Antimicrobial resistance on the rise: Are we running out of drugs?

The world of modern medicine was transformed in 1928 by Sir Alexander Fleming’s accidental discovery of penicillin, introducing the age of antibiotics. Today again the world of medicine teeters on the edge of another change, the post-antibiotic era. Sir Fleming predicted this ominous scenario in his Noble prize acceptance speech in 1945, warning that negligent use of penicillin could change the nature of the microbe and make penicillin ineffective for treatment. Despite these cautionary words and the development of many other antibiotics, antimicrobial resistance (AMR) has emerged as a serious global challenge.

Why is antimicrobial resistance so critical?

Since the discovery of penicillin, the repertoire of antimicrobials has increased substantially to save millions of lives, reduce the disease burden and make surgical procedures safe and accessible. But the emergence and spread of resistance to these antimicrobials has severe consequences as many infectious diseases fail to respond to empiric treatment leading to prolonged illness and even death. The impact of AMR covers all aspects of infectious diseases, from the common cold to dreaded diseases like tuberculosis(TB). AMR has an negative impact on healthcare systems as expensive higher antimicrobials, isolation facilities and extended stay in hospitals lead to spiraling costs for patients.

What is the cause of antimicrobial resistance?

AMR is the result of the “survival of the fittest” pathogens.When faced with antibiotic exposure, bacteria with intrinsic resistance to the antibiotics flourish or susceptible bacteria acquire resistance either by gene mutation or by transfer of genetic material between bacteria.  Antibiotic usage drives this process of selection as evidenced by the fact that multidrug resistant(MDR) strains are associated with hospitals. Sub optimal dosing and inappropriate drug choices further complicates the scenario by exposing bacteria to antibiotics in insufficient doses which enables selection of resistant bacteria. In the community, over the counter sales of antibiotics and over prescription of antibiotics when there is no clinical indication has lead to emergence of resistant bacteria. Antimicrobials used in agriculture and livestock farming further add to this burden.

Challenges in the hospital setting:

In India, over the last few years, widespread dissemination of resistant bacteria have been reported throughout the country. WHO reported an alarming rise in the prevalence of extended spectrum b-lactamases (ESBL) (20-95%) and carbapenemases (0-52%), rendering ineffective the most effective b-lactam antibiotics-3rd generation cephalosporins and carbapenems. With polymyxins being left as the last option for care of critically ill patients, reports of colistin resistant enterobacteriacea from India indicate pathogens have overcome the last resort of clinicians in Intensive care units (ICUs).The incidence of methicillin resistance staphylococcus aureus (MRSA) (30-55% )and vancomycin resistant enterococci (7-14%) is on the rise. On an alarming note, linezolid resistance in enterococcus is now being reported from India.

Fungal infections have risen dramatically in recent years due to the increased number of immunocompromised individuals (post transplant, chemotherapy patients) on prophylactic and empiric antifungal therapy, mainly azoles. Increased resistance to azoles and a shift to non-albicans Candida species which are inherently less susceptible to the azoles, as the predominant pathogens is a recent phenomenon.

Resistance to carbapenems and colistin, the last antibiotics available for use in critical care units, has left very little choice for therapy in patients.The increasing incidence of candida infections, not responding to azoles, are further complicating the picture.

Challenges in the community setting:

The challenges presented by MDR pathogens for prescribing effective therapy are no longer restricted to the hospital settings but are on the rise from the community setting. The rising incidence of ESBL fecal carriage in healthy individuals, signifies the spread of healthcare associated pathogens in the community. Fluoroquinolones which are often used as empiric treatment for community acquired infections are also no longer as effective, with resistance in E.coli ranging from 4-86%, Shigella spp 11-80% and salmonella 13-45% in India. MRSA has been reported to around 27% in outpatients by Indian Network for Surveillance of Antimicrobial Resistance – INSAR.

With drug resistance so common across the spectrum of bacteria in the community, the family physician can no longer rely on penicillins as the treatment of choice for skin infections or fluroquinolones for typhoid and dysentry.

India had the largest number of cases of tuberculosis(TB) across the world in 2014: 23% of the global 9.6 million people. With over a lakh of of diagnosed multidrug resistant TB and extensive drug resistant TB cases in India, spread of drug resistance may potentially contribute to ongoing TB transmission and hamper efforts to contain the spread of TB.

Presence of AMR is no longer a phenomenon that restricts itself to bacteria, with fungi, parasites and viruses too showing AMR. Malaria continues to be a major health problem for India compounded by emerging resistance in P.falciparum to chloroquine and sulfadoxine-pyrimethamine. Clinical resistance to artemisinin drugs, jeopardizing the most effective class of compounds available for malaria treatment, has been reported along the nearby Thai-Cambodia border. Technological advances in antiretroviral(ARV) therapy ensured that HIV infections no longer mean a death sentence, but resistance to ARV drugs is slowly increasing in India, threatening the continued success of ARV .

Control measures : Need of the hour

With such a phenomenal increase in the prevalence of MDR pathogens, there is a dire need for effective measures to be put in place to curtail the spread of AMR. As very few new antibiotics are coming up through research, the focus of control measures should be on increasing the sustainability of currently available therapeutic drugs.

Improved diagnostic facilities play an important role in encouraging rational prescribing practices.Rapid, sensitive, and specific diagnostic tests are available now to help the clinicians to make crucial decisions in making choice of antimicrobials. Culture and sensitivity tests for bacterial infections will result in better antibiotic conservation and slower development of resistance as appropriate antibiotics can be started at the right time.

The detection of MDR TB has been revolutionized by the advent of Genexpert to assess rifampicin resistance in hours instead of weeks required for culture. For detecting MDRTB, line probe assays to predict resistance to rifampicin, isoniazid, fluoroquinolones, aminoglycosides and ethambutol are available. Prompt initiation of second line therapy is invaluable for treatment and minimizing spread of MDRTB.

Follow-up and monitoring is essential in patients initiated on ARVs to track clinical progress and monitor wellbeing. The critical decision on when to switch from first-line to second-line therapy can be assisted by CD4, viral load and genotype testing of HIV-1 for predicting resistance to ARV drugs in conjunction with clinical presentation.

The Chennai Declaration in December 2012 saw various experts across India came together to enumerate workable solutions to the problem of AMR. This declaration emphasized the inclusion of changes in the medical curriculum to enhance the sensitivity of budding doctors to this issue and the importance of strict infection control policies in each hospital.Exact data on the prevalence on AMR has to be made available on a national level to know the dimensions of the problem and to develop strategies to combat it. Inappropriate use (overuse, underuse and misuse) of antimicrobials has to be curtailed. This can be done by monitoring the use of higher antibiotics within hospitals and regulating the sale of antibiotics in pharmacies across the country.

To conclude, treatment failure due to resistance to available drugs is a reality today leading to increased mortality and morbidity.Changes in physician prescribing behavior with availability of advanced diagnostic tests to monitor drug resistance, strengthening infection control and surveillance systems to monitor usage of drugs and spread of superbugs are the cornerstones of the fight against AMR.

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