Present knowledge and relevant bibliography including full titles of
articles relating to the project.
The discovery and development of antimicrobials has been considered as one of the
most important advances in the history of modern medicine — reducing the
suffering from disease and saving millions of lives. However, these effective
therapeutic agents are losing their efficacy due to the emergence of antimicrobial
resistance.
At the close of the twentieth century, more than 250 antibacterial agents are in the
use throughout the world, with such as abundance at the prescriber’s disposal it
might be imagined that bacterial infection has been a minor problem and that
bacterial drug resistance would be usable to keep pace, with resources available to
counteract it. Nothing could be further from the truth. Bacteria appear to possess a
limitless ingenuity in avoiding the effects of antimicrobial agents as well as finding
new way to invade the compromised host (Greenwood, 1998).
Infections caused by multi-drug resistant organisms are associated not only with
higher morbidity and mortality, but also with a prolonged and more expensive
treatment as well. Multi-drug resistant organisms are also an epidemiological
concern as they may spread locally, regionally or globally through individual
contacts, poor sanitation, travel, or the food chain.This not only threatens the
effectiveness of antimicrobials, but also risks jeopardising global health security.
Hence, World Health Organisation (WHO) has declared antimicrobial resistance as
the theme for the World Health Day, 2011. (World Health Day of 2011 – “Antibiotic
resistance: No action today, no cure tomorrow”).
Antimicrobial resistance (AMR) is resistance of a microorganism to an antimicrobial
medicine to which it was previously sensitive. Infections caused by resistant
microorganisms often fail to respond to conventional treatment, resulting in
prolonged illness and greater risk of death. Resistant organisms (they include
bacteria, viruses and some parasites) are able to withstand attack by antimicrobial
medicines, such as antibiotics, antivirals, and antimalarials, so that standard
treatments become ineffective and infections persist and may spread to others. AMR
is a consequence of the use, particularly the misuse, of antimicrobial medicines and
develops when a microorganism mutates or acquires a resistance gene. (WHO Fact
sheet No. 194, Antimicrobial resistance February 2011)
Moreover, mutations confessing resistance to one antibiotic can, at a stroke, render a
whole drug family impotent. Bacteria resistant to one Sulphonamide or one
tetracycline are usually resistant to all Sulphonamides, or all tetraclines; Methicillinresistant staphylococci are resistant to all β Lactam antibiotic. Even worse, bacteria
can assemble resistance genes for unselected clones of agents on plasmids that can
be readily transmitted between bacterial species or sometime genre (Kunin, 1993).
Thus inappropriate and irrational use of antimicrobial medicines provides
favourable conditions for resistant microorganisms to emerge, spread and persist.
AMR jeopardizes health-care gains to society & the achievements of modern
medicine, and threatens a return to the pre-antibiotic era. (World Health Day, 2011:
policy briefs)
The genesis of AMR is multifactorial. The underlying factors that drive AMR
include:
a) Inadequate national commitment to a comprehensive and coordinated
response,
ill-defined
accountability
and
insufficient
engagement
of
communities;
b) Weak or absent surveillance and monitoring systems;
c) Inadequate systems to ensure quality and uninterrupted supply of medicines
d) Inappropriate and irrational use of medicines, including in animal husbandry:
e) Poor infection prevention and control practices;
f) Depleted arsenals of diagnostics, medicines and vaccines as well as
insufficient research and development on new products.
(WHO Fact sheet No. 194, Antimicrobial resistance February 2011)
The ability of common bacteria to acquire novel mechanisms of resistance to widely
used antimicrobial therapies has been noted for many years. Each decade, the
number of bacteria that exhibit resistance to both single and multiple antimicrobial
agents has steadily risen (Felmingham, 2002 a) Antimicrobial resistance has been
observed in gram-negative and gram-positive bacteria isolated from patients with
community-acquired and nosocomial infections. This problem is particularly
prevalent among the most common etiologic pathogens associated with communityacquired respiratory tract infections (RTIs), including Streptococcus pneumoniae,
Haemophilus influenzae, Moraxella catarrhalis, and, to a lesser degree, Streptococcus
pyogenes, Staphylococcus aurius, Aerobic gram negative bacteria (Felmingham, 2002 b).
The morbidity and mortality associated with the RTIs caused by these pathogens
pose a significant and growing challenge to clinical practitioners.
Streptococcus pneumoniae is the most common causative pathogen of communityacquired respiratory tract infections. In vitro evidence indicates that S. pneumoniae is
increasingly resistant to commonly prescribed antimicrobial agents including the
macrolides. Increasing rates of resistance among S. pneumoniae present numerous
clinical challenges, and require carefully selected treatment strategies to preserve
antibacterial efficacy (Klugman, 2007).
Community-acquired pneumonia (CAP) is associated with high mortality. About 5.6
million cases of CAP are reported in the United States each year, with an associated
mortality rate of ∼14% (Bosker, 2002; Gleason 2002). The majority of cases of
bacterial CAP are caused by S. pneumoniae, although “atypical pathogens”
(e.g., Mycoplasma pneumoniae, Legionella species, and Chlamydia pneumoniae) have been
implicated in up to 40% of cases of CAP requiring hospitalization (Gleason 2002).
These atypical agents often occur as copathogens in cases of “mixed-infection” CAP,
which is associated with mortality rate as high as 25%.
All these information as stated above are largly of US and Europe, Indian data
however are grossly lacking.
The causative pathogens responsible for the majority of these infections are
developing resistance to our current antimicrobial armamentarium; thus, an urgent
need exists for new agents as well as for thorough surveillance programs designed to
track resistance patterns among respiratory pathogens, both at the state, regional, as
well as at the national level, and studies to assess the impact of degrees of resistance
on the efficacy of antimicrobial therapy (Destache, 2002; Tang et al., 2002).
There is a growing need to optimize the use of old and new antibiotics to treat
serious as well as less serious infections. The issue of how to use pharmacokinetic
and pharmacodynamic knowledge to conserve antibiotics for the future was a topic
of growing concern.
The optimization of dosing regimens is accomplished by
choosing the dose and schedule that results in the antimicrobial exposure that will
achieve the microbiological and clinical outcome desired while simultaneously
suppressing emergence of resistance. (Mouton et al., 2011).
It remains unknown why some strains and genes achieve wide spread whereas
others, equally resistant, fail to do so. There is no simple cure for resistance but the
best opportunities for control lie in lesser and better use of antibiotics backed by
swifter and more accurate microbiology; in developing new antibiotics; and in
protecting old ones from resistance determinants.
All this must be supported by good local knowledge of the epidemiology of
infections and resistance and of the likelihood of particular antibiotics to select
resistance (Livermore, 2000).
Several major international monitoring programs have recently been initiated; their
findings have revealed disturbing patterns of antimicrobial resistance among
respiratory tract pathogens (Tang et al., 2002; Kelly, 2001; Selman, 2000; Thornsberry,
1997, 1999 a, 1999 b). There is widespread variability in the resistance trends
identified, depending on factors such as the respiratory isolate evaluated, the class of
the antimicrobial agent tested, the geographic region where the specimen was
collected, and various patient characteristics, such as age and site of infection.
The Canadian Bacterial Surveillance Network, a major Canadian surveillance
initiative, started in 1988. In this initiative, 15,677 isolates of S. pneumoniaewere
collected at 181 laboratories throughout Canada and tested according to the National
Committee for Clinical Laboratory Standards protocols.
There has been an increase in resistance among S. pneumoniae to penicillin,
trimethoprim-sulfamethoxazole, macrolides, and fluoroquinolones (Tang et al.,
2002). The incidence of penicillin-resistant S.pneumoniae increased from 0 in 1988 to
7% in 2001, and the incidence of trimethoprim-sulfamethoxazole–resistant S.
pneumoniae increased from 3.7% to 12.0% over this same period. Of greater concern is
the increase in the frequency of S. pneumoniae that are macrolide-resistant. The
Canadian data indicate that the number of erythromycin-resistant S. pneumoniae
isolates increased from 1.2% to 13.1% and the number of clindamycin-resistant
organisms increased from 1.2% to 5.8% over the 13-year tracking effort (Tang et al.,
2002).
The Tracking Resistance in the United States Today (TRUST) study, started in 1996,
is currently the longest-running surveillance program conducted in the United States
to track resistance among respiratory tract pathogens (Kelly, 2001; Selman, 2000;
Thornsberry, 1997, 1999 a, 1999 b). A total of 45,310 respiratory isolates have been
evaluated in numerous laboratories throughout the United States between the years
1996 and 2001. The isolates include 33,499 isolates of S. pneumoniae, 7951 isolates
of H. influenzae, and 3860 isolates of M. catarrhalis.
The TRUST data have demonstrated an increase in high-level penicillin resistance
(MIC of ⩾2 µg/mL) among respiratory strains of S. pneumoniae, beginning as early as
the mid-1990s (Breiman et al., 1994; Doern et al., 1996). During the 1994–1995 RTI
season, the frequency of overall reduced susceptibility to penicillin (MIC of >0.1
µg/mL) was 23.6% and that of high-level resistance was 9.5%. A steady increase in
the frequency of high-level penicillin resistance among pneumococci was noted
during the 1997–1998 through 2000–2001 RTI seasons. During these periods, the
frequency of overall reduced susceptibility to penicillin ranged from 33.1% to 35.6%
and of high-level resistance ranged from 13% to 16.9% (Doern, 2001).
Another growing concern is the increase in the frequency of multidrug-resistant S.
pneumoniae (resistant to ⩾3 antimicrobial classes, most commonly penicillin,
trimethoprim-sulfamethoxazole, and macrolides). The TRUST data show that only
6.2% of S. pneumoniae isolates were multidrug-resistant during the 1998 RTI season,
whereas 13.5% were multidrug-resistant in the 2001 season (Kelly, 2001; Selman,
2000; Thornsberry et al., 2002; Selman et al., 2000).
Data compiled friom the major international surveillance programs, covering more
than a decade show that antimicrobial resistance among bacterial respiratory tract
pathogens is increasing. This may complicate an already significant clinical
challenge in the treatment of CAP and other potentially serious RTIs. When
considered in the light of reports of failure of therapy in patients infected by
organisms with in vitro resistance, the trends in antimicrobial resistance, as shown in
these surveillance programs, suggest that the selection of antimicrobial therapy for
the treatment of RTIs is more complex today than ever before. Furthermore,
changing antimicrobial resistance patterns may continue to narrow—instead of
expand—pharmacotherapeutic options. Surveillance information will aid the
clinician in appropriately targeting treatment in this increasingly difficult health care
arena.
Mechanism of Antimicrobial resistance
The prokaryotic cell is versatile and capable of adapting to the introduction of
antibiotics into the environment. The inherent genetic variation ensures a fair
amount of heterogeneity that ensures survivors in antibiotic charged environments.
Thus survey of bacterial isolates from the pre-antibiotic days show the presence of
resistant organisms, albeit in small numbers (Madeinos, 1997). Population dynamics
would keep this proportion low enough not to infl uence therapeutic outcome.
However, in an antibiotic charged environment a selection pressure builds up
favouring the resistant organisms. This ‘survival of the fi ttest’ principle enunciated
by Charles Darwin (1859) results in a steady rise in MICs. This phenomenon is well
illustrated in the case of Salmonella typhi susceptibility to ciprofloxacin (Wattal May
2000 to Oct 2005). Horizontal transfer of genetic material takes the phenomenon to a
different plane. Once the resistant genes get conveyed by plasmids, transposons or
integrons dissemination is rapid.
These mechanisms can be summarized as follows:
1) Antibiotic inactivating enzymes e.g. β-lactamases, aminoglycoside modifying
enzymes, chloramphenicol acetyl transferase etc.
2) Impaired uptake of antibiotics which can be natural due to cell envelope
characteristics. In the case of acquired resistance changes in porins may
interfere with antibiotic transport.
3) Drug efflux may be the operative mechanism in some cases. Mutations result
in over expressions in some cases.
Modification of the target resulting in less avid binding of the antibiotic is the
mechanism seen commonly in β-lactam resistance in gram positive organisms e.g.
Streptococcus pneumoniae and S. aureus. An extreme example due to ribosomal modifi
cation that makes streptomycin resistant organisms use the antibiotic as a growth
factor.
Development of an alternate metabolic pathway would allow the bacteria to grow in
the presence of the antibiotic. This mechanism is seen in glycopeptide,
aminoglycoside, macrolide, sulpha/trimethoprim resistance amongst others. In
many instances however, more than one mechanism is in operation (Streulens 2003).
Epidemiology
The growing literature on antimicrobial resistance in the post-antibiotic years,
particularly in the recent decades tends to convey the impression that the
phenomenon is recent. A study of the microbial world would impress that
“antibiotics are old-established natural products that have had common, but
changing and manifold, physiological uses throughout evolutionary time” even as
far back as the ‘RNA world’ (Chadwick et al. 1992), which probably was the
forerunner of the present DNA world. The extensive use of antibiotics in medicine
and agriculture has increased the reservoir of resistance genes. It is thus not
surprising that the introduction of a new agent is, practically invariably, followed by
heightened resistance. Legitimately used antibiotic therapy based on sound
evidences is justified, however, the inappropriate use largely exceeds this and
introduces a large amount of antibiotic into the environment (Wise et al. 1998). There
is a wide variation in the prescribing habits in different area based upon
geographical, economic, social-political and market mechanism.
In veterinary medicine antibiotics are used as growth promoters, prophylactics and
therapeutic agents in. It is estimated that this use equals that used in medicine. This
largely uncontrolled field adds to the antibiotic selection pressure. This has resulted
in the breeding of multi-drug rersistent pathogens in hospitals and community as
well as breeding resistant organisms of veterinary importance (Hubert et al. 1991).
These aspects are well highlighted (World Health Organization 2002). Certain areas
in hospitals like ICUs and areas with immunosuppressed and debilitated patients as
well as treatment modalities like topical and prophylactic use of antibiotics are foci
of generation of multidrug resistant (MDR) bacteria. Gradual dissemination to the
community through population interaction spreads the organisms widely (Streulens
2003). Over the years bacterial populations undergo changes in their antibiotic
susceptibility which may be foreseen considering changes in antibiotic prescribing
practices.
The most often inappropriately treated community infection is that of the upper
respiratory tract (URT). Viral URT infections do not need antibiotic therapy but are
not readily distinguishable from those that do, due to lack of readily available cost
effective laboratory tests. The “to be sure” attitude of the treating physician and
(often) patient pressure are other causes of the practice. Once antibiotic treatment
has been started the duration is illdefined. Obviously the shorter the treatment
course the less the antibiotic stress in the environment (Rice 2008).
There is therefore a strong case for initiation and continued surveillance at all levels,
the hospital, city/region, country and supra-national levels. It is only then the
ramifications of problem can be learnt. Such mechanisms are in position in the
industrialized countries but the developing world (including India) is an enigma
(Stewart 1967; World Health Organization 2002).
Surveillance of antimicrobial resistance and use is an essential prerequisite to
monitor the situation, for effective prevention and containment of antimicrobial
resistance and rational antimicrobial use.
Control of antimicrobial resistance
The common methods being focused on are (Carbon et al. 2002),
a) Surveillance of antibiotic use and resistance rates.
b) Optimizing antibiotic use with treatment guidelines.
c) Education of professionals and the public.
d) Prevention with infection control measures and immunization.
e) Industry
involvement,
fi
nancial
resource
mobilization
and
drug
development.
f) Regulatory issues with central prescribing restrictions and advertising
restrictions.
g) Audit with evaluation of interventions, audit of compliance and physician
feed back.
h) International cooperation.
The Indian scenario
The Indian scene is particularly grim due to various factors. Generally, there is little
control on the use of antibiotics. Community awareness of the issues involved in
antibiotic therapy is poor and this is compounded by over-the-counter availability.
Coupled with primitive infection control in hospitals and weak or defi cient
sanitation, the conditions are suited for transmission and acquisition of antibiotic
resistance. The facility with which enteric pathogens spread widely in India
illustrates this point.
Large parts of the country do not have the technical infrastructure to generate
useable data on the ground. Thus, the contribution of infectious diseases is greater in
the impoverished societies of our country.
In the absence of a Central Monitoring Agency the national scene in India with
regard to antimicrobial resistance is not known.
The two probable exceptions are M. tuberculosis and Leishmania donovani.
The former has been studied consistently by the Tuberculosis Research Centre,
Chennai, National Tuberculosis Institute, Bangalore and National JALMA Research
Institute, Agra (Paramasivam 1998). L. donovani has reemerged in a limited
geographic area and the intense interest has documented the evolution of drug
resistance in the pathogen (Jha 2006).
With the advent of oral rehydration therapy infant mortality due to diarrhoeal
diseases has decreased to levels below that due lower respiratory tract infection
(LRTI) which is now the leading cause in this population. The most important
pathogen causing bronchopneumonia is Streptococcus pneumoniae and a syndromic
antibiotic therapy is being used to control the mortality (Lalitha 2008).
This approach would be effective only if the pneumococcus remains sensitive to the
drugs used in the programme. However, the results of a carriage study in North
India
(Jain 2005, 2006) appear reassuring as far as penicillin resistance but alarming as
regards co-trimoxazole resistance – the drug used for syndromic treatment. This is
supported by the study of Goyal et al. (2007). Antibacterial resistance in S.
pneumoniae has now become a global phenomenon, particularly in India’s immediate
neighbourhood (Jae-Hoon Song et al. 2004). Except for a high degree of resistance to
cotrimoxazole, the Indian and Nepalese strains have retained their sensitivity to the
penicillins, macrolides and fluoroquinolones (Lalitha 2008).
Regarding the problem of antimicrobial resistance encountered in India, Dr D
Raghunath from Sir Dorabji Tata Centre for Research in Tropical Diseases,
Innovation Centre, Indian Institute of Science, Bangalore stresses on the steadily
increasing antibiotic resistance and decreasing numbers of newer antibiotics, which
appear to point to a post-antibiotic period during which treatment of infections
would become increasingly difficult (Raghunath, 2008) Raghunath D 2008 Emerging
antibiotic resistance in bacteria with special reference to India; J. Biosci. 33 593–603.
Since the 1980s, β-lactam antibiotics and quinolones have become frequently
prescribed antimicrobial agents, replacing many of the older, less expensive drugs,
such as doxycycline, minocycline, clindamycin, trimethoprim-sulfamethoxazole
(TMP-SMX), and nitrofurantoin. The widespread use of extended-spectrum
penicillins, cephalosporins, and carbapenems has occurred at the same time as the
emergence
of
organisms
resistant
to
these
agents.
Vancomycin-resistant
Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), methicillinresistant Staphylococcus epidermidis (MRSE), and penicillin-resistant Streptococcus
pneumoniae have become important community-acquired and nosocomial pathogens.
The appearance of newly recognized infectious diseases caused by Cyclospora,
Bartonella, and Chlamydia species as well as an increase in the tick-borne diseases,
ehrlichiosis, Lyme borreliosis, and babesiosis has caused renewed interest in many
of the older antimicrobial agents. Most of the older agents can be administered orally
as well as intravenously and are available in generic form, reducing their cost. In
many infectious diseases, administration of these older agents in oral form is as
effective as parenteral therapy, eliminating the need for intravenous administration
and shortening hospital stay (Natalie et al.., 2001).
Dr Karthikeyan Kumarasamy, Department of Microbiology, University of Madras,
Chennai reports gram negative enterobacteria NDM-1 (New Delhi metallo-βlactamase) mostly found among Escherichia coli (one of the most frequent causes of
many common bacterial infections, including cholecystitis, bacteremia etc.) and
Klebsiella pneumonia, (they cause pneumonia; inflammatory illness of the lungs,
urinary tract infections etc.) to be highly resistant to all antibiotics. NDM-1 can be a
worldwide public health problem and needs co-ordinated international surveillance,
according to Dr. Kumarasamy (Kumarasamy, 2010).
In the year 2011, Govt. of India lounged the National Policy for Containment of
Antimicrobial Resistance in India 2011 under the Chairpersonship of Dr. R. K.
Srivastava, Directorate General of Health Services, Ministry of Health & Family
Welfare Govt. of India (42). The task force has been constituted with following terms
of reference,
1) To review the current situation regarding manufacture, use and misuse of
antibiotics in the country.
2) To recommend the design for creation of a national Surveillance System for
Antibiotic Resistance.
3) To initiate studies documenting prescriptions patterns & establish a
Monitoring system for the same.
4) To enforce and enhance regulatory provisions for use of antibiotics in human
& veterinary and industrial use.
5) To recommend specific intervention measures such as rational use of
antibiotics and antibiotic policies in hospitals
6) Diagnostic Methods pertaining to antimicrobial Resistance Monitoring.
Global Antibiotic Resistance Partnership (GARP) - India Working Group, 2011
recommends for,
(i) Reducing the need for antibiotics;
(ii) Lowering resistance-enhancing drug pressure through improved antibiotic
targeting, and
(iii)Eliminating antibiotic use for growth promotion in agriculture.
The highest priority needs to be given to
(i) National surveillance of antibiotic resistance and antibiotic use - better
information to underpin decisions on standard treatment guidelines,
education and other actions, as well as to monitor changes over time;
(ii) Increasing the use of diagnostic tests, which necessitates behavioural changes
and improvements in microbiology laboratory capacity;
(iii)setting up and/or strengthening infection control committees in hospitals;
and
(iv) Restricting the use of antibiotics for non-therapeutic uses in agriculture.
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