Increased drug efflux
Widespread worldwide-U.S. disease reflects region of importation.
Abbreviations: PBP, penicillin binding protein; ICU, intensive care unit; tet, tetracycline; pen, penicillin; ESBL, extended spectrum ^-lactamase; amp, ampicillin; CAM, chloramphenicol; TMP, trimethoprim; SMZ, sulfamethoxazole; DHFR, dihydrofolate reductase; INH, isoniazid; TB, tuberculosis.
Multidrug resistance is defined as resistance to three or more classes of antimicrobial drugs except in the case of M. tuberculosis, in which it is defined as resistance to INH and rifampin. a Years vary between 1991 to 1999; see reference for exact year.
b Many are also multidrug resistant. Although not listed here, resistance to macrolides and fluoroquinolones is also important. c Ofloxacin.
d Enterococci are intrinsically resistant to ^-lactams, aminoglycosides, clindamycin, fluoroquinolones, and trimethoprim-sulfamethoxazole and readily acquire resistance to high concentrations of |3-lactams, high concentrations of aminoglycosides, tetracycline, erythromycin, fluoroquinolones, rifampin, chloramphenicol, fusidic acid, nitrofurantoin, in addition to the glycopeptides van-comycin and teicoplanin.
e Although we have listed only vancomycin, these staphylococci are multidrug resistant.
f Although only fluoroquinolones are listed, quinolone resistant N. gonorrhoeae is also penicillin and tetracycline resistant. g Ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole. h Based on an estimated 100-600 cases per year (HI).
i Ampicillin, chloramphenicol, streptomycin, sulfamethoxazole, tetracycline (linked resistance). j Predominantly Salmonella enterica serotype Typhimurium phage type 104 (DT104). k Centers for Disease Control and Prevention. Division of Tuberculosis Elimination. Unpublished data, 1998. l Primary mutations associated with zidovudine and other nucleoside reverse transcriptase inhibitors. m Based on an estimate of 40,000 new infections per year.
n Acyclovir requires activation by phosphorylation by viral enzymes-thymidine kinase in the case of herpes simplex. Cellular enzymes complete the phosphorylation. Then the drugs target viral DNA polymerase and prevent elongation of viral DNA by being preferentially incorporated into the elongating viral DNA chain thus terminating further viral DNA replication. o Centers for Disease Control and Prevention. Division of Bacterial and Mycotic Diseases. Unpublished data, 1999.
p Chloroquine resistance in falciparum malaria is widespread; among countries with endemic P. falciparum, only Central America and Egypt have not reported resistance (17). Multidrug resistance is also a significant global problem (17,22).
and death (29-31). Pneumonia caused by Streptococcus pneumoniae that has highlevel resistance to penicillin has been associated with increased mortality in some studies (32,33), and resistant pneumococcal meningitis has been associated with persistently infected spinal fluid (34-36). There is no typical relationship between antimicrobial resistance and virulence of the infecting organism; depending on the organism, resistant isolates may or may not be more virulent than their less resistant counterparts. However, because resistance can lead to treatment failure, resistant infections may result in more serious disease (37). For many organisms, evidence of increased mortality resulting from treatment with an ineffective or less effective drug is difficult to obtain because clinicians will either institute alternate empiric treatment based on knowledge of potential resistance or will change treatment based on lack of clinical response.
By 2000, there were few infections that were so resistant as to be practically untreat-able. Burkholderia cepacia infections in patients with cystic fibrosis and vancomycin-resistant Enterococcus (VRE) in hospitalized patients may not be treatable with routinely available agents, but they affect a relatively small number of patients. For those illnesses that affect large numbers of people, such as malaria and AIDS, some treatment alternatives are often available, but expense or other considerations may make them impractical for most patients (23).
Because of the risk of excessive morbidity and mortality related to resistance, public health agencies and the medical community have reacted aggressively to the rising trends in antimicrobial resistance. Pharmaceutical companies have begun new drug investigations (38-40); researchers are developing new vaccines (41); the public health community has implemented enhanced surveillance (3,4); and educational initiatives for physicians, veterinarians, and the general public have stressed the importance of appropriate use of antimicrobial agents (13,43,44,44a).
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