-lactamase
producing Klebsiella pneumoniae, ciprofloxacin-resistant
Salmonella enteric serovar Typhi, vancomycin-intermediate
staphylococci, fluoro-quinolone-resistant Salmonella enteric
serovar Paratyphi A, and ceftazidime-cefepime and ciprofloxacin
resistant Pseudomonas aeruginosa and Acinetobacter baumanni
[4]. Prevalence of Metallo-beta-lactamase producing organisms ranges
from 7-65% in India [4]. Sale of antibiotics in India is on the rise
with 40-60% increase observed over last five years [5]. Studies
conducted in Delhi and Vellore have shown high consumption of
fluoroquinolones [4]. The rising resistance has lead to longer hospital
stay, increased health care cost, increased antibiotic-related adverse
effects, and overall high morbidity and mortality. Some important
factors responsible for the rising antibiotic resistance in India are
indiscriminate use of antibiotics, over-the-counter availability of
antibiotics, laxity of regulatory bodies in approval of antibiotics,
lack of public awareness about antibiotic resistance, injudicious use in
veterinary practice, overburdened health infrastructure, and inequity in
healthcare [6].
The resistance has also been noted for other
infections like HIV, tuberculosis and malaria. As per WHO, there were
about 480 000 new cases of multidrug-resistant tuberculosis (MDR-TB) in
2013 [7]. The percentage of previously treated tuberculosis cases with
MDR-TB in India is 12-30%. Of late, extensively drug-resistant
tuberculosis (XDR-TB), and resistance to artemisinin-based combination
therapy (ACT) for malaria is also being noticed.
Efforts to Curtail Antimicrobial Resistance
A global strategy on containment of antimicrobial
resistance was introduced by the WHO in 2001 [2]. World Health Assembly
in 2005 also called for rationale use of antimicrobial agents [2].
Despite this, there was little progress on interventions for
antimicrobial resistance. Causes for the slow progress were cited as:
paucity of surveillance data on antimicrobial resistance; difficult to
regularly update diagnostic and treatment guidelines; lack of access to
rapid diagnostic facilities; lack of access to quality assured medicines
at affordable prices; poor provider knowledge; insufficient training and
supervision of health personnel; and perverse economic incentives.
Efforts were continued to tackle these obstacles in a limited manner.
Antimicrobial resistance was declared as the theme for World Health Day
2011, and a policy package released by the WHO to curtail the rising
resistance of antimicrobials (Box 1).
Box 1 WHO Policy
Package to Combat Antimicrobial Resistance
|
Commit to a comprehensive, financed
national plan with accountability and civil society engagement
Strengthen surveillance and laboratory
capacity
Ensure uninterrupted access to essential
medicines of assured quality
Regulate and promote rational use of
medicines, including in animal husbandry, and ensure proper
patient care· Enhance infection prevention and control
Foster innovations and research and
development for new tools.
|
In the United States of America, CDC guidelines on
management of multidrug- resistant organisms in health care settings
were released in 2006 [1]. In 2009, "Get smart for health care campaign"
was launched for improving the use of antimicrobials [1]. Further in
2013, the need to improve antimicrobial use was highlighted as one of
the key strategies to address the problem [1]. CDC in 2014 recommended
that all acute care hospitals should implement antimicrobial stewardship
program (ASP) to curtail the menace of antimicrobial resistance [1].
Antimicrobial Stewardship Program
Antimicrobial stewardship program (ASP) was formally
defined in 2007 by the Infectious Diseases Society of America as "a
cluster of interventions targeted towards the improvement and monitoring
of appropriate antimicrobial use by selecting the most optimal drug
regimen including the type of drug used, the dose, the duration of
therapy and the route of administration" [8].
Nathwani and Sneddon [9] have described a 30% rule on
antimicrobial prescription which states that 30% of all hospitalized
inpatients at any given time receive antimicrobials; over 30% of
antibiotics are prescribed inappropriately in the community; up to 30%
of surgical prophylaxis is inappropriate; and 30% of hospital pharmacy
costs are due to antimicrobial use. Looking at these figures, it is
essential that all hospitals should build up and implement ASP.
Need of ASP for Pediatric Age Group
Consumption of antibiotics is very high in pediatric
population. More than 60% of child patients receive at least one
antibiotic during their hospitalization; and more than 90% children
receive antimicrobials if they are undergoing surgery, having central
venous catheter, having prolonged ventilation, or are in the hospital
for >14 days [10]. Repeated antimicrobial use is most common in children
being treated for cancers, those having undergone transplants, and those
with immunosuppressive conditions like cystic fibrosis. Increased or
repeated use of antibiotics is often associated with adverse drug
events, especially due to dosing errors. Antimicrobial-associated
diarrhea caused by C. difficile infection has increased over the
last few years [11]. Neonates are especially vulnerable since they
receive broad spectrum antimicrobials much more frequently than older
children. Moreover, they are more prone to early upgradation of
antimicrobials due to high risk of morbidity and mortality. Neonates
also have maximum risk of antimicrobial associated severe adverse
effects, including necrotizing enterocolitis, invasive candidiasis,
increased hospital stay, and bacterial resistance. The risk of
necrotizing enterocolitis (NEC) increases by 4% with each added day of
hospitalization after 5 days [12]. Invasive candidiasis in neonates on
broad spectrum antimicrobials has shown an increase from 2.4% to 20.4%
[12].
With the recognition of the various challenges noted
with antibiotic use in pediatric and neonatal population, Pediatric
Infectious Disease Society (PIDS) in 2010 formed the Pediatric Committee
of Antimicrobial Stewardship with the mission of advancing pediatric
antimicrobial stewardship in various clinical settings, promoting
research, and developing antimicrobial stewardship educational programs
[13]. The American Academy of Pediatrics also recommends implementation
of ASP [13].
Standard guidelines on what to do and what not to do
have been developed by the WHO [14] to minimize selection of resistant
organisms, and maximize better outcomes. These are reproduced in
Box 2 and 3.
Box 2 What Needs
to be Done? |
Appropriate empirical antimicrobial therapy, with right dose,
for right duration and at right time.
Delayed therapy or modifying the initial
antimicrobial therapy does not improve the outcome.
Multidrug-resistance organism predisposes
for inappropriate therapy.
Early and accurate identification of the
pathogen and susceptibility.
Combination or monotherapy chosen on the
basis of the pathogen identified.
De-escalation of initial broad spectrum
therapy after definitive diagnosis (generally based on
microbiology reports).
|
Box 3 What Should Not be Done?
|
Treat non-infectious or nonbacterial syndrome
Treat colonization or contamination
Treat longer than necessary
Fail to make adjustment in a timely manner
Prescribe antibiotic with spectrum of
activity not indicated
|
Antimicrobial stewardship program should be developed
so as to get the best clinical outcome for the treatment or prevention
of infection with minimal toxicity to the patient and minimal impact on
resistance and other ecological adverse events. The main goals include:
Improve patient outcome: improve infection cure
rate, reduce surgical infection rate, reduce mortality and morbidity;
Improve patient safety: reduce antimicrobial
consumption without increasing mortality or infection related
readmissions; reduce C. difficile colonization or infection by
controlling the use of higher antimicrobial;
Reduce resistance: restrict relevant agents; and
Reduce health care costs.
Assessing the success
Successfull implementation of antimicrobial
stewardship program (ASP) can be assessed based on antimicrobial
consumption in terms of daily dose, cost and days of treatment,
antimicrobial adverse events, resistance patterns, intervention and
monitoring. Clinical outcome measurements are assessed based on cure
versus failure, (both clinically, and microbiologic), superinfection,
and reinfection [1].
Implementing Antimicrobial Stewardship
The first step is to have a policy on optimal
antimicrobial use to ensure documentation of doses, duration, and
indications for antibiotics; and developing facility specific treatment
recommendations in the health facility [1]. Other interventions for
antimicrobial stewardship include the following:
Designing and executing policies on
antimicrobial "time out" which means there should be a reassessment
of the need and choice of the antibiotics started empirically at the
time of admission. This is usually done after 48 hours once more
clinical and laboratory data is available.
Adhering to the dictum of "Prior authorization"
that requires the availability of an antibiotic expert who can
review and decide the need of antibiotics before the therapy is
initiated.
Prospective audit and feedback: This
involves an external review by an antibiotic expert regarding
antibiotic therapy in very sick patients where broad spectrum
antibiotics are given. An audit is done by a team separate from the
treating team.
Regular changes from intravenous to oral
treatment so that patients need less intravenous access.
Dose adjustments in cases with organ
dysfunction and dose optimization like those with therapeutic drug
monitoring, higher doses for achieving CNS penetration, doses for
highly resistant bacteria.
Automatic alerts to avoid unnecessary
duplication of drugs which have overlapping spectra.
Time sensitive automatic stop orders for
certain prescriptions like antibiotics given for surgical
prophylaxis.
Capacity building and sensitization of all the
stake-holders is an integral pre-requisite of this program. The
multidisciplinary team members comprise of an infectious disease
physician, clinical pharmacist, microbiologist, infection preventionist,
hospital epidemiologist, infor-mation system specialist, quality
improvement staff, laboratory staff and nurses.
The eight key steps for implementing an ASP have been
outlined and explained in an earlier publication [9].
Success Stories
At present, antimicrobial stewardship programs are
being implemented in various pediatric clinical fields including
neonatology, community-acquired pneumonia, inpatients, and longterm-care
patients. Majority of current programs have started after 2007. Though
there are lots of barriers in implementation of stewardship policies as
discussed previously, lately hospitals have started producing data with
a successful outcome. Newland, et al. [15] reported that 38% and
36% of Freestanding Childrens Hospitals in US have an ASP in place in
2014; or in the process of implementation, respectively.
In a major study done in pediatric population with
community-acquired pneumonia [16], a significant change was noted in the
pattern of antibiotic prescription after the release of stewardship
guidelines. The use of ampicillin increased from 2% to 44% whereas
prescrip-tions of ceftriaxone decreased from 56% to 28%. The change was
followed for one year and was found to remain constant. In another study
by Bizarro, et al. [12], conducted in NICU setting, a significant
decrease in the incidence of central line associated blood stream
infection (from 8.4 to 1.28 per 1000 central lines) was noted after an
educational intervention as a part of antibiotic stewardship program.
Current Status in India
With the available data, the situation is not too
promising. The first global survey conducted by Howard, et al.
[17] reported 53% coverage in Asia. According to another survey
conducted on antimicrobial programs in India by Sureshkumar, et al.
[18], more than 50% hospitals in India do not have an ASP. The common
barriers reported include: lack of funding and human resource, lack of
infor-mation technology, higher priorities, lack of awareness of
administration, and prescriber opposition [7].
The first major step towards curtailing the rising
antibiotic resistance was taken in 2009 with the launch of Global
Antibiotic Resistance Partnership [19]. It was started to create a
platform for developing actionable policy proposals on antibiotic
resistance in low- and middle-income countries. India, Kenya, South
Africa and Vietnam in 2011, in a multidisciplinary approach, made
multiple recommendations so as to implement it at a priority stage and
second-tier stage. Priority stage recommendations included
surveillance on antibiotic resistance and use, increasing use of
diagnostic tests, strengthening infection control committee, in-service
training for physicians, continuing education for pharmacist,
distributing Standard Treatment Guidelines (STGs) to the hospital staff,
and regulate veterinary use. The second tier recommendations were
to regulate over the counter sale, prioritize funding for research,
issue guidelines and checklists, and study impact of seasonal influenza
vaccine on pregnant females.
The National Policy for Containment of Antimicrobial
Resistance [20] has created a task force to review the current situation
regarding manufacture, use and misuse of antibiotics in the country; to
recommend the design for creation of a national surveillance system for
antibiotic resistance; to initiate studies documenting prescriptions
patterns and establish a monitoring system for the same; to enforce and
enhance regulatory provisions for use of antibiotics in human and
veterinary and industrial use; to recommend specific intervention
measures such as rational use of antibiotics and antibiotic policies in
hospitals; and to review the diagnostic methods pertaining to
antimicrobial resistance monitoring.
Chennai Declaration
A joint meeting of Medical Societies in India was
held in 2012 at the 2nd Annual Conference of the Clinical Infectious
Disease Society (CIDSCON) in Chennai to develop a road map to tackle the
challenge of antimicrobial resistance [21]. Chennai Declaration was a
major step towards antibiotic stewardship policy in India. The aim was
to initiate efforts to formulate a policy to control the rising trend of
antimicrobial resistance with following objectives:
To regulate over-the-counter sale of
antibiotics;
In-hospital antibiotic usage monitoring;
Audit and feedback;
Initiate measures to step up microbiology
laboratory facilities; and
National antimicrobial resistance surveillance
system.
The measurable goals of the Policy are reproduced in
Box 4.
Box 4 Goals of the Chennai Declaration [21] |
First year
Formulation of a national policy to combat
antimicrobial resistance
efforts to implement major components of
the policy
60% compliance rates to major
recommendations by stakeholders
Second year
Compliance rate 70%
efforts to implement minor components of
policy
India achieving the status of a country
with a functioning antibiotic policy despite limitations
Next five years
>90% compliance to major components of the
policy
India achieving the status of a country
with a functioning antibiotic policy comparable to countries
with high quality infection control and antibiotic policy
compliance rates
|
Efforts by Indian Council of Medical Research and
Indian Academy of Pediatrics
In 2012, Indian Council of Medical Research (ICMR)
started a program on antibiotic stewardship, prevention of infection and
control [22]. This program brings together from the disciplines of
clinical pharmacology, microbiology, infectious disease, nursing,
intensive care, hospital infection control and surgical specialties; and
is delivered through a training workshop involving participation of 20
centers. The workshop is aimed to train the participants with skills and
understanding required for infection prevention and control practice;
knowledge and skills required for development and implementation of
antimicrobial policy guidelines for rational use of antibiotics to curb
antibiotic resistance; and ability to plan and conduct research projects
in antibiotic policy, infection preventi
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