Causes of antibiotic treatment failure

Question 3.3 from the second paper of 2014 and Question 17.3 from the second paper of 2010 both ask, "Why aren't my antibiotics working? Why won't this stubborn sepsis resolve?"

There could be numerous reasons. A 1972 issue of the BMJ has three different entries with the same title ("Causes of failure in antibiotic treatment") of which the first is an exploration by L.P. Garrod, and the others are letters to the editor by Cargill and Pollock. The Garrod paper is slightly dated but the issues remain current.

For rapid revision, thw whole thing can not be boiled down any better than the college answer to Question 3.3 from the second paper of 2014:

  • Wrong antibiotic choice
  • Delayed administration of antibiotics
  • Inadequate source control
  • Inadequate antimicrobial blood levels
  • Inadequate penetration of the antimicrobial to the target site,
  • Antimicrobial neutralization or antagonism,
  • Superinfection or unsuspected secondary bacterial infection,
  • Non-bacterial infection
  • Non-infectious source of illness

In greater detail, one can separate the issues into a series of heading:

There is no infection.

The infection is not susceptible to antibiotics

  • There is a viral cause of illness, without an accepted antiviral therapy.
  • The infection is fungal, protozoal, parasitic, or algal (yes, by algae).
  • The source of infection is subject to severe circulatory neglect (eg. an ischaemic toe) in which case surgical source control is the only way to manage it.

You are using the wrong antibiotics.

  • The drug is plainly inappropriate for its application (eg. nitrofurantoin for pneumonia).
  • The drug would normally be appropriate, but this organism happens to be resistant.

You are using the wrong route of administration.

  • The oral drug may not be getting absorbed due to the sluggish gut of critical illness
  • The IV drug is not effective in treating an infection in the gut lumen (eg. IV vancomycin instead of oral vancomycin for C.difficile infection

Your antibiotic dosing is inappropriate

  • The dose is too small, and does not reach far enough over MIC
  • The dosing interval is too long
  • The administration was delayed (in septic shock, every hour counts)
  • The course was too brief
  • You have failed to adjust for increased clearance by dialysis
  • You must by neccessity use a lower dose, or shorten the course, due to unacceptable toxicity (Garrod dryly remarks that "treatment may reasonably be said to have failed when a patient dies as a direct result of it").

Source control is inadequate

  • The source is subject to surgical neglect
  • The debridement was incomplete (more surgery is needed)
  • The clearance of secretions in pneumonia is poor (more physiotherapy is needed)

Eagle effect (paradoxical loss of effect)

  • Essentially it is the paradoxical failure of an antibiotic to which the organism seems to be exquisitely sensitive in vitro, eg. in the case of S.pyogenes and benzylpenicillin. Several mechanisms haev been proposed. For instance, in a large colony, many organisms are not reproducing, and so there is a reduced expression of penicillin binding proteins during stationary growth phase.

Antibiotic penetration to the target site is poor

  • The chosen antibiotic happens to penetrate that specific tissue poorly.
  • The tissue in question has poor blood supply (the ischaemic toe again)

Antibiotic activity is being inhibited

Some examples:

  • Acidic environments inhibit the activity of macrolides and aminoglycosides
  • Lung surfactant inhibits daptomycin

Antibiotic antagonism has developed

  • Classically, it is said that giving a bacteriostatic antibiotic together with a bactericidal one will result in antagonism, as the bacteriostatic drug prevents the bacteria from reproducing, and the bactericidal drug can only kill bacteria while they are trying to reproduce.

Antibiotics are working just fine, but the clinical state has deteriorated anyway

For instance, you have destroyed the streptococci, but the streptococcal toxic shock syndrome has laid to waste your patient's organ systems, giving the overall impression of treatment failure.


Garrod, L. P. "Causes of failure in antibiotic treatment." BMJ 4.5838 (1972): 473-476.

Cargill, J. S. "Causes of failure in antibiotic treatment." BMJ 4.5843 (1972): 791-791.

Pollock, A. V. "Causes of failure in antibiotic treatment." BMJ 4.5843 (1972): 790-791.

García, Miguel Sánchez. "Early antibiotic treatment failure." International journal of antimicrobial agents 34 (2009): S14-S19.

Cunha, Burke A., and Antonio M. Ortega. "Antibiotic failure." The Medical clinics of North America 79.3 (1995): 663-672

Arancibia, Francisco, et al. "Antimicrobial treatment failures in patients with community-acquired pneumonia: causes and prognostic implications."American journal of respiratory and critical care medicine 162.1 (2000): 154-160.

Sanders, E., and P. F. Jurgensen. "Remediable causes of failure of" appropriate" antimicrobial therapy." Postgraduate medicine 50.5 (1971): 161. -Not available even as an abstract! Oh well, it was 1971.

Cox, G. Erika, J. D. Wilson, and Pamela Brown. "Protothecosis: a case of disseminated algal infection." The Lancet 304.7877 (1974): 379-382.

Stevens, Dennis L., et al. "The Eagle effect revisited: efficacy of clindamycin, erythromycin, and penicillin in the treatment of streptococcal myositis." Journal of Infectious Diseases 158.1 (1988): 23-28.