Indian Pediatrics 2001; 38: 29-36
Methicillin Resistant - Staphylococcus Aureus
Before introduction of penicillins in 1940, patients with invasive staphylococcal disease had a mortality rate of about 90%. There was a remarkable improvement in the outcome of these patients after the introduction of penicillins(1). Staphylococcus aureus became resistant to penicillins very rapidly. For a few years, only hospital acquired S. aureus was resistant to penicillin, but ultimately commu-nity acquired S. aureus too became resistant to this drug. This resistance is due to hydrolysis of b-lactam ring of penicillins by b-lactamase enzyme produced by S.aureus(1). In 1960, methicillin-semisynthetic penicillin, relatively resistance to hydrolysis by b-lactamase was introduced. Very soon after its introduction, methicillin resistant Staphylococcus aureus (MRSA) was reported. Till few years ago, only nosocomially acquired MRSA (NAMRSA) was found to be resistant to methicillin, but recently even community acquired MRSA (CAMRSA)(2,3) has started showing resistance to methicillin. Fortunately, so far no case of community acquired MRSA has been reported from India.
Although antibiotics like oxacillin, nafcillin and cloxacillin have replaced methicillin in clinical practice, the term methicillin resistant S. aureus (MRSA) is still being used for resistance to all these antibiotics(1). MRSA is defined as an isolate having MIC of >4mg of oxacillin/ml(4). Methicillin sensitive S. aureus (MSSA) is defined as an isolate with MIC of <2 mg of oxacillin/ ml(4). Isolates having MIC of 2-4 mg/ml are defined as borderline resistant S. aureus (BRSA). Though, nosocomial acquired MRSA (NAMRSA) has been defined by some authors as one isolated from a specimen obtained within 72 hours of admission, this definition needs to be clarified, because so called CAMRSA may be due to presence of carrier stage after a previous hospitalization(5). If this is true, such strain is not community acquired in true sense.
Prolonged hospital stay, frequent contact with health care environment, surgical wounds, proximity to an infected or colonized patient, receipt of antibiotics in the previous 60 days and surgical procedures are known risk factors for NAMRSA(6). CAMRSA has been seen even in patients without any risk factors.
Resistance of S. aureus to methicillin is mediated by the production of a penicillin binding protein (PBP), which has low affinity for binding with b-lactam antimicrobials. Mec A is the gene encoding PBP present on the chromosome of all isolates of MRSA that had been described so far. This type of resistance is called intrinsic resistance. NAMRSA is usually also resistant to other antibiotics, e.g. aminoglycosides, erythromycin, clindamycin, trimethoprim-sulfamethoxazole. This has been attributed to the DNA, which flanks the Mec A gene and has many potential sites for integration of transposons (genetic elements mediating resistance to antibiotics)(5). BRSA have decreased susceptibility to methicillin because of a very high level of production of b-lactamase. Therefore, this type of resistance appears to be different from the intrinsic resistance(4).
The principal mode of transmission of MRSA is patient-to-patient transfer of the organism via transiently colonized hands of the hospital personnel. Hospital personnel acquire these organisms after direct patient contact or after handling the contaminated material. Air borne transmission is another important mode of transmission in patients with tracheostomies in Intensive Care Unit(7).
Experimental as well as clinical trials have shown that MRSA strain is as virulent as MSSA(8). Collopy et al. have shown that MRSA are more likely to be colonizing bacteria, whereas MSSA are more likely to be associated with infection(9). There are few differences in clinical presentation of CAMRSA and NAMRSA strains. It has been seen that CAMRSA in patients without risk factors usually presents with skin infections, e.g. cellulitis, impetigo and abscess. In one study, abscess was the diagnosis in 6/22 children with CAMRSA without risk factors compared with none of the 10 children with CAMRSA with risk factors and only 1/12 children with NAMRSA(5). In contrast NAMRSA presents more frequently with bacteremia without any focus(1).
Infected in-patients, hospital personnel and inanimate hospital environment are potential reservoirs for the organism. The common site for colonization of MRSA is anterior nares(10). Therefore, colonization usually remains undetected as this site is seldom cultured for clinical purposes. Cultures obtained from anterior nares are best to identify nasal carriage. In a study, 1600 employees with direct exposure to infected or colonized inpatients were surveyed for nasal carriage and 2% of them were found to be positive for MRSA(8). However, it has been observed that cultures of rectal swabs, cutaneous wounds and skin lesions may be helpful in identifying the carrier stage(11). It has been seen in one study that throat and perianal site screening have a higher sensitivity in children colonized with MRSA than nasal carriage(12). It has been shown experimentally that MRSA strains can survive on hands for more than 3 hours(8).
Strains of CAMRSA in patients without predisposing factors are usually resistant to only methicillin. NAMRSA is usually resistant to multiple antibiotics, e.g., b-lactam agents, erythromycin, clindamycin, and frequently to gentamicin and ciprofloxacillin also(13). In a study, it was observed that 76% of NAMRSA isolates were not susceptible to clindamycin, whereas only 24% of CAMRSA were not susceptible to clindamycin(1). It has been seen that multiple strains of MRSA can cause an epidemic in intensive care unit(4). Recently, resistance to vancomycin is also being reported in the literature(15). Table I shows mechanism of action and resistance of commonly used anti-staphylococcal antibiotics and Table II summarizes the drug dosages and availability of these antibiotics.
Till more reports of CAMRSA come, b- lactam antibiotics should be used as first line empiric. In centers, where CAMRSA is a problem and child with suspected staphylo-coccal infections is critically ill, vancomycin/clindamycin may be used as an alternative drug. As NAMRSA is resistant to multiple antibiotics, vancomycin should be the treat-ment of choice for NAMRSA.
Resistance of MRSA to Vancomycin
Vancomycin has been considered as the antibiotic of choice for MRSA(16). There is paucity of literature on use of vancomycin for MRSA in India, but no case of resistance to vancomycin have been reported from India. However, therapeutic failure of vancomycin for MRSA infections is a matter of great concern nowadays in the west(17). The first case of vancomycin resistance was reported in a 29-days-old child after cardiac surgery(18). The mechanism of this new resistance is not very clear. This new resistance is not due to Van A or Van b-genes-resistance genes of enterococci. It has been found that there is accumulation of cell wall component in S. aureus strains as well as increased binding to cell wall material(19).
Various other drugs used against MRSA are briefly enumerated below:
Rifampicin is highly bactericidal for MRSA. Therefore, in case of failure to response to only vancomycin, rifampicin can be added to vancomycin. Bacteria can develop resistance to rifampicin rapidly by developing mutations in RNA polymerase. Therefore, this drug should never be used alone for MRSA(16). Sanchez et al. have shown the effectiveness of combination of cotrimoxazole and rifampicin in patients with osteoarticular infections(20). Bahl et al. have also reported the benefits of combination of ciprofloxacillin and rifampicin for deep seated staphylococcal infections(21). However, Pulmood et al. from India have shown that only 57% strains of MRSA were susceptible to rifampicin(22).
Vancomycin and gentamcin have synergestic action against MRSA, even when organism is resistant to gentamycin in vitro. When this combination is being used, patient should be monitored closely for ototoxicity and nephrotoxicity. Pulmood et al. and Pal et al. from India have reported resistance to this drug as high as 84.2% and 51.8%, respectively(22,23).
It is a good alternative for vancomycin for staphylococcal disease. It has an additional advantage that it can be given orally. In a study by Markowitz et al., in adults. TMP-SMZ was effective against most of the strains of MRSA(24). Kimura et al. have shown the efficacy of TMP-SMZ for prevention of MRSA pneumonia in burn patients(25). How-ever, Indian studies have shown resistance to this drug as high as 97%(22,23). This may be due to excessive use of this drug for many other infections in our country.
Daum et al. have shown that 55% of the MRSA strains were resistant to cipro-floxacillin, whereas Blumberg et al. have shown this figure to be as high as 70% of strains(26,27). Similar is the experience of other authors(28). Pulmood et al. from Vellore have shown that 90% of 1382 isolates were resistant to ciprofloxacillin and 30 out of 39 isolates were resistant to this drug in a study from Chandigarh(22,23). The mechanism of this rapidly emerging resistance to cipro-floxacillin is not clearly understood.
Teicoplanin is a newer antibiotic chemically related to vancomycin(29). Lie et al. have used teicoplanin and vancomycin in a randomized trial and have seen that treatment was successful in 17 (85%) of 20 patients who were randomized to teicoplanin group and in 15 (75%) of 20 patients randomized to vancomycin group. In addition nephrotoxicity was significantly higher with vancomycin. Therefore they have concluded that teicoplann is as efficacious as vancomycin and has fewer side effects. Another advantage of teicoplanin is that it can be given by intramuscular route, has a longer half life and can be given in once daily dosage(30). There is no literature about use of this drug in India.
It is not much used in western literature for MRSA. However, Pulmood et al. from India have shown that 88% strains were sensitive to netilmycin(22).
In western literature, clindamycin has been shown to be a very effective drug for commu-nity acquired MRSA. However, Indian studies have not mentioned its use for MRSA.
Quinupristin/dalfopristine is a potent antistaphylococcal agent(31). Its activity has been shown to be superior to that of teico-planin and similar to that of vancomycin. Sambatakou et al. have shown that activity of this drug is enhanced, when it is combined with rifampicin or ciprofloxacillin(32). How-ever, this drug is not available in India.
A single strain of MRSA can spread rapidly and cause an epidemic in no time. Roman et al. shown the ability of a strain of MRSA to cause epidemic and global spread within 6 weeks(33). Therefore the spread should be controlled as soon as possible. Strict wound and skin precautions should be taken for colonized and infected wounds.
There should be strict isolation of patients with extensive burns and lower respiratory infections because of potential for airborne transmission. The Hospital Infection Control Practices Advisory Committee (HICPAC) and Communicable Disease Center (DCD) recommend that hospitalized children colo-nized or infected with MRSA should be kept in contact hospitalization(34). Requirements for the contact isolation are private room, gloves when touching infective material, masks for those who come close to patient and gowns, if soiling is likely(7). It is also recommended that patients with similar organisms should be kept either in single room or such patients should be cohorted. Although, it has been shown that there is not much use of gloves and gowns, their use can be justified as MRSA is found on environmental surfaces. There should not be any sharing of medical equipment between colonized and non-colonized patient. Colonized patient should be isolated till cultures obtained on three conse-cutive weeks demonstrate no colonization. Isolated children should not attend playroom and should not eat in the common canteen. There should be a system to identify a colonized patient, so that at the time of re-admission, immediate isolation can be done. All staff members should be educated about the importance of washing hands, even when they are using gloves. Although, it is recommended that antimicrobial soaps should be used for patients with contact isolation, actual 15-second hand washing is much important than type of soap used(11). Hexachlorophene hand washing has been found to be better than chlorhexidine, because of development of resistance to chlor-hexidine(35).
It has been recommended that, in case of epidemic in the hospital, all health care providers should be examined for MRSA colonization.
There are mainly two indications for eliminating carrier stage of MRSA. One is to stop an outbreak in health care setting and other is to prevent recurrent infections in a particular individual. In case of outbreak, carrier should be identified and should be removed from the workplace temporarily and treated.
Winner et al. have shown effectiveness of combination of topical bacitracin and orally administered rifampicin for 5 days. but there are chances of development of resistance to rifampicin. So, a combination of oral rifampicin-sulfamethoxazole may prevent emergence of rifampicin resistant mutants(36). Intranasal mupirocin has been shown to be effective in eliminating nasal carriage in few cases, but it is not much effective in patients with indwelling catheters or lesions on their skin. There are instances of development of resistance to these drugs with their repeated use. Bartzokas et al. have shown effectiveness of whole body wash with antiseptic solution in control and eradication of MRSA from a surgical unit(37).
An attempt should be to discharge the MRSA colonized patient as early as possible. There is little risk for the spread of MRSA to healthy persons residing in patientís house-hold. Discharge card of the patient should have clear mention of the patientís colonization. Similarly, at the time of transfer, colonization status of the patient should be mentioned in the transfer summary, so that adequate precautions are taken by the receiving hospital.
There is a great need to be aware of MRSA strains. MRSA is the new challenge for the physicians. Emerging resistance to vanco-mycin is the latest threat for the management of MRSA.
Presently, community acquired S. aureau should be treated with b-lactams and vancomycin is the treatment of choice for NAMRSA. Contact isolation of carriers as well as patients along with education of health personnel needs to be emphasized repeatedly.
Contributors: MS reviewed the literature and drafted the paper. MS critically revised the manuscript.