Case study

A 40-year-old woman with diabetes and end-stage renal disease requiring hemodialysis presented in March 2001 with non-healing metatarsal ulcers. Amputation was required; wound cultures grew methicillin-susceptible Staphylococcus aureus. In May 2001, wound cultures from a recurrent foot ulcer grew both vancomycin-susceptible Enterococcus fecalis and methi-cillin-resistant S. aureus (MRSA). From January 2002 to March 2002 the

patient received multiple courses of systemic antibiotics, including vancomycin, for recurrent lower extremity infections (Chang et al., 2003).

During an April 2002 hospitalization for further amputation, the patient developed an MRSA dialysis fistula abscess and bacteremia. In May 2002, cultures from the exit site of a new dialysis catheter grew MRSA, requiring further treatment with vancomycin and replacement of the catheter. In June 2002, cultures from a suspected catheter exit site infection grew the world's first-ever reported vancomycin-resistant clinical isolate of S. aureus (defined as a MIC >32 |g/ml). The catheter tip culture also grew a garden-variety vancomycin-resistant Enterococcus VRE) fecalis. DNA sequencing revealed the presence of the vanA gene, which conferred high-level van-comycin resistance in both strains and apparently had "jumped" from the enterococcal to the staphylococcal strain (Chang et al., 2003).

The emergence of vancomycin-resistant S. aureus (VRSA) represents a cautionary tale. Although S. aureus displayed exquisite susceptibility to penicillin in the 1940s, it soon acquired a penicillin-hydrolyzing penicillinase enzyme, rendering it penicillin resistant. Only a year after the introduction of methicillin, a penicillinase-resistant penicillin derivative, nosocomial methicillin-resistant isolates of S. aureus emerged, and in the later 1990s MRSA began its run as a major community threat (Deresinski, 2005; see also Figure 9.1). From vancomycin's introduction in 1956 until 2002 this drug remained the agent of choice, and in some cases sole bactericidal option, for the treatment of invasive MRSA infections. Even as VRSA becomes a reality - five cases have been reported - S. aureus has also evolved resistance to novel agents such as quinupristin/dalfopristin, lin-ezolid, and daptomycin (Malbruny et al., 2002; Hayden et al., 2005; Peeters and Sarria, 2005). Other microbes, such as Acinetobacterand Pseudomonas, also have developed resistance to all mainline antimicrobials (Manikal et al., 2000; Deplano et al., 2005). The story of S. aureus illustrates microbes' ability to adapt. The seemingly relentless progression toward multi-drug antibiotic resistance, coupled with an anemic new drug pipeline, evokes the possibility that we may be entering a post-antibiotic era during which we may struggle vainly to deal with increasingly resistant pathogens (Cohen, 1992; CDC, 2004).

The genetic events that drive the evolution of drug resistance do not occur in a vacuum. Whether drug-resistant mutants inch forward by gradually accumulating uncorrected nucleotide substitutions that occur an estimated 10~6 to 10~9 times per replicative cycle per gene, or bound ahead by whole-scale inter-species transmission of fully-formed genetic elements, human behavior dramatically affects the selection pressures that drive drug resistance (Livermore, 2003). In this chapter we will examine the social forces that contribute to antibiotic resistance, including antibiotic over-use in health care and agriculture; characterize

Figure 9.1 New drug development and the emergence of antibiotic-resistant Staphylococcus aureus. Reproduced from Low (2005), with permission.

the epidemic of nosocomial infections (Figure 9.2); consider the impact of socio-cultural factors, such as the increased acuity of inpatient medicine, population aging, and use of invasive and prosthetic devices; and finally address potential remedies, such as antibiotic stewardship, improved application of surveillance and infection control programs, enhanced regulatory oversight, and public reporting.

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