Antibiotic resistance

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When the early antibiotics such as penicillin and streptomycin went into use, individual general and species of bacteria tended either to be susceptible to them, or the drug had no effect. As antibiotics have been widely used, broadening the definition to include antiprotozoal, antifungal and antiviral drugs, organisms once exquisitely sensitive to specific drugs are no longer effective. In some cases, there may be partial resistance, so extremely high dosage levels, usually parenteral, may work, but in such cases, it is probably a matter of time until fully resistant forms emerge.

Given that resistant strains are developing faster than new antibiotics, resistance is a worldwide threat, according to U.S. intelligence analysis of patterns of infectious diseases and impacts. The first antibiotics became available a little more than a half-century ago, and antivirals are quite recent — yet a challenge of HIV therapy is the constant appearance of resistant viral strains. Multidrug resistant tuberculosis is a worldwide problem, given that any treatment of this disease is prolonged.

Development of resistance

At the microbial level, this may be due either to the antibiotic therapy allowing the survival of naturally resistant organisms of the species, or of the transfer of resistance genetic factors among bacteria. It is not, as once thought, a matter of natural selection, where a few organisms within a species randomly mutate, become resistant, and thus become better equipped for survival.

After a patient uses an antibiotic, the risk of resistant organisms is greatest after one month, but the risk may continue for one year.[1]

Other mechanisms, not yet fully understood in the ecology, include the transfer of resistance genes among totally different species.

Human activities promoting antibiotic resistance

A number of organisms have developed resistance to antibiotics resistant to them. Assorted human actions cause much of the development of resistance, with reasons ranging to overprescribing antibiotics to patients stopping therapy prematurely, to the use of antibiotics as agricultural growth stimulants.

Factors affecting physician behavior:

  • "Physicians were more likely to prescribe antibiotics to patients who they believed expected them, although they (the physicians) correctly identified only about 1 in 4 of those patients".[2]
  • Physicians may be more likely to prescribe antibiotics when the physicians are tired during clinical care.[3]
  • The use of antibiotics varies among countries.[4]

Slowing the development of resistance

Interventions to reduce overprescribing have been systematically reviewed.[5] Multifactorial interventions aimed at both physicians and patients can reduce inappropriate prescribing of antibiotics. [6]

Delayed prescriptions

Delaying antibiotics for 48 hours while waiting on improvement of respiratory tract infections[7][8] or cystitis[9] may reduce antibiotic usage and reconsultation; however, this strategy may reduce patient satisfaction.

Biomarker-guided therapy

C-reactive protein and procalcitonin levels may have similar utility when compared.[10]. Regarding individual studies:

Antibiotic stewardship

At the Centers for Disease Control, a program called Get Smart for Healthcare has been instituted under Arjun Srinivasan, Associate Director of Healthcare-associated Infection Prevention Programs, One of its tenets is a three-step concept of responsible antibiotic use, called antibiotic stewardship:[16]

  1. "All antibiotic orders should have 3 pieces of information -- a dose, duration, and is certainly harder to stop therapy if you don't know why it was started in the first place. This challenge is compounded in today's healthcare system where the primary responsibility for patient care is frequently transitioned from one clinician to another.
  2. "When placing orders, make certain that they include getting microbiology cultures. Knowing the susceptibility of the infecting organism can allow you to narrow a broad spectrum therapy, change the therapy to better treat resistant pathogens, or stop antibiotics when the cultures results suggest an infection is unlikely."
  3. "When your culture results come back in 24-48 hours, let's take an antibiotic time-out. Stop and reassess therapy. Antibiotics are generally started before a patient's full clinical picture is known. Now that you have additional information including microbiology, radiographic and clinical information, ask yourself -- Is this antibiotic still warranted? Or more importantly, is this antibiotic still effective against this organism?"

Treating resistant forms

When a form was found resistant, especially if the mechanism of resistance was known, a variant of the same class of antibiotics might be useful.

Bacterial resistance to the penicillins

For example, the earliest example of bacterial resistance to penicillins was bacterial production of an enzyme called penicillinase, or, more precisely, penicillin beta-lactamase, which breaks a chemical bond in the key lactam structure of penicillin molecules.

Among the first responses were the synthesis of penicillins, such as methicillin, which protected this bond. In time, however, methicillin did not work on some bacteria, beginning with Staphylococcus aureus. Since S. aureus is an important pathogen, common in wound infection but also appearing in systemic disease, methicillin-resistant staphylococcus aureus ('MRSA) became a matter of close surveillance by infectious disease specialists.

Another approach was to co-administer a penicillin with a penicillinase inhibitor, such as clavulanic acid.

In serious infections with MRSA, the "last resort" tended to be vancomycin. Since vancomycin, for systemic infections, must be administered intravenously, it was relatively easy to restrict it to controlled hospital use, only for specific strains. Eventually, vancomycin resistance was seen among staphylococci; acquired resistance was first observed in Enterococci.

Bacterial resistance to the tetracyclines

Glycylcyclines were developed to "evade" resistance mechanisms of tetracyclines.

Multiple antibiotic therapy

A desperately ill patient may be treated with "shotgun" therapy before there is a firm diagnosis, using several antibiotics of which one or more reasonably may be expected to be effective. Cultures are taken before therapy begins, and the drugs changed when sensitivity results are back.

Several antibiotics are always given together for synergistic effect, such as trimethoprim-sulfisoxazole. In other cases, multiple antibiotics are given to avoid resistance formation in certain species, such as Mycobacteria. Quinupristin-dalfopristin, however, are a pair of streptogramin-class indicated for critical resistant forms, such as MRSA.


  1. Costelloe, Ceire; Chris Metcalfe, Andrew Lovering, David Mant, Alastair D Hay (2010-05-18). "Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis". BMJ 340 (may18_2): c2096. DOI:10.1136/bmj.c2096. Retrieved on 2010-05-19. Research Blogging.
  2. Ong S, Nakase J, Moran GJ, Karras DJ, Kuehnert MJ, Talan DA (2007). "Antibiotic use for emergency department patients with upper respiratory infections: prescribing practices, patient expectations, and patient satisfaction". Annals of emergency medicine 50 (3): 213-20. DOI:10.1016/j.annemergmed.2007.03.026. PMID 17467120. Research Blogging.
  3. Linder JA, Doctor JN, Friedberg MW, Reyes Nieva H, Birks C, Meeker D et al. (2014). "Time of Day and the Decision to Prescribe Antibiotics.". JAMA Intern Med. DOI:10.1001/jamainternmed.2014.5225. PMID 25286067. Research Blogging.
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  5. Ranji SR, Steinman MA, Shojania KG, Gonzales R (August 2008). "Interventions to reduce unnecessary antibiotic prescribing: a systematic review and quantitative analysis". Med Care 46 (8): 847–62. DOI:10.1097/MLR.0b013e318178eabd. PMID 18665065. Research Blogging.
  6. Metlay JP, Camargo CA, MacKenzie T, et al (2007). "Cluster-randomized trial to improve antibiotic use for adults with acute respiratory infections treated in emergency departments". Annals of emergency medicine 50 (3): 221-30. DOI:10.1016/j.annemergmed.2007.03.022. PMID 17509729. Research Blogging.
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  9. Little P, Turner S, Rumsby K, et al (March 2009). "Dipsticks and diagnostic algorithms in urinary tract infection: development and validation, randomised trial, economic analysis, observational cohort and qualitative study". Health Technol Assess 13 (19): iii–iv, ix–xi, 1–73. DOI:10.3310/hta13190. PMID 19364448. Research Blogging.
  10. Oliveira CF, Botoni FA, Oliveira CR, Silva CB, Pereira HA, Serufo JC et al. (2013). "Procalcitonin versus C-reactive protein for guiding antibiotic therapy in sepsis: a randomized trial.". Crit Care Med 41 (10): 2336-43. DOI:10.1097/CCM.0b013e31828e969f. PMID 23921272. Research Blogging.
  11. Cals JW, Butler CC, Hopstaken RM, Hood K, Dinant GJ (2009). "Effect of point of care testing for C reactive protein and training in communication skills on antibiotic use in lower respiratory tract infections: cluster randomised trial". BMJ 338: b1374. PMID 19416992. PMC 2677640[e]
  12. Christ-Crain M, Stolz D, Bingisser R, et al. (July 2006). "Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial". Am. J. Respir. Crit. Care Med. 174 (1): 84–93. DOI:10.1164/rccm.200512-1922OC. PMID 16603606. Research Blogging.
  13. Stolz D, Christ-Crain M, Bingisser R, et al. (January 2007). "Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy". Chest 131 (1): 9–19. DOI:10.1378/chest.06-1500. PMID 17218551. Research Blogging.
  14. Christ-Crain M, Jaccard-Stolz D, Bingisser R, et al. (February 2004). "Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial". Lancet 363 (9409): 600–7. DOI:10.1016/S0140-6736(04)15591-8. PMID 14987884. Research Blogging.
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  16. Arjun Srinivasan (15 November 2010), Three Steps to Antibiotic Stewardship, [{Centers for Disease Control]]