wall thickening/permeability-mediated resistance increases, resulting in the loss of vanco-
mycin usefulness (1,68,69). As mentioned, the extensive use of vancomycin has also resulted in
resistance to other agents, i.e., daptomycin.
There have been reports of daptomycin resistance in treating MRSA infections that have
occurred during therapy. A review, to date, of all the cases of daptomycin resistance occurring
during therapy have occurred in patients who previously received vancomycin (70–74). The
best way to preserve the activity of daptomycin for MRSA infections is to minimize/avoid
parenteral vancomycin use whenever possible and instead preferentially use another
anti-MRSA antibiotic, linezolid, minocycline, quinupristin/dalfopristin, or tigecycline (55).
In cases of vancomycin or daptomycin resistance, quinupristin/dalfopristin or tigecycline may
be effective.
There have been reports of linezolid “tolerance” with both VRE and MRSA infections
(75–77). The phenomenon of “tolerance” refers to isolates that have a minimal bactericidal
concentration (MBC) 32 MIC. Such isolates appear susceptible with in vitro susceptibility
testing. Clinicians assume that if using antibiotics is reported as susceptible with a predictable
serum concentration, the organism should be eliminated. However, with “tolerant strains,”
unless the MBC of the isolate is determined, patient isolated with susceptible MICs will appear
susceptible but not respond to therapy. In the differential diagnosis of apparent/actual
therapeutic failure, antibiotic “tolerance” needs to be considered (Table 7) (75–78). In treating
MRSA infections, “tolerance” is an uncommon occurrence but is most likely with vancomycin
or linezolid. Because of concerns of antibiotic “tolerance” and antibiotic resistance, linezolid,
should be used sparingly to preserve its ability to treat infections for which there are few other
therapeutic alternatives, i.e., MRSA CNS infections.
For CA-MRSA infections use minocycline in place of doxycycline. Doxycycline
ineffectiveness for MRSA may be due to less intrinsic anti-MRSA activity/efflux mediated
resistance (doxycycline, but not minocycline) (1,79).REFERENCES- Cunha BA. Antibiotic Essentials. 8th ed. Sudbury, MA: Jones & Bartlett, 2009.
- Cunha BA. MRSA & VRE: in vitro susceptibility versus in vivo efficacy. Antibiot Clin 2000; 24:61–65.
- Junior MS, Correa L, Marra AR, et al. Analysis of vancomycin use and associated risk factors in a
university teaching hospital: a prospective cohort study. BMC Infect Dis 2007; 7:88. - Fishbane S, Cunha BA, Shea KW, et al. Vancomycin-resistant Enterococcus (VRE) in hemodialysis
patients. Am J Infect Control 1999; 20:461–462.
Table 7 Causes of Antibiotic Failure (Apparent or Actual)
l In vitro susceptibility but clinically ineffective in vivo (MRSA: doxycycline vs. minocycline)
l Antibiotic “tolerance” with gram-positive cocci
l Inadequate coverage/spectrum
l Inadequate antibiotic blood levels
l Inadequate antibiotic tissue levels
l Undrained abscess
l Foreign body–related infection
l Protected focus (e.g., cerebrospinal fluid abscess, device associated, etc)
l Organ hypoperfusion/diminished blood supply (e.g., chronic osteomyelitis in diabetics)
l Drug interactions
Antibiotic inactivation
Antibiotic antagonism
l Decreased antibiotic activity in tissue (pH, local hypoxia, cellular debris)
l Fungal superinfection
l Treating colonization (not infection)
l Noninfectious diseases
Medical disorders mimicking infection (e.g., SLE)
Drug fever
l Antibiotic-unresponsive infectious diseases
Viral infections
Source: Adapted from Ref. 1.508 Cunha