Antimicrobial Resistance: Substandard Antibiics and Overuse as Key Drivers of the Problem (Overview of Medical Literature)
26.06.2017
Antimicrobial Resistance: Substandard Antibiics and Overuse as Key Drivers of the Problem (Overview of Medical Literature)
Antimicrobial Resistance: Substandard Antibiics and Overuse as Key Drivers of the Problem
(Overview of Medical Literature)
Antimicrobial resistance is a global issue whose progressive escalation is accompanied by increasingly dramatic developments in both medicine and pharmaceuticals. The growing gaps in our “medicinal defenses” leave little hope for a rational solution, while the temporary effectiveness of measures implemented by public health and governmental institutions has so far failed to yield a unified strategy to combat antibiotic resistance.
Antibiotics as a Panacea
Antibiotic resistance has the most devastating impact on developing countries. Uncontrolled use and easy access to antibiotics have led to alarmingly high resistance levels [World Health Organization, 2014]. According to WHO surveys conducted across various countries in 2015, in India, for example, 75% of respondents believed that colds and flu could be treated with antibiotics, and 42% had no understanding of what a “treatment course” is—assuming antibiotics could be taken indefinitely. The same survey showed that 76% of respondents had taken antibiotics in the past 6 months, with 90% of those prescriptions issued by healthcare professionals.
Analyzing these figures points to a striking conclusion: in India—as in many other Asian and African nations—a mindset has taken root among medical professionals that a doctor is only as good as their willingness to prescribe antibiotics. Even modest increases in demand for medical services and growth in the paying population in these countries are accompanied by surging antibiotic use [N.K. Ganguly et al., 2011].
Рисунок: http://kraspharma.ru/images/u/eat_antibiotics.jpg
Microbial Resistance as a Consequence of Substandard Antibiotics
Despite the wave of accessible antibiotics sweeping across Asia and Africa, India still faces enormous mortality rates from infectious diseases: 416.75 per 100,000 population [World Bank, 2015].
In the volatile mix of a relatively weak healthcare system, lack of control over hospital-acquired infections, and cheap antibiotics, microbial resistance has taken root and continues to strengthen, manifesting in untreatable forms of sepsis in newborns and infections related to healthcare [R. Laxminarayan et al., 2015; J. Reuben et al., 2017].
Let us recall that the New Delhi metallo-β-lactamase (NDM) beta-lactamase was first discussed in 2008; today this enzyme has spread worldwide. In India, one-third of Escherichia coli isolates are resistant to aminoglycosides, and 83% of all isolated strains are resistant to third-generation cephalosporins. Among the "Indian" strains of Klebsiella pneumoniae, resistance to fluoroquinolones and carbapenems reached 73% and 52%, respectively, in just a few years [S. Datta et al., 2012 and data from http://www.resistancemap.org].
A study by H. Goossens et al. [H. Goossens et al., 2005] showed a strict correlation between the growth in antibiotic consumption and the steady increase in antibiotic resistance. However, another study, based only on a mathematical model, demonstrated a link between rising antibiotic resistance and the concept of a "subtherapeutic window"—inadequate (insufficient) concentrations of antimicrobial agents in biological fluids that promote the selection of resistant strains ("windows for resistant mutants") [L. Opatowski et al., 2011]. Essentially, these "windows for resistant mutants" are created by using drugs with low active ingredient content, poor bioavailability, or antibiotics with altered molecular configurations or excessive impurities. These drugs, which exist because of weak regulatory and supervisory bodies in the countries where they are produced, have spread beyond Asia and Africa and reached several European countries and Russia.
For ethical reasons, comparative randomized studies of dubious antibiotics versus the "gold standard" are impossible, but laboratory studies indirectly support this theory [A.A. Nikulin, Yu.P. Tsuman, et al., 2010]. In such conditions, when the concentration of an antibiotic, created by administering a dose of a drug with low active ingredient content or poor-quality substance, is sufficient to affect highly sensitive strains but insufficient to exert an antimicrobial effect on strains with intermediate sensitivity, favorable conditions are created for the selection, rapid multiplication, and dissemination of resistant mutants.
"Substandard" antimicrobial drugs are usually produced quite legally by both large and small enterprises, for example, in India, China, and other Asian countries. It should also be noted that many of these countries are exporters of "substandard" active ingredients. This issue was highlighted in the global media three years ago [www.forbes.com].
Here is a striking example: in Vietnam, a tablet form of ciprofloxacin was legally purchased with a declared dosage of 500 mg on the package. Upon analysis, it was found that each tablet contained only 20 mg of ciprofloxacin (25 times less than stated) [I.N. Okeke et al., 1999].
More Does Not Mean Better
Healthcare in Asian countries has indeed become dependent on cheap antibiotics of questionable quality. The uncontrolled prescription of antibiotics, which has become possible due to the oversaturation of the market with cheap "substandard" (containing insufficient amounts of active ingredients), and often simply poor-quality or counterfeit products, has launched a chain of events that now poses a global threat to all humanity. In these processes, the key factors are both the "lack of control" over prescriptions, as well as the "substandard quality," "cheapness," and, consequently, the widespread availability of drugs in this group.
It is only possible to state the fact that, even when access to antibiotics through pharmacies is "closed," the drama of antibiotic resistance continues to unfold in hospitals, which are also dependent on drugs of uncertain origin and quality. And, as in the known scenario, resistant strains that originate in hospitals turn into community-acquired ones.
In this regard, it is critically important to assess certain features that become apparent when analyzing the Russian national State Register of Medicines.
As an example, consider the registry records for two antibiotics included in the list of Vital and Essential Medicines (VEM) – cefepime and meropenem.
A search for meropenem (INN) yields "Found: 62 entries."
A search for meropenem (INN) and the manufacturer location "India" yields "Found: 42 entries."
A simple calculation shows that 68% of all meropenems in Russia are produced in India.
A search for cefepime (INN) yields "Found: 53 entries."
A search for cefepime (INN) and the manufacturer location "India" yields "Found: 30 entries."
A simple calculation shows that 57% of all cefepimes in Russia are produced in India.
How is this possible? In India? Yes, exactly in India, where the level of microbial resistance is excessive, where antibiotics are cheap not because they are produced through particularly profitable and innovative technologies, but because of the well-known "substandard quality" and, consequently, questionable safety and effectiveness. It is precisely about these drugs that the media write, urging that "India Must Fix Its Drug Quality Problem" [www.forbes.com]. This issue certainly deserves reflection.
Considering Pharmacodynamic/Pharmacokinetic Parameters Means Preventing Microbial Resistance
Due to the predominantly conservative approaches prevalent in domestic healthcare, medical specialists rarely assess the significance of pharmacodynamic and pharmacokinetic prerequisites for optimizing drug therapy and tend to focus on clinical outcomes. However, in the context of the progressive rise in microbial resistance, this is far more important than simply attempting to combat a stubborn infection by increasing the dose or duration of therapy. Unfortunately, the existing guides and clinical recommendations available to physicians focus mostly on clinical outcomes, with little information about strategies for preventing microbial resistance development [M.H. Abdul-Aziz et al., 2015].
References Used:
1. Abdul-Aziz MH, Lipman J, Mouton JW, Hope WW, Roberts JA. Applying pharmacokinetic/pharmacodynamic principles in critically ill patients: optimizing efficacy and reducing resistance development. Semin Respir Crit Care Med. 2015 Feb;36(1):136-53.
2. Asante KP, Boamah EA, Abdulai MA, Buabeng KO, Mahama E, Dzabeng F, Gavor E, Annan EA, Owusu-Agyei S, Gyansa-Lutterodt M; Ghana Antimicrobial Resistance Working Group. Knowledge of antibiotic resistance and antibiotic prescription practices among prescribers in the Brong Ahafo Region of Ghana; a cross-sectional study. BMC Health Serv Res. 2017 Jun 20;17(1):422.
3. Datta S, Wattal C, Goel N, Oberoi JK, Raveendran R, Prasad KJ. A ten year analysis of multi-drug resistant blood stream infections caused by Escherichia coli & Klebsiella pneumoniae in a tertiary care hospital. The Indian journal of medical research. 2012;135(6):907–12.
4. Domingues IL, Gama JA, Carvalho LM, Dionisio F.nSocial behaviour involving drug resistance: the role of initial density, initial frequency and population structure in shaping the effect of antibiotic resistance as a public good. Heredity (Edinb). 2017 Jun 21.
5. Ganguly NK, Arora NK, Chandy SJ, Fairoze MN, Gill JP, Gupta U, et al. Rationalizing antibiotic use to limit antibiotic resistance in India. The Indian journal of medical research. 2011;134:281–94.
6. Goossens H, Ferech M, Vander Stichele R, Elseviers M; ESAC Project Group. Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet. 2005 Feb 12-18;365(9459):579-87.
7. India Must Fix Its Drug Quality Problem. Accessible: https://www.forbes.com/sites/theapothecary/2014/09/17/india-must-fix-its-drug-quality-problem/#32800....
8. Laxminarayan R, Matsoso P, Pant S, Brower C, Barter D, Klugman K, et al. Access to effective antimicrobials: a worldwide challenge. Lancet. 2015;387: 168–175.
9. Okeke IN, Lamikanra A, Edelman R. Socioeconomic and behavioral factors leading to acquired bacterial resistance to antibiotics in developing countries. Emerg Infect Dis. 1999; 5: 18–27.
10. Opatowski L, Guillemot D, Boëlle PY, Temime L. Contribution of mathematical modeling to the fight against bacterial antibiotic resistance. Curr Opin Infect Dis. 2011 Jun;24(3):279-87.
11. Reuben J, Donegan N, Wortmann G, DeBiasi R, Song X, Kumar P, McFadden M, Clagon S, Mirdamadi J, White D, Harris JE, Browne A, Hooker J, Yochelson M, Walker M, Little G, Jernigan G, Hansen K, Dockery B, Sinatro B, Blaylock M, Harmon K, Iyengar P, Wagner T, Nelson JA; HARP Study Team. Healthcare Antibiotic Resistance Prevalence - DC (HARP-DC): A Regional Prevalence Assessment of Carbapenem-Resistant Enterobacteriaceae (CRE) in Healthcare Facilities in Washington, District of Columbia. Infect Control Hosp Epidemiol. 2017 Jun 15:1-9. doi: 10.1017/ice.2017.110. [Epub ahead of print]
12. Walach H. Complementary Medicine: A Serious Option as We Are Facing the Problem of Bacterial Antibiotic Resistance. Complement Med Res. 2017 Jun 19;24(3):132-134.
13. World Bank. World Development Indicators. http://data.worldbank.org/indicator. 2015
14. World Health Organization. Antimicrobial Resistance: Global Report on Surveillance, 2014 Accessible: http://apps.who.int/medicinedocs/en/m/abstract/Js21405en/
15. Data http://www.resistancemap.org.
16. Nikulin A.A., Tsuman Yu.P., Martinovich A.A., Eidelstein M.V., Kozlov R.S. On the interchangeability of intravenous forms of original and generic drugs: is comparative research necessary? Clin Microbiol Antimicrob Chemother. 2010; 12(1):31-40.
(Overview of Medical Literature)
Antimicrobial resistance is a global issue whose progressive escalation is accompanied by increasingly dramatic developments in both medicine and pharmaceuticals. The growing gaps in our “medicinal defenses” leave little hope for a rational solution, while the temporary effectiveness of measures implemented by public health and governmental institutions has so far failed to yield a unified strategy to combat antibiotic resistance.
Antibiotics as a Panacea
Antibiotic resistance has the most devastating impact on developing countries. Uncontrolled use and easy access to antibiotics have led to alarmingly high resistance levels [World Health Organization, 2014]. According to WHO surveys conducted across various countries in 2015, in India, for example, 75% of respondents believed that colds and flu could be treated with antibiotics, and 42% had no understanding of what a “treatment course” is—assuming antibiotics could be taken indefinitely. The same survey showed that 76% of respondents had taken antibiotics in the past 6 months, with 90% of those prescriptions issued by healthcare professionals.
Analyzing these figures points to a striking conclusion: in India—as in many other Asian and African nations—a mindset has taken root among medical professionals that a doctor is only as good as their willingness to prescribe antibiotics. Even modest increases in demand for medical services and growth in the paying population in these countries are accompanied by surging antibiotic use [N.K. Ganguly et al., 2011].
Рисунок: http://kraspharma.ru/images/u/eat_antibiotics.jpg
Microbial Resistance as a Consequence of Substandard Antibiotics
Despite the wave of accessible antibiotics sweeping across Asia and Africa, India still faces enormous mortality rates from infectious diseases: 416.75 per 100,000 population [World Bank, 2015].
In the volatile mix of a relatively weak healthcare system, lack of control over hospital-acquired infections, and cheap antibiotics, microbial resistance has taken root and continues to strengthen, manifesting in untreatable forms of sepsis in newborns and infections related to healthcare [R. Laxminarayan et al., 2015; J. Reuben et al., 2017].
Let us recall that the New Delhi metallo-β-lactamase (NDM) beta-lactamase was first discussed in 2008; today this enzyme has spread worldwide. In India, one-third of Escherichia coli isolates are resistant to aminoglycosides, and 83% of all isolated strains are resistant to third-generation cephalosporins. Among the "Indian" strains of Klebsiella pneumoniae, resistance to fluoroquinolones and carbapenems reached 73% and 52%, respectively, in just a few years [S. Datta et al., 2012 and data from http://www.resistancemap.org].
A study by H. Goossens et al. [H. Goossens et al., 2005] showed a strict correlation between the growth in antibiotic consumption and the steady increase in antibiotic resistance. However, another study, based only on a mathematical model, demonstrated a link between rising antibiotic resistance and the concept of a "subtherapeutic window"—inadequate (insufficient) concentrations of antimicrobial agents in biological fluids that promote the selection of resistant strains ("windows for resistant mutants") [L. Opatowski et al., 2011]. Essentially, these "windows for resistant mutants" are created by using drugs with low active ingredient content, poor bioavailability, or antibiotics with altered molecular configurations or excessive impurities. These drugs, which exist because of weak regulatory and supervisory bodies in the countries where they are produced, have spread beyond Asia and Africa and reached several European countries and Russia.
For ethical reasons, comparative randomized studies of dubious antibiotics versus the "gold standard" are impossible, but laboratory studies indirectly support this theory [A.A. Nikulin, Yu.P. Tsuman, et al., 2010]. In such conditions, when the concentration of an antibiotic, created by administering a dose of a drug with low active ingredient content or poor-quality substance, is sufficient to affect highly sensitive strains but insufficient to exert an antimicrobial effect on strains with intermediate sensitivity, favorable conditions are created for the selection, rapid multiplication, and dissemination of resistant mutants.
"Substandard" antimicrobial drugs are usually produced quite legally by both large and small enterprises, for example, in India, China, and other Asian countries. It should also be noted that many of these countries are exporters of "substandard" active ingredients. This issue was highlighted in the global media three years ago [www.forbes.com].
Here is a striking example: in Vietnam, a tablet form of ciprofloxacin was legally purchased with a declared dosage of 500 mg on the package. Upon analysis, it was found that each tablet contained only 20 mg of ciprofloxacin (25 times less than stated) [I.N. Okeke et al., 1999].
More Does Not Mean Better
Healthcare in Asian countries has indeed become dependent on cheap antibiotics of questionable quality. The uncontrolled prescription of antibiotics, which has become possible due to the oversaturation of the market with cheap "substandard" (containing insufficient amounts of active ingredients), and often simply poor-quality or counterfeit products, has launched a chain of events that now poses a global threat to all humanity. In these processes, the key factors are both the "lack of control" over prescriptions, as well as the "substandard quality," "cheapness," and, consequently, the widespread availability of drugs in this group.
It is only possible to state the fact that, even when access to antibiotics through pharmacies is "closed," the drama of antibiotic resistance continues to unfold in hospitals, which are also dependent on drugs of uncertain origin and quality. And, as in the known scenario, resistant strains that originate in hospitals turn into community-acquired ones.
In this regard, it is critically important to assess certain features that become apparent when analyzing the Russian national State Register of Medicines.
As an example, consider the registry records for two antibiotics included in the list of Vital and Essential Medicines (VEM) – cefepime and meropenem.
A search for meropenem (INN) yields "Found: 62 entries."
A search for meropenem (INN) and the manufacturer location "India" yields "Found: 42 entries."
A simple calculation shows that 68% of all meropenems in Russia are produced in India.
A search for cefepime (INN) yields "Found: 53 entries."
A search for cefepime (INN) and the manufacturer location "India" yields "Found: 30 entries."
A simple calculation shows that 57% of all cefepimes in Russia are produced in India.
How is this possible? In India? Yes, exactly in India, where the level of microbial resistance is excessive, where antibiotics are cheap not because they are produced through particularly profitable and innovative technologies, but because of the well-known "substandard quality" and, consequently, questionable safety and effectiveness. It is precisely about these drugs that the media write, urging that "India Must Fix Its Drug Quality Problem" [www.forbes.com]. This issue certainly deserves reflection.
Considering Pharmacodynamic/Pharmacokinetic Parameters Means Preventing Microbial Resistance
Due to the predominantly conservative approaches prevalent in domestic healthcare, medical specialists rarely assess the significance of pharmacodynamic and pharmacokinetic prerequisites for optimizing drug therapy and tend to focus on clinical outcomes. However, in the context of the progressive rise in microbial resistance, this is far more important than simply attempting to combat a stubborn infection by increasing the dose or duration of therapy. Unfortunately, the existing guides and clinical recommendations available to physicians focus mostly on clinical outcomes, with little information about strategies for preventing microbial resistance development [M.H. Abdul-Aziz et al., 2015].
References Used:
1. Abdul-Aziz MH, Lipman J, Mouton JW, Hope WW, Roberts JA. Applying pharmacokinetic/pharmacodynamic principles in critically ill patients: optimizing efficacy and reducing resistance development. Semin Respir Crit Care Med. 2015 Feb;36(1):136-53.
2. Asante KP, Boamah EA, Abdulai MA, Buabeng KO, Mahama E, Dzabeng F, Gavor E, Annan EA, Owusu-Agyei S, Gyansa-Lutterodt M; Ghana Antimicrobial Resistance Working Group. Knowledge of antibiotic resistance and antibiotic prescription practices among prescribers in the Brong Ahafo Region of Ghana; a cross-sectional study. BMC Health Serv Res. 2017 Jun 20;17(1):422.
3. Datta S, Wattal C, Goel N, Oberoi JK, Raveendran R, Prasad KJ. A ten year analysis of multi-drug resistant blood stream infections caused by Escherichia coli & Klebsiella pneumoniae in a tertiary care hospital. The Indian journal of medical research. 2012;135(6):907–12.
4. Domingues IL, Gama JA, Carvalho LM, Dionisio F.nSocial behaviour involving drug resistance: the role of initial density, initial frequency and population structure in shaping the effect of antibiotic resistance as a public good. Heredity (Edinb). 2017 Jun 21.
5. Ganguly NK, Arora NK, Chandy SJ, Fairoze MN, Gill JP, Gupta U, et al. Rationalizing antibiotic use to limit antibiotic resistance in India. The Indian journal of medical research. 2011;134:281–94.
6. Goossens H, Ferech M, Vander Stichele R, Elseviers M; ESAC Project Group. Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet. 2005 Feb 12-18;365(9459):579-87.
7. India Must Fix Its Drug Quality Problem. Accessible: https://www.forbes.com/sites/theapothecary/2014/09/17/india-must-fix-its-drug-quality-problem/#32800....
8. Laxminarayan R, Matsoso P, Pant S, Brower C, Barter D, Klugman K, et al. Access to effective antimicrobials: a worldwide challenge. Lancet. 2015;387: 168–175.
9. Okeke IN, Lamikanra A, Edelman R. Socioeconomic and behavioral factors leading to acquired bacterial resistance to antibiotics in developing countries. Emerg Infect Dis. 1999; 5: 18–27.
10. Opatowski L, Guillemot D, Boëlle PY, Temime L. Contribution of mathematical modeling to the fight against bacterial antibiotic resistance. Curr Opin Infect Dis. 2011 Jun;24(3):279-87.
11. Reuben J, Donegan N, Wortmann G, DeBiasi R, Song X, Kumar P, McFadden M, Clagon S, Mirdamadi J, White D, Harris JE, Browne A, Hooker J, Yochelson M, Walker M, Little G, Jernigan G, Hansen K, Dockery B, Sinatro B, Blaylock M, Harmon K, Iyengar P, Wagner T, Nelson JA; HARP Study Team. Healthcare Antibiotic Resistance Prevalence - DC (HARP-DC): A Regional Prevalence Assessment of Carbapenem-Resistant Enterobacteriaceae (CRE) in Healthcare Facilities in Washington, District of Columbia. Infect Control Hosp Epidemiol. 2017 Jun 15:1-9. doi: 10.1017/ice.2017.110. [Epub ahead of print]
12. Walach H. Complementary Medicine: A Serious Option as We Are Facing the Problem of Bacterial Antibiotic Resistance. Complement Med Res. 2017 Jun 19;24(3):132-134.
13. World Bank. World Development Indicators. http://data.worldbank.org/indicator. 2015
14. World Health Organization. Antimicrobial Resistance: Global Report on Surveillance, 2014 Accessible: http://apps.who.int/medicinedocs/en/m/abstract/Js21405en/
15. Data http://www.resistancemap.org.
16. Nikulin A.A., Tsuman Yu.P., Martinovich A.A., Eidelstein M.V., Kozlov R.S. On the interchangeability of intravenous forms of original and generic drugs: is comparative research necessary? Clin Microbiol Antimicrob Chemother. 2010; 12(1):31-40.
