Indian Journal of Medical Microbiology Medknow Publications on behalf of Indian Association of Medical Microbiology ISSN: 0255-0857 EISSN: 1998-3646 Vol. 24, Num. 3, 2006, pp. 182-185

Indian Journal of Medical Microbiology, Vol. 24, No. 3, July-September, 2006, pp. 182-185

Original Article

Risk factors and associated problems in the management of infections with methicillin resistant Staphylococcus aureus

Srinivasan S, Sheela D, Shashikala, Mathew R, Bazroy J, Kanungo R

Department of Clinical Microbiology, Pondicherry Institute of Medical Sciences, Pondicherry - 605 014
Correspondence Address:Department of Clinical Microbiology, Pondicherry Institute of Medical Sciences, Pondicherry - 605 014, rebakanungo2001@yahoo.com

Code Number: mb06055

Abstract

Keywords: Hospital acquired infection, MRSA, multidrug resistance

Requirement for newer agents to treat infections caused by gram positive organisms is being increasingly felt as resistance to existing agents emerge and spread around the world. This is true particularly for infections due to methicillin resistant Staphylococcus aureus (MRSA). Ever since its first isolation in 1961, MRSA has emerged as one of the commonest causes of hospital acquired infection (HAI) and continues to remain an important factor contributing to failure of management.[1] Most of the isolates of MRSA have acquired resistance to commonly available antibiotics in the market. Several reports have appeared in medical literature regarding the prevalence and incidence in hospitals across the globe including India.[2],[3],[4],[5] Infections due to MRSA are associated with increased morbidity and mortality in hospitalized patients. It also has the potential to cause sudden outbreaks in hospitals. Cost of treatment is another major problem faced by patients in the developing countries. Vancomycin, the antibiotic of choice for serious infections has the potential for toxic side effects like renal impairment besides its prohibitive cost. Concerns about its reduced effectiveness and the development of resistance are mounting. The present study was carried out to identify the pattern and the factors influencing the persistence of MRSA. An effort was also made to determine the out come of treatment including costs with some effective antibiotics and their minimum inhibitory concentrations.

Materials and Methods

All clinically significant Staphylococcus aureus isolated in the department of clinical microbiology, PIMS between March and August 2004 were screened for methicillin resistance. Standard screening procedure using 1 µg/mL oxacillin disc was carried out.[6],[7] All MRSA were tested against vancomycin (30 µg), teicoplanin (30 µg), linezolid (30 µg), ofloxacin (5 µg), rifampicin (5 µg), chloramphenicol (30 µg), gentamicin (10 µg) and clindamycin (2 µg) by Kirby- Bauer disc diffusion technique. Minimum inhibitory concentration (MIC) of vancomycin, linezolid, chloramphenicol, gentamicin and ciprofloxacin was estimated for 50 clinical isolates by agar dilution method as per NCCLS guidelines. ATCC Staphylococcus aureus 25923 was used as a reference strain.

With a preset protocol, relevant history from the 50 patients with MRSA collected which included history of prior antibiotics, prior hospitalization, presence of other underlying disease and admission in ICU/burns unit. They were followed up till repeat cultures showed negative results. Analysis of the data was done by using simple proportions and also by comparison of means of two independent samples.

Results

A total of 150 Staphylococcus aureus were isolated during the study period. Fifty strains (33.3%) were identified as MRSA among the isolates. Surgical units (postoperative wound infections) accounted for 80% (40) of the isolates when compared to 20% (10) in medical units. Postoperative infections in orthopedic surgery accounted for 28% (14), plastic and general surgery with 26% (13) each followed by 16% (8) in surgical ICU. Bacteraemia and respiratory infections were 8% (4) each, catheter associated UTI due to MRSA was the least with 4% (2) isolates in the medical units. The highest number of isolation was found during the second week followed by fifth week and third week. This difference was not statistically significant. The distribution of risk factors among fifty patients is shown in the figure. Prior antibiotic use was most commonly noted in 44% (22) of the patients followed by emergency surgery in 32% (16), prior hospitalization in 26% (13), presence of other disease 22% (11) and admission in ICU/burns unit in 14% (7).

Analysis of risk factor distribution with the day of MRSA isolation is shown in [Table - 1]. There was significant statistical difference ( P < 0.01) between the mean day of isolation in emergency admissions when compared to three other risk factors namely presence of underlying disease, admission in ICU/burns unit and prior antibiotic use. A significant statistical difference ( P < 0.05) was noted between mean day of isolation and underlying diseases and prior antibiotic use. Hence the risk factors observed were prolonged post operative morbidity, prior antibiotic therapy and emergency admissions.

MIC of antibiotics tested were within the breakpoint range for vancomycin (≤ 4 µg/mL) and linezolid (≤ 4 µg/mL) whereas for gentamicin and ciprofloxacin only 2 and 4% of the strains were within the breakpoint range (≤ 4 µg/mL and ≤ 1 µg/mL) respectively [Table - 2].

Postoperative morbidity, catheterization, respiratory intubation were the common contributing factors to infection by MRSA. Complete eradication was noted in patients treated with vancomycin, ofloxacin, clindamycin and combination of ofloxacin with rifampicin [Table - 3]. Chloramphenicol did not control wound infections in those patients who were treated with this antibiotic. [Table - 3] also shows the cost of treatment using each of the antibiotics. Wide variation of cost was noted. Ofloxacin was found to be the cheapest and vancomycin the most expensive, for a full course of seven days treatment.

Discussion

Presently MRSA along with Pseudomonas and Acinetobacter are the common organisms associated with hospital acquired infections worldwide. Prevalence of MRSA varies markedly by institutions. The prevalence of MRSA in this hospital was determined to be 33%, generally conforming to the average Indian data.[8],[9] Antibiotic pressure is known to select mutants that can survive the adverse conditions. In a hospital, constant use of antibiotics results in survival and spread of MRSA, extended spectrum beta lactamase producers and multidrug resistant enterococci.[8],[10] By virtue of changing the penicillin binding sites PBP, MRSA survives in the presence of almost all beta lactam antibiotics, the mainstay of treating most infections in modern hospital practice. Major factor in the mechanism of resistance to betalactams in MRSA is known to be the alteration at the site of penicillin binding protein, PBP2′or PBP2 resulting in low affinity for the betalactams.[11] Prior antibiotic treatment primes the organism to develop resistance.[12] As evident in our study 44% of the patients who developed infection by MRSA, had consumed antibiotics either as outpatients or as inpatients for more than one to two weeks either continuously or intermittently. Ten percent of patients who were admitted elsewhere for treatment and subsequently referred to this hospital were found to be infected with MRSA at the time of admission. Hospital to hospital transmission may also be responsible for increasing the load of MRSA in referral hospitals.

Maximum number of MRSA were recovered from postoperative surgical site infections in the present study. This has also been reflected in a study conducted by Krisnaparakash et al.[11] Although it is logical that longer the patient stays in the hospital, greater is the chance of acquiring infections by MRSA,[10] our study showed that 44% of the isolation was during the first two weeks while 56% were isolated between third and eighth weeks. The study conducted by Mehta et al .[3] found that patients staying for more than 15 days in the hospital had increased risk of infection. However, it must be noted that 44% of the isolation was within the first two weeks of hospital stay. Our study also highlights that emergency admissions have an earlier chance of infection compared to those with other risk factors and presence of underlying diseases led to earlier chance of MRSA being isolated than those who had history of prior antibiotic use.

Resistance to most betalactam antibiotics and some of the other classes of antibiotics poses a problem in treating an infection with MRSA.[9] Vancomycin, a glycopeptide antibiotic has been the drug of choice[12],[13] for treatment of serious staphylococcal infections for decades with no resistance emerging until the late 90s. MRSA with reduced susceptibility to vancomycin was first reported in 1997 in Japan.[14] Full blown resistance to this antibiotic has been reported from US.[15],[16] Resistant strains responsible in serious infections underscore the need for the development of alternate antimicrobial agents to vancomycin. Non compliance is often a problem among poor patients due to the high cost of a full course of vancomycin or other glycopeptides.

In the present study, response to treatment with vancomycin, linezolid, ofloxacin, clindamycin, chloramphenicol and combination of ofloxacin and rifampicin, against the MRSA strains have been assessed. Linezolid was found to be as effective as vancomycin in the treatment of nosocomial pneumonias as well as skin and soft tissue infections. Similar findings have also been noted by Brent et al[17] and Michael et al .[18]

Linezolid appears to be one of the few available antimicrobial agents with proven activity against multiresistant Staphylococcus aureus including strains with reduced susceptibility to glycopeptides.[18] In the present study all isolates were sensitive to linezolid and oxazolidinone with a MIC range between 0.25-2 µg/mL. All the patients receiving linezolid had full recovery as shown by negative follow up cultures. Linezolid has been approved for human use[10] following in vitro studies to demonstrate antimicrobial activity against gram positive pathogens such as Staphylococcus aureus, CONS, Streptococcus pneumoniae and vancomycin resistant enterococci.[17] The antibiotic showed a good in vitro activity in the present study. However, the drug being bacteriostatic has to be given for longer duration, which may counterbalance its cost efficacy.

Although intermediate and high level resistance to vancomycin has been reported,[19] the present study showed a MIC value of ≤ 4 µg/mL. Hence, it is still effective in the management of MRSA. One isolate from bloodstream infection, two from urinary tract infection and three from wound infection were inhibited at 4 µg/mL of vancomycin. This is of concern as the level is at the higher margin of susceptible level. This may be prelude to developing tolerance or frank resistance. Alternate antibiotics need to be evaluated. Ofloxacin when given in combination with rifampicin was found to be a good and cheap alternative to vancomycin. Seven patients with wound infections, who were treated with this combination were cured.

Clindamycin, (lincosamide antibiotic) was found to be another useful alternative in treating patients with MRSA. Arjanne et al have found that 99% of MRSA were sensitive to clindamycin.[20] All 50 isolates in this study were sensitive to clindamycin by the Kirby-Bauer disc diffusion technique. Clindamycin, however, has not found favour as it can cause pseudomembranous colitis. Although chloramphenicol showed consistent sensitivity in vitro by disc diffusion and a low MIC level, it failed to eradicate infection in two of the patients with wound infections who were treated for two weeks. Its role as a topical agent to eradicate nasal and skin carriers may be explored.

Minimum inhibitory concentration of gentamicin and ciprofloxacin showed high levels (> 32 µg /mL and > 16 µg /mL respectively), thereby ruling out their role in the treatment of MRSA infection. These two antibiotics are presently being used both in the hospital and community for gram negative infection and have no role in the treatment of MRSA infection. High cost of treatment is one of the major causes of non compliance by patients. In a developing country like ours, majority of the patients are unable to afford a full course. This results in a vicious cycle of inadequate treatment leading to emergence of further resistance and spread of MRSA. Therefore, it is imperative to explore alternate effective antibiotic regimen to eradicate MRSA from the hospital and avoid spread in the community. In conclusion, the present study identified prior antibiotic use and admission to intensive care units as some of the risk factors associated with infections due to MRSA. Emergency admissions had a higher chance of early isolation. Oxazolidinone (linezolid), clindamycin and combination of ofloxacin and rifampicin were found to be effective alternatives to vancomycin. Clindamycin showed very good in vitro activity. Its use may be explored cautiously. Effective prevention and control of infections due to MRSA depends on practice of infection control measures such as hand washing. Minimizing risk factors and attention to alternate cost effective combination therapy may ease the problem of management of infections with MRSA.

References

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