METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS
Following its introduction into clinical practice in the 1940s, penicillin became the treatment of choice for infections caused by Staphylococcus aureus; however, penicillin-resistant strains of S. aureus rapidly emerged. The problem of resistant staphylococci appeared to have been eliminated with the development of the semisynthetic penicillins, such as methicillin and oxacillin, in the early 1960s. However, in 1961, strains of S. aureus resistant to the semisynthetic penicillins were isolated in England, and within 10 years, outbreaks of hospital-associated infections became common throughout Europe.
Before 1976, only sporadic outbreaks of nosocomial infection with methicillin-resistant S. aureus (MRSA) were reported in the United States. Since that time, hospital-acquired disease caused by MRSA has reached epidemic proportions. Although the initial outbreaks were confined to university medical centers, by 1979, more than 30% of community hospitals had patients with MRSA bacteremia, and by 1989, more than 90% of all acute-care hospitals reported having patients infected with this microbe. The fact that few antimicrobials are available to treat infected patients and the observation that the organism can be difficult to eliminate from an institution contribute to the concern about MRSA as a nosocomial pathogen. That concern has been dramatically accentuated since strains with reduced susceptibililty to vancomycin have been isolated in Japan and the United States.
The resistance of S. aureus to penicillin is mediated by a b-lactamase, which is an enzyme usually produced under the control of extrachromosomal DNA (plasmid). The b-lactamase is capable of hydrolyzing the b-lactam ring and thus chemically inactivating penicillin. In contrast, resistance to methicillin and related drugs is chromosomally linked, and it does not involve the inactivation of the antimicrobial. Rather, methicillin-resistant staphylococci express a penicillin-binding protein that possesses a greatly reduced affinity for b-lactam antimicrobials, including the semisynthetic penicillins; this protein is referred to as penicillin-binding protein 2a. The phenotypic expression of this intrinsic resistance can be modified by a number of factors; for example, raising the pH of the culture media or lowering the incubation temperature below 35°C increases the expression of methicillin resistance. The heterogeneity in the phenotypic expression of resistance is clinically relevant; if an intrinsically resistant strain is incubated at 37°C, only 1 in 105 or 106 bacteria will express resistance, and the isolate may be incorrectly characterized as methicillin-susceptible. Of note, MRSA often contains plasmids that convey resistance to other antimicrobials. Finally, methicillin-resistant strains possess all the virulence factors found in methicillin-susceptible staphylococci, and so the organism is capable of producing life-threatening disease in humans.
MRSA is usually introduced into a hospital by patients who are transferred from other institutions, especially nursing homes, in which the organisms are endemic. Physicians have also been implicated as the source of interhospital spread. On occasion, spouses of patients have been found to be reservoirs of MRSA. Once introduced into a hospital, MRSA can disseminate rapidly and colonize patients and personnel, who then serve as sources of continued transmission. Diseases of the skin, including decubitus ulcers, burns, surgical wounds, and chronic dermatitis, increase the probability of colonization. In addition, colonization of the anterior nares of patients and hospital employees can occur and contribute to the spread of MRSA.
The risk for development of infection with MRSA is increased among colonized patients who are aged and debilitated, who have received prior antimicrobial therapy, who reside in ICUs, who undergo chronic hemodialysis, or who are hospitalized for prolonged periods of time. Resistant staphylococci can produce a number of potentially life-threatening diseases, including endocarditis, pneumonia, bacteremia, osteomyelitis, and septic thrombophlebitis. Because of the prevalence of serious underlying illnesses among patients infected with MRSA, case-fatality rates are high; among patients with bronchopneumonia, for example, mortality rates above 50% have been reported.
The management of patients with infections caused by MRSA remains problematic, in part because of the limited number of useful antimicrobials. These organisms are invariably resistant to all penicillins. Some strains are susceptible in vitro to the cephalosporins; however, clinical experience indicates that patients infected with MRSA and treated with cephalosporins respond poorly, and MRSA must be considered resistant to this class of antimicrobials. Virtually all strains of MRSA exhibit susceptibility to vancomycin, and clinical studies have confirmed that vancomycin is an effective drug in the management of patients with serious infections. Vancomycin is the treatment of choice for patients with potentially life-threatening disease caused by MRSA, but it is not an ideal agent; some strains of MRSA are only inhibited by the drug, not killed, and treatment failures can occur in patients infected with these tolerant strains. Some strains of S. aureus resistant to the b-lactam antimicrobials are sensitive to trimethoprim-sulfamethoxazole, and the drug can be employed to treat patients infected with MRSA. Ciprofloxacin has also been used on occasion with success. The glycopeptide teicoplanin, which is not yet available in the United States, also appears to have excellent activity against MRSA, and the drug has been used with success abroad. Of note, patients cured of MRSA infection often remain colonized by the pathogen.
Vancomycin is usually administered at a dosage of 1 g every 12 hours, although alternate dosing regimens are under investigation. Because the drug is excreted by the kidneys, dosage adjustments are mandatory in patients with renal dysfunction. Serum levels should be monitored, and peak concentrations of 30 to 40 g/mL and trough levels of 5 to 10 g/mL should be maintained. Vancomycin alone rarely produces nephrotoxicity; however, the potential for renal injury is substantially augmented in patients also receiving aminoglycosides. In general, renal function should be assessed two to three times weekly, and the use of other nephrotoxic drugs should be avoided. Vancomycin has been reported to cause hearing loss, although this complication is very rare. Finally, antimicrobial antagonism can occur when a second drug is combined with vancomycin; therefore, in most circumstances, vancomycin should be used alone. If the patient fails to respond to therapy with vancomycin, the addition of rifampin or an aminoglycoside should be considered; in general, the combination of vancomycin with rifampin or an aminoglycoside will produce synergistic killing.
To control the spread of MRSA within a hospital, patients known to be infected with the organism should be isolated or perhaps cohorted with other infected patients. Stringent adherence to the isolation techniques is mandatory, and scrupulous attention must be paid to hand washing and the use of gloves, gowns, and masks, as required by the type of isolation implemented. Patients who are colonized and require prolonged hospitalization should be cohorted with other carriers; the specific isolation precautions necessary should be determined by the infection control officer on a case-by-case basis. Carriers of MRSA should be discharged as soon as possible; many adult patients discharged to home will eliminate the bacterium within a month.
If standard infection control measures fail to arrest an outbreak of MRSA disease, surveillance cultures should be obtained to identify colonized patients who may be the source of continuous person-to-person transmission. Physicians, nursing personnel, and other persons in contact with patients who are infected or colonized with MRSA should be screened for carriage by culturing the anterior nares and cutaneous lesions, including furuncles, carbuncles, and areas of paronychia and chronic dermatitis. If the survey of personnel fails to detect MRSA carriage but the outbreak continues, additional cultures of the health care workers’ nares, throat, hands, axillae, rectums, and inguinal regions should be considered; environmental cultures will also be required in selected circumstances. Hospital personnel colonized with MRSA should be removed from direct patient contact. Occasionally, ICUs must be closed to new admissions to control an outbreak of infection.
In the setting of outbreaks of infection, the use of antimicrobials in the management of patients and health care workers who are carriers of MRSA in concert with other infection control measures has proved effective in controlling the epidemics. In particular, studies have shown that treatment of carriers is frequently associated with eradication of colonizing MRSA and control of epidemics. Thus, antimicrobials should be employed if an outbreak of MRSA disease is not terminated by alternate infection control procedures.
Data from a number of studies have shown that topical 2% mupirocin applied to the anterior nares two to three times daily for 5 to 7 days represents a highly effective means of eliminating the nasal carrier state. Most experts recommend the concurrent use of rifampin (600 mg daily for 5 days) and trimethoprim-sulfamethoxazole (1 DS tablet for 5 to 10 days). Because of a number of unique properties, rifampin is effective in treating the carrier state; it is active against most strains of MRSA, appears in high concentrations in external secretions, and achieves high levels within phagocytic cells, where it kills sequestered organisms. Resistance to rifampin can develop rapidly; thus, the agent should never be use alone to treat staphylococcal carriers. Minocycline (100 mg twice daily) together with mupirocin and rifampin has also been highly effective in eradicating the nasal carrier state. Of note, although these antibiotic regimens have produced nasal clearance rates approaching 100%, antimicrobial combinatiions have been found to be only 60% to 80% effective in eradicating MRSA from extranasal sites, such as surgical wounds or decubitus ulcers.
Most carriers of MRSA will be cleared of the organism with one of the outlined protocols; however, patients with MRSA at sites that contain copious secretions, such as decubitus ulcers and tracheostomy wounds, often fail treatment. Further, the use of topical or systemic antimicrobials in the setting of foreign bodies, such as nasogastric or percutaneous gastrostomy tubes, will usually be unsuccessful in eliminating colonization, and the intervention may lead to the development of drug resistance. Finally, after the completion of a course of antimicrobials directed at the carrier state, follow-up cultures are necessary to ensure that the methicillin-resistant staphylococci have been eradicated from colonized patients and health care workers. (A.L.E.)
Bradley SF, et al. Methicillin-resistant Staphylococcus aureus: colonization and infection in a long-term care facility. Ann Intern Med 1991;115:417.
Even in a chronic care facility with endemic MRSA, in 65% of the residents colonization never developed, and only 3% of the colonized patients experienced an infection.
Brumfitt W, Hamilton-Miller J. Methicillin-resistant Staphylococcus aureus. N Engl J Med 1989;320:1188.
A comprehensive, well-referenced review of the topic.
Centers for Disease Control. Update: Staphylococcus aureus with reduced susceptibility to vanomycin—1997. MMWR Morb Mortal Wkly Rep 1997;46:765.
In 1997, the first U.S. isolate of S. aureus intermittently susceptibe to vancomycin (minimum inhibitory concentration, 8 µg/mL) was isolated in Michigan.
Cohen SH, Morita MM, Bradford M. A 7-year experience with methicillin-resistant Staphylococcus aureus. Am J Med 1991;91 (Suppl 3B):233S.
The authors detail a comprehensive infection control program that has been effective in restricting the spread of MRSA in a university hospital setting.
Darouiche R, et al. Eradication of colonization by methicillin-resistant Staphylococcus aureus by using oral minocycline-rifampin and topical mupirocin. Antimicrob Agents Chemother 1991;35:1612.
By using a combination of systemic (minocycline and rifampin) and topical (mupi-rocin) antimicrobial therapy, the authors eradicated MRSA colonization from 91% of the patients and 95% of the sites.
Doebbeling BN, et al. Elimination of Staphylococcus aureus nasal carriage in health care workers: analysis of six clinical trials with calcium mupirocin ointment. Clin Infect Dis 1993;17:466.
After analyzing the data from double-blinded studies performed at six institutions that involved 339 health care workers with stable nasal carriage of S. aureus, the authors concluded that calcium mupirocin ointment administered intranasally for 5 days was safe and effective in eliminating the organism.
Fung-Tomac J, et al. Emergence of homogeneously methicillin-resistant Staphylococcus aureus. J Clin Microbiol 1991;29:2880.
In a study of 47 clinical isolates, the authors note that 100% of the strains recovered before 1987 were inhibited in vitro by ciprofloxacin but that only 60% of the strains obtained after 1987 were susceptible to the drug.
Haley RW, et al. The emergence of methicillin-resistant Staphylococcus aureus infections in United States hospitals. Ann Intern Med 1982;97:297.
Describes the onset of the problem of MRSA in U.S. hospitals and implicates “the house staff-patient transfer circuit” as contributing to the interhospital spread of the microbe.
Harbarth S, et al. Impact of methicillin resistance on the outcome of patients with bacteremia caused by Staphylococcus aureus. Arch Intern Med 1998;158:182.
In a retrospective study of almost 200 patients with staphylococcal bacteremia, the authors concluded that methicillin resistance alone exerted no significant impact on mortality rates.
Hershow RC, Khayr WF, Smith NL. A comparison of clinical virulence of nosocomially acquired methicillin-resistant and methicillin-susceptible Staphylococcus aureus in a university hospital. Infect Control Hosp Epidemiol 1992;13:587.
Patients infected with methicillin-susceptible and methicillin-resistant strains have similar demographic features, underlying diseases, clinical presentations, and outcomes.
Hicks NR, Moore EP, Williams EW. Carriage and community treatment of methicillin-resistant Staphylococcus aureus: what happens to colonized patients after discharge? J Hosp Infect 1991;19:17.
The majority of infants and mothers colonized with MRSA at discharge had persistent carriage after 4 weeks; the most common site of colonization was the perineum in mothers and the throat in infants.
Hsu CC. Serial survey of methicillin-resistant Staphylococcus aureus nasal carriage among residents in a nursing home. Infect Control Hosp Epidemiol 1991;12:416.
In this prospective study of nursing home patients, the authors found that MRSA colonization was present in 70% to 80% of the residents who were bedridden or had decubitus ulcers or foreign bodies, and that the presence of the organism within the facility was perpetuated by persistently or intermittently colonized residents.
Kauffman CA, et al. Attempts to eradicate methicillin-resistant Staphylococcus aureus from a long-term care facility with the use of mupirocin ointment. Am J Med 1993;94:371.
Although mupirocin ointment was effective in eliminating MRSA from the nares and wounds of colonized patients in a long-term care institution, recurrence rates were high and long-term use selected for resistant strains; these observations led the authors to conclude that mupirocin should be utilized only in the setting of an outbreak of infection with MRSA.
Kitagawa Y, et al. Rapid diagnosis of methicillin-resistant Staphylococcus aureus by nested polymerase chain reaction. Ann Surg 1996;224:665.
The use of polymerase chain reaction to detect the gene that codes for methicillin resistance represents a potential technique for the rapid determination of resistance.
Levine DP, Fromm BS, Reddy BR. Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis. Ann Intern Med 1991;115:674.
In this randomized study of 42 consecutive patients with MRSA endocarditis, therapy with vancomycin alone or vancomycin plus rifampin was equally effective.
Muder RR, et al. Methicillin-resistant staphylococcal colonization and infection in a long-term facility. Ann Intern Med 1991;114:107.
In this prospective cohort study, the investigators noted that staphylococcal infection was almost four times more likely to develop in patients colonized with methicillin-susceptible strains.
Mulhausen PL, et al. Contrasting methicillin-resistant Staphylococcus aureus colonization in Veterans Affairs and community nursing homes. Am J Med 1996;100:24.
In this prospective survey of more than 200 nursing home patients, the authors found that the prevalence of colonization was about 30% in Veterans Affairs nursing homes and 10% in community facilities.
Mulligan ME, et al. Methicillin-resistant Staphylococcus aureus: a consensus review of the microbiology, pathogenesis, and epidemiology with implications for prevention and treatment. Am J Med 1993;94:313.
Superb review that contains recommendations for the eradication of the carrier state and guidelines for infection control in a variety of settings.
Panililo AL, et al. Methicillin-resistant Staphylococcus aureus in U.S. hospitals, 1975– 1991. Infect Control Hosp Epidemiol 1992;13:582.
In a retrospective review of susceptibility data from 66,132 hospital isolates of S. aureus, the authors found that the percentage of strains resistant to methicillin had risen from 2.4% in 1975 to 29% in 1991; for hospitals with 500 beds or more, 38.3% of the isolates in 1991 were methicillin-resistant.
Piercy EA, et al. Ciprofloxacin for methicillin-resistant Staphylococcus aureus infections. Antimicrob Agents Chemother 1989;33:128.
The use of ciprofloxacin in the therapy of infections with MRSA can produce clinical cures; however, ciprofloxacin-resistant strains can emerge during therapy.
Sheretz RJ, et al. A cloud adult: the Staphylococcus aureus-virus interaction revisited. Ann Intern Med 1996;124:539.
The importance of the colonized anterior nares as a potential reservoir for epidemics of MRSA infection is highlighted by this report.
Tokue Y, et al. Comparison of a polymerase chain reaction assay with a conventional microbiologic method for detection of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 1992;36:6.
The polymerase chain reaction assay was found to be a sensitive method for the detection of MRSA.