It is difficult to imagine modern medicine without antibiotics. Chemotherapy, organ transplantation, and even basic surgical procedures would not be possible if it weren’t for the use of antibiotics. It has been a mere 80 years since the serendipitous discovery of penicillin in 1929, and its first application in the 1940s, but we are now faced with a grim but very real possibility of reverting to the conditions of a pre-antibiotic era.

Bacteria are champions of evolution. They existed long before homo sapiens did, and will continue to persist long after we are gone. They can survive in extreme conditions, reproduce asexually within minutes, and are adapting at a rate which far exceeds that with which we are able to discover and synthesise new antibiotics. This bleak situation has been borne from decades of widespread antibiotic misuse.

The clinical applications of penicillins were quickly limited by the ß-lactamases, enzymes that cleave the ß-lactam bond rendering the antibiotic ineffective. The scientific and medical community responded with the discovery of cephalosporins and carbapenems. The most prevalent Gram-negative pathogens, such as Escherichia coli, Salmonella enterica, and Klebsiella pneumoniae, are responsible for many common community-acquired infections, but a strong correlation between antibiotic use in the treatment of these diseases and antibiotic resistance development has been observed over the past half-century.

As 3rd generation cephalosporins are no longer able to be used as empirical therapy in many countries, carbapenems have represented the last line of defense against Gram-negative bacilli.

Until the 2000s, carbapenems were almost uniformly active against resistant Gram-negative organisms, but new mechanisms of resistance have now emerged. They include changes to the cell membrane ‘porins’ that block the entry of the antibiotic, or via ‘efflux pumps’ that cause the antibiotic to be effectively pumped out of the bacterial cell.

Mycobacterium tuberculosis is the archetypical human pathogen; it evolved with the human race and currently infects as much as one third of the world population.

While the ground-breaking discoveries of streptomycin and isoniazid provided vital treatments, resistance development was rapid.

The introduction of cocktails of anti-tuberculosis drugs has become an essential treatment regimen, with considerable success; however, multidrug resistance continues to compromise therapy throughout the world. M. tuberculosis strains resistant to four or more of the front-line treatments (i.e. extremely drug-resistant [XDR] strains) have appeared and spread rapidly in the last decade or so. And now there are TDR strains, which are ‘totally drug-resistant’.

Among the Gram–positive organisms, methicillin resistant Staphylococcus aureus (MRSA) represents a great therapeutic challenge. MRSA appeared within just three years of the introduction of methicillin in 1959 and inexorably lead to multi-antibiotic resistant variants.

The acronym now denotes multidrug-resistant S. aureus. Some MRSA strains have shown a disturbing trend in resistance to glycopeptides and even more recently introduced agents, such as daptomycin and the oxazolidinones.

Concerning hospital-acquired diseases, Pseudomonas aeruginosa has evolved from being an infection of burn wounds into a major nosocomial threat. Again in this case, antibiotic resistance mechanisms evolved coincidentally with the introduction of new antibiotic derivatives, compromising the most effective treatments (such as the ß-lactams and aminoglycosides).

Currently, the clinical frequency of antibacterial resistance in Australia to P. aeruginosa with amoxicillin, macrolides, clindamycin, tetracycline and most cephalosporins is 100%, and 15-30% with gentamicin, ciprofloxacin and norfloxacin. P. aeruginosa is of considerable concern for patients with cystic fibrosis; the pathogen is highly persistent and can avoid human immune defenses. Resistance development is associated with the lengthy antibiotic treatments of cystic fibrosis patients.

Perhaps the greatest cause for global concern is the novel enzyme – the New Delhi metallo ß-lactamase-1 (NDM-1), a growing but insufficiently publicised pandemic. It was first reported in 2009 in a Swedish patient who travelled to New Delhi and acquired a urinary tract infection due to a carbapenem-resistant K. pneumoniae strain.

This strain was resistant to every antimicrobial tested with the exception of colistin. The NDM-1 encoding gene is located on bacterial plasmids, which are easily transferable and capable of wide rearrangement, suggesting widespread transmission and plasticity among bacterial populations.

What is most disconcerting is that transfer may occur amongst unrelated bacterial isolates via horizontal gene transfer. NDM-1 has been isolated widely in enterobacteriaceae species including K. pneumoniae, E. coli, E. cloacae, Proteus spp., Citrobacter freundii, K. oxytoca, M. morganii and Providencia spp.

Most isolates remain susceptible to colistin and tigecycline, except those Enterobacteriaceae endowed with a natural resistance to these compounds such as M. morganii, Proteus spp. and Providencia spp. Presently, there have been at least 150 cases in India and Pakistan, 70 in the United Kingdom and several cases arising globally including Canada, Australia, Asia, Europe and the United States, illustrating widespread dissemination.

Concern about antimicrobial resistance in bacteria is not new. Numerous articles were published half a century ago highlighting this fact. Some action has been taken in response to the threat. Few countries have had the foresight to implement more stringent policies to mitigate the spread of resistance through Antibiotic Stewardship programs.

The Infectious Diseases Society of America, US Centers for Disease Control and Prevention (CDC), European Commission, and European Center for Disease Prevention and Control (ECDC) have campaigned to raise awareness and provoke the desperately needed action from governments and the pharmaceutical industry.

The reality is that the net commercial value of antibiotics is low and so antibiotic research is not a high priority for pharmaceutical companies. Among the proposals to overcome this barrier are orphan drug benefits, government incentives toward research and development, prolonged patents and expedited approval. Proposals and pronouncements lack the result that may only come from action.

So in the meantime, we have only the option of revisiting treatments that are more than 30 years old – antibiotics with unfavorable toxicity profiles and limited pharmacodynamic guidance while we wait for new antibiotics to emerge from the pipeline, and sense a pervasive belief in the scientific community that increasing antibiotic resistance is the new norm – an extremely costly attitude.

In 2000, the World Health Organisation produced comprehensive recommendations for curbing antibiotic resistance. These recommendations include national surveillance programs, rigorous infection control policies, banning of non-prescribed antibiotics, prudent antibiotic usage in hospitals and increased international collaboration. Unfortunately, many countries have failed to adopt such methods.

As long as people are able to purchase antibiotics without prescriptions, which is largely the case in many developing countries, and as long as prescribers continue to issue antibiotic prescriptions to treat viral infections, we will continue to see the treasury of antibiotics, which has served modern medicine so well, be stripped of its value.

References:

  1. Walsh TR. New Delhi metallo-ß-lactamase-1: detection and prevention. Can Med Association J 2011; 183 (11): 1240–41.
  2. Moellering Jr, RC. NDM-1 – A cause for worldwide concern. New Eng J Med 2012; 363 (10): 2377–79.
  3. Rolain JM, Parola P, Cornaglia G. New Dehli metallo-beta-lactamase (NDM-1): towards a new pandemia? Clin Microbiol Infec 2010; 16 (12): 1699–1701.
  4. Arias CA, Murray BE. Antiobiotic-resistant bugs in the 12st century – A clinical super-challenge. New Engl J Med 2009; 360: 439–43.
  5. Davies J, Davies D. Origins and evolution of antibiotic resistance. Microbiol Mol Biol R 2010; 74 (3): 417–43.
  6. Nordmann P, Poirel L, Toleman MA, Walsh TR. Does broad-spectrum ß-lactam resistance due to NDM-1 herald the end of the antibiotic era for treatment of infections caused by Gram-negative bacteria? Antimicrob Chemoth 2011; 66 (4): 689–92.
  7. Carlett J, Collingnon P, Goldman D, Goossens H, Gyssens IC, Harbarth S, et al. Society’s failure to protect a precious resource: Antibiotics. Lancet 2011; 378 (9788): 23–29.

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