Overview global scope and cost of antibiotic resistance

Before discussing the social determinants of antibiotic resistance, we must place the problem into a context that considers its global scale, clinical importance, and economic impact. Gram-negative bacteria containing extended spectrum beta-lactamases (ESBLs), that hydrolyze third-generation cephalosporins and most other beta-lactam antibiotics, have a global presence. In 2003, the Study for Monitoring Antimicrobial Resistance Trends (SMART) collected intra-abdominal wound culture isolates from 74 medical centers, located in 23 different countries comprising five geographic regions. ESBLs were most prevalent within nosocomial Enterobacter isolates from the Asia/Pacific region (Figure 9.3; Paterson

Urinary Tract Infections

Catheter-related Bloodstream Infections

Ventilator Associated Pneumonia

Figure 9.2 United States intensive care unit nosocomial infection rates. Adapted from NNIS System (1998).

E.coli □ Klebsiella species □ Enterobacter species

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Figure 9.3 Worldwide distribution of ESBL-containing Gram-negative bacilli from intra-abdominal sources. Adapted from Paterson etal. (2005).

etal, 2005). In 1997, SENTRY, a similar global resistance surveillance program, examined isolates from 48 medical centers throughout Canada, the US, and Latin America; the highest rate of ESBL-containing bloodstream isolates, 33 percent, was from Latin America (Diekema et al., 1999). Lautenbach and colleagues conducted a case-control study of clinical and economic impacts of infection with ESBL-containing Gram-negative bacilli. Compared to 66 matched controls, with non-ESBL containing Gram-negative infections, 33 ESBL-infected case patients had longer median lengths of stay (11 vs 7 days), longer duration until appropriate antibiotic administration (72 hours vs 11.5 hours), lower clinical response rates (76 percent vs 83 percent), and higher hospital costs ($66,590 vs $22,231) (Lautenbach et al., 2001).

Significant global rates of resistance and clinical and economic impact also have been demonstrated among Gram-positive bacteria. SENTRY reported susceptibility results for over 4900 enterococcal clinical isolates collected between 1997 and 1999, documenting a 17 percent US rate of vancomycin resistance for 1999 (Low et al., 2001). In 2003, the European Antimicrobial Resistance Surveillance System (EARSS), which surveys antibiotic resistance rates from 1300 hospitals in 28 European countries, found high rates of vancomycin resistance in invasive Enterococcus faecium infections in Portugal (50 percent), Italy (25 percent), Greece (23 percent), and Ireland (19 percent) (EARSS Management Team, 2004).

Although clinicians regularly question enterococcal virulence and impact on morbidity, an extensive meta-analysis has linked vancomycin resistance among enterococci with increases in mortality. DiazGranados and colleagues evaluated 1614 enterococcal bloodstream infections (683 vancomycin-resistant vs. 931 vancomycin-susceptible), from nine separate studies. They found that bacteremia with VRE led to a mortality rate 2.5 times that associated with vancomycin-sensitive enterococcal (VSE) bacteremia (DiazGranados et al., 2005). A smaller, single-site study, comparing VRE bacteremia (n = 21) and VSE bacteremia (n = 32), showed that patients with VRE bacteremia had higher mortality (76 percent vs 41 percent), longer lengths of stay (35 vs 17 days) and, on average, $27,000 higher hospital costs per episode (Stroser et al., 1998).

These examples largely reflect health-care associated infections, but the problem of antibiotic resistance pervades the community as well. Streptococcus pneumoniae represents the leading cause of community-acquired bacterial pneumonia, meningitis, and middle ear infections worldwide. Before the first report of reduced susceptibility in 1967, pneumococci were uniformly sensitive to penicillin (Low, 2005). Since then, the Alexander Project, set up in 1992 to monitor antibiotic resistance among respiratory tract pathogens worldwide, has revealed rising rates of pneumococcal resistance - for example, in 1998-2000, worldwide resistance was nearly 32 percent. The highest rates were in the Far East (56 percent), the Middle East (54 percent), and Africa (52 percent) (Jacobs et al., 2003). Rates of penicillin resistance in pneumococci have also increased

Figure 9.4 Worldwide penicillin and erythromycin resistance, 2002-2003. Rates of macrolide and penicillin resistance in Streptococcus pneumoniae from Prospective Organism Tracking and Epidemiology for the Ketolide telighromycin, for 2002-2003, with penicillin resistance defined as MIC >2 yg/ml, and erythromycin resistance defined as MIC >1 ug/ml. Reproduced from Low (2005), with permission.

Figure 9.4 Worldwide penicillin and erythromycin resistance, 2002-2003. Rates of macrolide and penicillin resistance in Streptococcus pneumoniae from Prospective Organism Tracking and Epidemiology for the Ketolide telighromycin, for 2002-2003, with penicillin resistance defined as MIC >2 yg/ml, and erythromycin resistance defined as MIC >1 ug/ml. Reproduced from Low (2005), with permission.

in the US, from 7 percent in 1992-1993 to 22 percent in 1999-2000 (Jacobs, 2003). More recent data have confirmed high rates of penicillin and macrolide resistance worldwide (Low, 2005; see Figure 9.4). Numerous reports have documented penicillin treatment failure in cases of meningitis caused by pneumo-cocci with reduced sensitivity to penicillin (Paris et al., 1995). Moreover, a study specifically looking at the effects of higher-level penicillin resistance found an association between penicillin resistance and pneumococcal pneumonia-related mortality (Feiken et al., 2000).

Much of the morbidity and mortality associated with antibiotic resistance results from ineffective empiric treatment. When initial treatment for intra-abdominal sepsis failed to "cover" resistant organisms, patients experienced two times more complications (Mosdell et al., 1991). Similarly, intensive care unit patients given ineffective versus effective initial antibiotic therapy had a 42 percent versus 17 percent in-hospital, infection-related mortality rate (Kollef et al., 1999; Figure 9.5).

Fear of such treatment failure spurs the use of newer, often more costly, agents. For instance, if concern about pneumonia due to penicillin-resistant pneumo-cocci led to a 10 percent market share increase for the fluoroquinolone levo-floxacin, spending on empiric therapy could increase more than 100 percent based on 1999 prices for a course of amoxicillin of ($6) versus levofloxacin of ($69)

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Figure 9.5 ICU infection-related mortality based on appropriateness of initial antibiotic therapy. Reproduced from Kollef etal. (1999), with permission.

(Howard etad, 2003). Antibiotic resistance concerns have driven an estimated $20 million increase in therapeutic choices for otitis media (Howard and Scott, 2005).

Estimating the overarching economic burden of antibiotic resistance has proven difficult. The now defunct US Congressional Office of Technology Assessment (OTA) estimated annual costs related to hospital-acquired infection caused by six antibiotic-resistant microbes at $1.5 billion (US Congress, Office of Technology Assessment, 1995). A study of "all costs" related to antibiotic resistance, including the economic impact of longer hospital stays, premature death, and the prescribing of more expensive drugs, estimated the cost at $100 million to $300 billion annually (Phelps, 1989).

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