Antibiotic Usage and Microbial Resistance: Indian Scenario

Dr. Srinivas Murki , Consultant Neonatologist ,Fernandez Hospital, Hyderabad, Andhra Pradesh-503001, India

Email: srinivas_murki2001@yahoo.com

Abstract

Most common organisms isolated in neonatal sepsis in India are Klebsiella, E coli

and Staphylococcus aureus. Inappropriate use of antibiotics has resulted in the

emergence of extended spectrum beta-lactamase producing Gram-negative

bacteria, methicillin-resistant Staphylococcus aureaus, vancomycin-resistant

enterococci, carbepenem-resistant Pseudomonas/ Acinetobacter and other

multidrug-resistant bacteria. This ever-increasing problem can be encountered

with better infection control measures, antibiotic stewardship and formulation of

local and national antibiotic guidelines.

Introduction

Antibiotic misuse and microbial resistance is an ever increasing problem in the

neonatal intensive care units (NICU) of our country. Over the years,

undisciplined use of broad spectrum antibiotics, prolonged courses of antibiotic

therapy, overdependence on C-reactive protein for initiating, changing and

stopping antibiotics and absence of culture facilities have resulted in increased

incidence of extended-spectrum beta-lactamase (ESBL), methicillin-resistant

Staphylococci aureus (MRSA), vancomycin-resistant Enterococci, carbepenem-

resistant Pseudomonas/ Acinetobacter and multi-drug-resistant bacteria.1

Neonates with resistant infections are more likely to require prolonged

hospitalization and are more likely to die.1

Microbial resistance

It is now well known that antibiotic use selects for antibiotic resistant bacteria.

When penicillin was discovered in 1940, all strains of Staphylococci were

sensitive to benzyl penicillin. Very soon widespread use of penicillin resulted in

disease causing strains of Staphylococci that were resistant to penicillin. Broad

spectrum antibiotics are potent selectors of antibiotic resistance.2,3 Ampicillin and

third generation cephalosporins (cefotaxime, ceftriazone and ceftizidime) select

for Gram-negative bacilli that produce extended spectrum beta-lactamases,

which render the bacteria resistant to many antibiotics not just beta lactams.

E.coli and Klebsiella acquire antibiotic resistance via the plasmid-mediated

extended spectrum beta-lactamase (ESBL) production. Owing to the presence of

other resistance conferring genes on these transferable plasmids, such

organisms are also resistant to other drugs, including aminoglycoside

antibiotics.4 The carbepenams such as imipenem and meropenem are used in

the laboratory to induce expression of beta lactamases in the organisms where

these genes are repressed.5 Therefore extensive use of carbepenems will select

for beta-lactamases producing and imipenem/meropenem-resistant organisms.

Resistance to antibiotics may also occur due to chromosomal mutations, by the

capture of integron of antibiotic resistance genes that are part of discrete mobile

cassettes and possibly also by interspecies genetic transformation. Excessive

and extended use of broad spectrum antibiotics also increases the risk of fungal

infections in neonates.6 Emergence and spread of microbial resistance is more

common in the neonatal intensive care units because of relative immuno-

compromised status of neonates, frequent need of invasive lines and skin-

breaking procedures and high frequency of staff-to-patient contact. In addition

poor compliance to hand-washing routines, use of broad spectrum antibiotics and

non-availability of disposables can increase the emergence and spread of

microbial resistance.

Microbes and Resistance pattern

From the National Neonatal Perinatal Database (NNPD) 2000, the incidence of

neonatal sepsis has been reported to be 38 per 1000 live births in tertiary care

institutions.7 Meningitis was diagnosed in 0.5 per 1000 live births. Among inborn

neonates, Klebsiella was the most frequently isolated pathogen (31.2%), followed

by Staphylococcus aureus (17.5%), E.Coli (10.5%) and Pseudomonas (6.8%).

Among extramural neonates admitted in tertiary care hospitals, Klebsiella was

the commonest organism (36.4%), followed by Staphylococcus aureus (14.3%)

and Pseudomonas (13.2%). Most of the Klebsiella isolates were resistant to

ampicillin (97.2%), gentamicin (88.6%) and cefotaxime (60.6%). However the

organism was sensitive to amikacin (64.4%) and ciprofloxacin (73.3%). Similarly

E.Coli isolates were resistant to ampicillin (86.3%), gentamicin (60%) and

cefotaxime (52.3%). Ninety percent of the Staphylococcus isolates were

resistant to penicillin and 10% to vancomycin.

In a study from North India, among the 75 cases with Gram-negative

septicemia the common isolates were Klebsiella, E.Coli, Acinetobacter, Proteus

and Enterobacter species.1 Overall 61.5% of Gram-negative isolates and 52.2%

of Klebsiella isolates were ESBL producers. Most of the isolates were resistant

to gentamicin (57.2%) and cefotaxmine (68.3%). However majority were

sensitive to amikacin (55.6%), piperacillin-tazobactum (92.1%) and meropenem

(96.8%). .

In year 2008 and 2009, the incidence of neonatal sepsis in our unit (a

tertiary care maternal hospital with only inborn admissions) was 16.5 per 1000

live births.8 Of the 139 isolates 56% were Gram-negative and 40% were Gram-

positive. Common Gram-negative isolates were Klebsiella (30%), Pseudomonas

(9%), E.coli (8%) and Enterobacter species. Coagulase-negative

Staphylococcus (19%) and Staphylococcus aureus (9%) were the common

Gram-positive isolates. Half of the Klebsiella isolates was resistant to

cephalosporin, 36% to amikacin, 24% to pipericillin-tazobactum and 17% to

meropenem. Three-fourth of the Staphylococcus aureus isolates were resistant

to methicillin and none to vancomycin.

The SENTRY surveillance programme reported the frequency of

Klebsiella pneumoniae to be 37% in Latin America as compared to 7% in United

States.9 Frequency of ESBL producing bacteria in the Asia-Pacific region is

reported as 5% from Japan, 21.7% from Taiwan, 31% from Philippines, and 38%

from Malaysia/Singapore.10 From the available data, the incidence of resistant

bacteria in our country is higher than that reported from neighboring countries

and also from resource rich nations.

Steps to reduce microbial resistance to antibiotics

1. Infection control measures: Continuous availability of water, ventilation,

cleanliness, hand washing, hand rubs, availability of disposables, effective

management of diapers, appropriate disposal of medical waste and adequate

staff-patient ratio can decrease the spread of antimicrobial resistant bacteria.

Improved hand washing has consistently been shown to reduce the incidence

of nosocomial infections. Early introduction of enteral feeds, preferably

breast milk, allows intravenous access to be removed quicker, reducing the

risk of sepsis.6

2. Appropriate use of antibiotics

• Prophylactic antibiotics should not be stated in conditions like severe

asphyxia, neonatal jaundice, prematurity, caesarean delivery and

exchange transfusion.

• Bacterial colonization do not need antibiotic therapy. Routine culture of

tips of endotracheal tubes, central lines and urinary catheter is not

helpful.

• Without exception blood culture should be obtained before starting

antibiotics. Laboratories should use culture techniques that are highly

sensitive such as BacTec® and BacTAlert®. With use of specific

techniques sample volume as less as 0.2ml has been observed to be

sufficient to isolate the organisms from neonate’s blood. 11

• Positive C- reactive protein (CRP), elevated micro-ESR and abnormal

blood counts are only markers of inflammation and are not specific for

infections. In a well baby with negative cultures, persisting positive

CRP is not a marker of infection.

• If the blood culture is sterile after 48-72 h of incubation, it is almost

always safe and appropriate to stop antibiotics. Recommended

durations of antibiotics are 5 days for pneumonia, 10 days for culture-

positive sepsis and 14-21 days for meningitis.

3. Restrict use of broad spectrum antibiotics

• The best empiric antibiotic for neonate is a penicillin or semisynthetic

penicillin (crystalline penicillin, cloxacillin, ticarcillin-clavulanic acid, and

pipericillin-tazobactum) together with an aminoglycoside (gentamicin,

netilmicin, amikacin, tobramicin).12 The choice of penicillin will depend

on the organism causing sepsis (ampicillin for Listeria, group B

streptococcus and cloxacillin for Staphylococcal aureus). In units were

Gram-negatives’ resistance to ampicillin or cephalosporin is high, the

appropriate antibiotic should be ticarcillin-clavulanic acid or pipericillin-

tazobactum. Empiric Vancomycin is not necessary unless MRSA is

common. Choice of aminoglycoside should be based on the local data.

If colonizing and infecting bacteria in a neonatal unit is resistant to

gentamicin, it may become sensitive again, after a prolonged period of

using another aminoglycoside such as netilmicin. In a telephonic

survey by the author from 25 neonatal units in the country, in 23 the

empiric antibiotic is either a cephalosporin or amoxicillin-clavulanic acid

or a quinolone along with an aminoglycoside. Only 2 units are using

either a single aminoglycoside or penicillin as an empiric antibiotic.

Most of the neonates referred to the neonatal units are already on

empiric broad-spectrum antibiotics.

• Use of cephalosporins, quinolones and carbapenems should be

restricted to microbes resistant to aminoglycosides or penicillins. In a

study done by Lee J, et al. on pediatric patients, the incidence of ESBL

producing Gram-negative bacteria decreased from 39.8% to 22.3%

with cephalosporin restriction.13 Similarly in our experience,

cephalosporin restriction reduces the incidence of ESBL producing

bacteria from 46.8% to 19.5%.8 In a study from Brazil, neonatal health

care associated infections were reduced from 32% to 11% after

education and restriction of the use of cephalosporins.14

• There should be national and local antibiotic policies to restrict the use

of broad spectrum antibiotics. Blood culture facilities should be

available near or at all neonatal service centers.

4. Rotation of antibiotics

• Using antibiotics in rotation has been effective in some settings in

reducing resistance. In a systematic review on antibiotic cycling

(mostly from surgical ICU’s, two from NICU and one from pediatric

hospital) reduced microbial resistance to gentamicin was observed.15

However the optimal cycle duration, when to start cycling and the

antibiotic spectrum needed to cycle are questions yet to be answered

in well designed prospective studies.

Conclusions

Antimicrobial resistance has emerged as a major public health issue all over the

world, especially in developing countries like India. Current evidence suggests

that controlling the use of broad spectrum antibiotics and implementation of

infection control measures can result in decreased microbial resistance.

Ensuring blood culture facilities, minimizing the use of cephalosporins,

quinolones and carbepenems, reducing the duration of antibiotic therapy and

formulation of national and local antibiotic policies is the need of the hour to

prevent the extinction of available antibiotics.

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