Supported by an unrestricted educational grant from Glaxo Wellcome Inc
Volume IV, Issue 1 - September 1997
Supported by an unrestricted educational grant from Glaxo Wellcome Inc
Therefore, it is important for every healthcare provider to understand the underlying mechanisms, clinical consequences, and management of antimicrobial resistance. Furthermore, issues related to emergence of such resistance and its containment should be communicated and explored with all who prescribe these agents. This brief overview addresses some of the issues related to drug resistance in bacteria, emphasizing some of the more important pathogens, including penicillin-resistant Streptococcus pneumoniae (PRSP), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), multidrug-resistant gram-negative bacilli (MDR-GNB), and multidrug-resistant Mycobacterium tuberculosis (MDR-TB).
Antibiotic resistance is a global problem, because the ease of international travel often results in rapid spread of resistant microorganisms around the world. Infections with resistant microorganisms can occur in hospitals and in the community. In the community, resistance can result from nosocomial acquisition of drug-resistant pathogens (MRSA), emergence of resistance due to use of antibiotics within the community (PRSP, and penicillin- and quinolone-resistant Neisseria gonorrhoeae), or acquisition of resistant pathogens as a result of travel (antibiotic-resistant shigella). Emergence of resistance can also occur as a result of using antimicrobial agents in animals with subsequent transmission of resistant pathogens to humans (antibiotic-resistant Salmonella). Antibiotic resistance in hospitals most often results from the overuse of antibiotics and has been an important problem with MRSA, MDR-GNB (especially in Enterobacter, Klebsiella, Serratia, Citrobacter, and Pseudomonas, and even in Escherichia coli), and VRE. The potential for the emergence of vancomycin-resistant MRSA has long been recognized and recent reports from Japan and the United States of low-level vancomycin resistance in clinical isolates of S. aureus have grave implications. A few outbreaks of MDR-TB have occurred in hospitals and correctional facilities, often as a result of delayed diagnosis and inadequate therapy, frequently in HIV-infected patients.
Antimicrobial resistance generally results from 3 mechanisms (Table 1). The drug target may be a novel or altered homologue introduced so the antimicrobial agent binds poorly and has a diminished effect. Examples include novel or altered penicillin-binding proteins in MRSA and PRSP, altered pentapeptide in the nascent cell wall of VRE, and altered DNA gyrase in fluoroquinolone-resistant bacteria. Furthermore, in some cases hyperproduction of the drug target can reduce the effect of the drug. Second, there may be reduced access of the drug to the target as a result of impaired penetration as in some ß-lactam-resistant GNB or as a result of active efflux out of the cell in fluoroquinolone-resistant S. aureus. Third, their may be enzymatic inactivation of the drug by ß-lactamases as in ß-lactam-resistant GNB, gonococci, or S. aureus or by aminoglycoside-modifying enzymes, as in aminoglycoside-resistant enterococci or GNB.
Bacteria can become resistant as a result of genetic mutations or acquisition of preexisting genes that confer resistance. Mutation can occur either in the DNA of bacterial chromosomes or in extrachromosomal, transferable DNA called plasmids. Such resistance characteristics, which are generally permanent, may then disseminate to other bacteria by the plasmids.
Selecting resistant strains of bacteria occurs as exposure to antibiotics inhibits and kills susceptible bacteria while allowing resistant strains to proliferate. Increased use of antibiotics leads to expanded selective pressure and, therefore, greater prevalence of resistance.
Multidrug resistance may result from plasmids bearing multiple resistance genes (MDR-GNB); mechanisms that alter permeability in GNB resistant to quinolones, trimethoprim, and chloramphenicol; or accumulation of multiple resistance genes on the chromosome (MDR-TB).
The prevalence, risk factors, microbiology, prevention, and control of infections caused by PRSP, MRSA, VRE, and MDR-GNB are summarized in Tables 2, 3, 4, and 5. Other pathogens in which emerging resistance is of clinical concern include penicillin-resistant meningococci; quinolone-resistant gonococci; and multidrug-resistant diarrheal pathogens (salmonella, shigella, and campylobacter).
Drug-resistant tuberculosis in the United States increased from 3.5% (resistant to 1 drug) or 1% (resistant to 2 drugs) in 1961 to 1968 to 13.9% (resistant to 1 drug) and 4.5% resistant to isoniazid (INH) and rifampin (RIF) in 1991. The increase has been attributed to inadequate prior therapy, persons coming from endemic areas, intravenous drug use, homelessness, an institutional residential setting, or nosocomial outbreaks. Resistance emerges from chromosomal mutations in specific genes that confer resistance to various agents. Fortunately, MDR-TB does not have any plasmids and these resistance genes are not chromosomally linked. Therefore, spread of resistance genes between cells is unlikely. MDR-TB, defined as resistant to at least INH and RIF and, in some instances, to as many as 7 antituberculosis agents, has resulted in outbreaks of disease caused by MDR-TB in hospitals and correctional institutions. These outbreaks of MDR-TB were characterized by co-infection with HIV, delay in diagnosis, delay of effective therapy, rapid progression from infection to disease to death, significant transmission to healthcare workers, and high mortality.
The treatment options for MDR-TB are limited, since the majority of effective antituberculosis agents are compromised. The principles of treating tuberculosis are to start therapy with at least 4 drugs (INH, RIF, pyrazinamide, and either ethambutol or streptomycin) unless the incidence of INH resistance in the area is <4% (ethambutol or streptomycin can be omitted). Modify the regimen once susceptibility results are available (about 6 to 8 weeks). If the strain is susceptible treat with INH and RIF for a total treatment course of at least 6 months. Monitor closely for clinical and microbiological response and for adverse effects of medication. If the organism is drug-resistant or response to therapy is inadequate, check compliance, consult an expert, and never add a single new agent to a failing regimen. Always consider TB in the differential diagnosis of an undiagnosed pulmonary infiltrate in a patient with risk factors. Promptly institute respiratory isolation and maintain it until TB is excluded or the patient is responding to appropriate antituberculosis therapy. Notify the health department and consider directly observed therapy to ensure compliance.
Newer antimicrobial agents can be developed to deal with resistance. However, development of new antimicrobial agents has slowed considerably and often, when available, such agents are far more expensive. Furthermore, given time, the microorganisms would eventually develop resistance to these newer agents. Barrier isolation precautions may help reduce transmission of resistant bacteria among hospitalized patients and control outbreaks but such approaches are not generally applicable to the community.
It is thus incumbent on physicians to prevent emergence of resistance. Since resistance is often a result of the selection pressure exerted by use or misuse of antibiotics, prudent and appropriate employment of these valuable agents would likely reduce emergence of resistance and prolong their usefulness.
George J. Alangaden, MD
Assistant Professor of Medicine
and
Stephen A. Lerner, MD
Professor of Medicine
Division of Infectious Diseases
Wayne State University School of Medicine
Detroit, MI
