculated by open EPI calculator, and
the confidence level was set at 95% and prevalence at 6% as given in previous studies the
calculated sample size was 245.

Sample Technique:

Simple Random Sampling

Selection criteria:

Inclusion criteria

1. Patient giving informed consent

2. Pateint who have clinical sign and symptom of bacterial infection and whom blood culture
have been sent by primary team.

Exclusion Criteria

1. Patient who will not consent

2. Patient who is already a known case of CRE

Data collection procedure

All patients whose meet the inclusion criteria will be approached. Their blood culture reports will be
retrieved from microbiology laboratory. Their bacterial identification and its susceptibility will be
noted. Patient clinical presentation clinical diagnosis will be noted from their charts. All invasive lines
and catheter placement if any, and exposure to ventilator will be noted. Their recent previous
hospitalization will be noted. And their clinical outcome wheather patient is discharged or patient
expired will be noted.

Data analysis procedure:

Data will be collected on given performa and will be double enetered on SPSS v16. Prevelance of
CRE of will be calculated for individual species. Frequency of sensitivities of isolates will be
calculated. Frequency of clinical parameters of CRE patient which include clinical outcome, and
invasive lines, previous hospitalization and exposure to ventilator will be calculated. P values and
confidence interval will also be calculated for prevalence and clinical parameters.
References

1. Diekema DJ, Richter SS, Heilmann KP, Dohrn CL, Riahi F, Tendolkar S, et al. Continued emergence
of USA300 methicillin-resistant Staphylococcus aureus in the United States: results from a
nationwide surveillance study. Infect Control Hosp Epidemiol 2014;35:28592
2. Wauters G, Vaneechoutte M Approach to the identification of aerobic Gram-negative bacteria
In: Versalovic J, Carroll KC, Funke G, Jorgensen JH, Landry ML, Warnock DW, editors. Manual of
Clinical Microbiology. Washington, DC: ASM press; 2011. pp 539548.
3. Paterson DL Resistance in gram-negative bacteria: Enterobacteriaceae. Am J Infect
Control. 2006; 34: S20S28 16813978
4. Pfeifer Y, Cullik A, Witte W Resistant to cephalosporins and carbapenems in Gram-
negative bacterial pathogens. Int J Med Microbiol. 2010; 300: 371379
doi: 10.1016/j.ijmm.2010.04.00520537585
5. Poirel L, Pitout JD, Nordmann P Carbapenemases: molecular diversity and clinical
consequences. Future Microbiol. 2007; 2: 501502 17927473

6. Xu y, Gu B, Huang M. Epidemiology of carbapenem resistant Enterobacteriaceae (CRE)

during 2000-2012 in Asia. JTD 2015 3(7): 205-78
7. Ahmed R, Kumar M. Frequency of Class B Carbapenemases (MbL) in enterobacteriacae.
JPMA 2014, 64: 519
Data Collecting Instrument

Consent given: yes no

MR no:_____________________

AGE:______________________ Gender:______________________

Previous hospitalization for last 3 months: yes no

Invasive lines: yes no

If yes than specify____________________________

Exposure to ventilator:yes No

Bacterial Culture: Positive Negative

Bacterial identification:___________________________

Sensitivities of bacteria isolated:

_________________________________________________

_________________________________________________

_________________________________________________

_________________________________________________

_________________________________________________

_________________________________________________

_________________________________________________

Clinical outcome: Discharged Expired

Clinical diagnosis:_________________________________________