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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 1  |  Page : 23-30

Safety and efficacy of linezolid treatment in comparison with vancomycin for methicillin-resistant Staphylococcus aureus nosocomial infection: A prospective study in Mysore City, South India


1 Department of Pharmacology, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, Karnataka, India
2 Department of Biotechnology and Bioinformatics, School of Life Sciences, JSS Academy of Higher Education and Research, Mysore, Karnataka, India

Date of Submission07-May-2020
Date of Decision05-Aug-2020
Date of Acceptance11-Oct-2020
Date of Web Publication2-Feb-2021

Correspondence Address:
M K Jayanthi
Department of Pharmacology, JSS Medical College, JSS Academy of Higher Education and Research, Mysore - 570 015, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijhas.IJHAS_42_20

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  Abstract 


BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent causative agent of nosocomial infection in health-care setups causing morbidity and mortality. Treatment with vancomycin remains the standard protocol for the antibiotic treatment. However, the emergence of vancomycin-resistant strains has prompted the use of alternate drug therapies. Linezolid is the best alternative to combat this resistant strain. In the present study, we aim to evaluate the clinical evidence of linezolid treatment in MRSA-infected patients within Mysore city.
METHODS: This prospective study assessed the efficacy of linezolid and vancomycin for the treatment of MRSA infections. Fifty patients who fit into the inclusion criteria were considered from four tertiary hospitals. Five milliliters venous blood (only once), pus, urine, sputum, and aspirates were collected from MRSA patients and evaluated by culture studies for its susceptibility to various antibiotics.
RESULTS: Results of this study demonstrate that linezolid treatment as oral and intravenous preparations is as effective as vancomycin with 100% efficiency and fewer adverse effects (79 in 40 patients vs. 64 in 16 patients) for the treatment of MRSA nosocomial infection. The observed adverse effects includes local pain (P = 0.312) and thrombophlebitis (P = 0.005) with vancomycin; and anemia (P = 0.348) and thrombocytopenia (P = 0.313) with the use of linezolid. The findings were consistent with the existing knowledge database.
CONCLUSION: The results from the study indicate that linezolid offers the same benefit as vancomycin with far fewer drawbacks.

Keywords: Linezolid, methicillin-resistant Staphylococcus aureus, nosocomial infection, vancomycin


How to cite this article:
Jatin V K, Jayanthi M K, Ramu R. Safety and efficacy of linezolid treatment in comparison with vancomycin for methicillin-resistant Staphylococcus aureus nosocomial infection: A prospective study in Mysore City, South India. Int J Health Allied Sci 2021;10:23-30

How to cite this URL:
Jatin V K, Jayanthi M K, Ramu R. Safety and efficacy of linezolid treatment in comparison with vancomycin for methicillin-resistant Staphylococcus aureus nosocomial infection: A prospective study in Mysore City, South India. Int J Health Allied Sci [serial online] 2021 [cited 2021 Apr 13];10:23-30. Available from: https://www.ijhas.in/text.asp?2021/10/1/23/308587




  Introduction Top


Methicillin-resistant Staphylococcus aureus (MRSA)/oxacillin-resistant S. aureus is a frequent causative agent of nosocomial infection in health-care set ups all over the world, causing morbidity and increase in the duration of hospital stay and associated cost.[1],[2],[3],[4] Nosocomial infections are among the most prevalent in the intensive care unit and responsible for about 99,000 deaths worldwide as per a recent data by the center for disease control.[5] These infections are known to affect 1 in 10 patients admitted to the hospital. A recent report from the National Nosocomial Infection Surveillance System indicates that about 60% of the presently identified S. aureus isolates are resistant to some of the standard antibiotics such as methicillin, oxacillin, or nafcillin.[6] About 25%–50% of all S. aureus isolates were obtained from hospitals (known as hospital-acquired MRSA [HA-MRSA]) in the United States and several other industrialized countries.[7],[8] In India, 40% of the S. aureus isolates were of the methicillin-resistant variety in 2009.[9]

Especially methicillin resistance is now considered an endemic in India with close to 25% incidence in the western India whereas over 50% in the southern India.[10],[11] Yet another source of acquiring MRSA is community-acquired MRSA (CA-MRSA) and has been increasing remarkably in the country.[12] MRSA infection is confounded by the existence of comorbid conditions and the limited choice of drugs available for the treatment, as compared to methicillin-susceptible S. aureus infections.[6],[10],[11],[12] The Indian Network for Surveillance of Antimicrobial Resistance was set up with the support of the World Health Organization (WHO) to network microbiology laboratories of premier medical institutions from all over India with the aim to monitor the antimicrobial susceptibility patterns of common bacterial isolates including S. aureus.

Most strains of MRSA can be treated with vancomycin, a glycopeptide antibiotic.[13] although vancomycin resistance has been emerging and is likely to be a major cause of concern.[14] Linezolid, a member of the oxazolidinone group of antibiotics, offers a promising alternative to the conventional treatment by vancomycin, and is now considered as the best option to treat MRSA infections as it is effective against both CA-MRSA and HA-MRSA.[15] While vancomycin acts by inhibiting the cell wall synthesis by binding to the specific D-Ala-D-Ala terminal of the growing peptide during cell wall synthesis thereby preventing peptidoglycan cross-linking, linezolids act as a protein synthesis inhibitor thereby arrests the growth of bacteria by disrupting their production of proteins and in turn the cell functions. However, among the two antibiotics, bacterial resistance to linezolid has remained very low since it was first detected in 1999, although it may be increasing.[16] Several studies have proved that linezolid fared much better than vancomycin and were associated with fewer ill effects.[17],[18],[19],[20] While most research proves better or equal efficacy exerted by linezolid as compared to vancomycin, a meta-analysis of nosocomial pneumonia proved that on the evaluation of 8 randomized control trials, linezolid was not superior to vancomycin.[21],[22] Therefore, the aim of the present study was to evaluate the safety and efficacy of linezolid in comparison with that of vancomycin in treating patients with confirmed MRSA infections.


  Methods Top


This was an observational prospective cohort study conducted from June to August 2013, at Mysore city, the third-largest city in Karnataka. The Mysore district has a total population of 29,94,744.[23] The initial sample size was taken as 50 individuals who exactly fit into the inclusion criteria for the study [Table 1]. Four tertiary care hospitals within the city limits were included in this study. We obtained approval from the Institutional Ethics Committee, and each patient selected for observational evaluation signed a written informed consent, explained in his/her own language before participating in the study.
Table 1: General and infection-specific inclusion and exclusion criteria for patients in a study of linezolid versus vancomycin for treatment of methicillin-resistant Staphylococcus aureus infections

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A list of MRSA culture-positive patients was made after visiting the department of microbiology in the various tertiary care hospitals. Individuals were selected based on the inclusion criteria [Table 1]. Some of the samples were resubmitted to ensure the consistency of results. The patients were provided details regarding the foreseeable risk or discomfort to the subject resulting from participation in the study. The procedures mentioned in this study have been reported to be safe and only experienced medical experts are going carry out these procedures. The participating patients were given the right to prevent use of his/her biological sample at any time of conduct of the research. 5 ml venous blood (only once), pus, urine, sputum, aspirates were collected from MRSA patients for the study. The microbiology data included collection and processing of blood cultures positive for S. aureus only; culture and antibiotic sensitivity for each of the sample were performed using antibiotics such as amoxicillin/clavulanic acid, cefotaxime, ceftriaxone, ciprofloxacin, clindamycin, co-trimoxazole, erythromycin, gentamycin, imipenem, levofloxacin, linezolid, oxacillin, ofloxacin, penicillin, teicoplanin, and vancomycin.

Antibiotic susceptibility test was performed as per the procedure given by Kirby–Bauer disk diffusion method. The above-mentioned antibiotics were used for the assay as per standard protocols and the obtained results were interpreted using the guidelines given by Clinical and Laboratory Standard Institute, 2015. Minimum inhibitory concentration assay for vancomycin was using agar dilution method.

Efficacy variables

There were three possible clinical outcomes, “cure,” “failure of treatment,” and “missing.” The categorization depended on the duration of therapy and the resolution of the symptoms. “Cure” was when the symptoms subsided after a minimum of 10 doses of the study drug and/or minimum of 1-week duration, with no demonstrable microbiological proof of MRSA. “Failure of treatment” was the when the signs and symptoms persisted for a duration of more than or equal to 2 days, with a minimum of four doses of the drug administered and microbiologically demonstrable MRSA. The outcomes were assigned missing if the duration of treatment was <2 days or 2 doses.

Safety variables

All adverse events were recorded from patients who received at least one dose of either drug under consideration. The vitals were monitored in such cases with appropriate hematological testing. We noted the type of adverse event, hematological parameters, and serum electrolytes in all studies. A random blood sugar of >200 mg/dL (11.1 mmol/l) in association with typical symptoms was considered as indication for diabetes mellitus.[24] Normal values considered for the study are shown in [Table 2].[25]
Table 2: Normal Reference Ranges for Hematological investigations

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Statistics

The results were expressed as mean ± standard deviation and categorical data are expressed as proportions and percentages. Furthermore, the following separate analyses were performed: (i) Data entry of patient details from the records, pooling of the data; (ii) assessment of the outcomes across all the recordings; (iii) One-way analysis of variance along with tests for significance, Student's t-test for clinical cure; (iv) Calculation of odds ratio, 95% confidence intervals and determining risk differences. A two-tailed P < 0.05 was considered statistically significant. Missing data were reported as is instead of being imputed.


  Results Top


One hundred and thirteen patients were initially screened, 56 of which exactly satisfied the inclusion and exclusion criteria of having MRSA nosocomial infection. 40 (71.43%) patients received treatment with linezolid (hereafter labeled as “Linezolid group”) and 16 (28.57%) received vancomycin (hereafter labeled as “Vancomycin group”). Most patients were more than 60 years of age (n = 8 [50%]) in the vancomycin group as compared to the linezolid group (n = 12 [30%]). There was a difference in mean ages between treatment groups (mean age, 49.65 ± 19.82 years vs. 59.75 ± 12.06 years; P = 0.03). The male: female ratio was 29:11 for linezolid group and 11:5 for vancomycin group. Other than this, patients were evenly distributed between the groups, based on other demographic variables [Table 3]. The most common type of infection comprised the skin and soft-tissue infections (SSTIs) representing 80.35% (n = 45) of all the cases. Skin ulcers and abscesses (n = 25 [44.65%]) remained the commonest presentations of SSTIs. Other SSTIs include cellulitis (n = 18 [32.14%]) and infected surgical incision or wounds (n = 2 [3.6%]). Ventilator-associated pneumonia was present in 5 individuals, 3 (5.4%) of which belonged to the linezolid group and 2 (3.6%) to the vancomycin group. Bacteremia was reported in 4 (7.1%) individuals from linezolid group and 2 (3.6%) individuals from the vancomycin group [Table 3].
Table 3: Summary of baseline demographics and clinical characteristics of study population

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As far as the existing comorbidities were concerned, there were a total of 34 conditions reported in 29 (51.78%) individuals. Diabetes mellitus was the highest reported comorbidity (n = 15 [26.78%]) followed by congestive cardiac failure (n = 8 [14.28]), renal insufficiency (n = 9 [16.07%]) and finally active malignancies (n = 2 [3.57]). These seemed to show varying prognosis in due course of treatment.

Out of the 56 isolates of MRSA, the antibiotic sensitivity testing showed that all isolates were resistant to penicillin and oxacillin. There were 9 isolates (8 [14.3%]) that were either resistant or had inducible resistance (n = 1 [1.8%]) to vancomycin, 3 (5.4%) were resistant to linezolid, the other drugs under consideration. A large proportion of the results showed the resistance to the third generation cephalosporins-cefotaxime (54 [96.4%]) and ceftriaxone (44 [78.6%]), while a sizeable proportion remained sensitive to antibiotics such as clindamycin (31 [55%]), co-trimoxazole (26 [46.4%]), erythromycin (27 [48.2%]), and gentamycin (33 [58.9%]). Isolates were not simultaneously resistant to both linezolid and vancomycin [Table 4]. Linezolid group had 100% cure rates while two treatment failures were noted with vancomycin. This was however not statistically significant (P > 0.05) [Table 5]. There was no incidence of dropout of participants.
Table 4: Antibiotic susceptibility test pattern of Methicillin- resistant Staphylococcus aureus isolates in the study (n=56)

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Table 5: Clinical and microbiological outcomes in the study of linezolid versus vancomycin for treatment of methicillin-resistant Staphylococcus aureus infections

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Safety data

There were a total of 143 adverse events reported during the study. As expected, there were more cases of thrombocytopenia with linezolid use (10 [12.6%]) than with vancomycin (2 [3.1%]). This was, however, not statistically significant. Diarrhea and thrombophlebitis (P = 0.005) were a more common occurrence among the vancomycin group (P = 0.004) [Table 6].
Table 6: Summary of the most frequent adverse events encountered in the study of linezolid versus vancomycin in the treatment of methicillin- resistant Staphylococcus aureus infections

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Two deaths were reported during the study, both under vancomycin treatment. Although the death could not be comprehensively linked to the use of the drug, it could not be conclusively excluded either. The two deaths were associated with multi-system organ failure. Neutrophilia was more commonly encountered with linezolid use (19 [47.5%]), while lymphocytosis was higher in vancomycin group (2 [12.5%]) than in linezolid group (5 [8.92%]) [Figure 1] and [Figure 2].
Figure 1: Differential leukocyte count patterns of patients of linezolid group. Note: The dotted lines indicate the upper and lower limits for the normal range of neutrophils in the differential count [Table 2]

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Figure 2: Differential leukocyte count patterns of patients of vancomycin group. Note: The dotted lines indicate the upper and lower limits for the normal range of neutrophils in the differential count [Table 2]

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  Discussion Top


Previous studies on the efficacy of linezolid treatment over that of vancomycin has given contrasting findings. Some results like the randomized control trial for nosocomial pneumonia proved that linezolid produced benefit in clinical response when compared to vancomycin,[17] keeping the 60-day mortality rate similar.[17],[18] Even the retrospective analysis of two randomized, double-blind studies showed that linezolid was associated with significantly better clinical cure and survival rates.[19] The systematic review of nosocomial PNA showed that despite superiority in pK/pD, linezolid failed to show clear advantage compared to vancomycin in clinical trials carried out recently.[20] In addition, there were fewer adverse events and incidences of thrombocytopenia (1.3% vs. 2.2%), anemia (5.2% vs. 7.2%), cardiac arrest (1.8% vs. 2.2%), pancreatitis (0.8% vs. 0.2%), pancytopenia/neutropenia (0.6% vs. 0.4%), paresthesia (0 vs. 0.2%), polyneuropathy (0 vs. 0.2%), and renal failure (3.7% vs. 7.3%) with the use of linezolid as compared to vancomycin.[18] While most research proves better or equal efficacy of linezolid when compared to vancomycin, a meta-analysis of nosocomial pneumonia proved that on evaluation of 8 randomized control trials, linezolid was not superior to vancomycin.[22]

In the foregoing prospective research work, a variety of factors influence the outcome of nosocomial MRSA infection. S. aureus, which is a frequent part of the normal human skin flora and anterior nares of nasal passages,[26],[27] gets access to cross the protective barrier of the skin whenever the hospital interventions cause a breach in its continuity. The presence of comorbid conditions also generally has a negating effect on the clinical and microbiological cure of MRSA infections as is demonstrated in this study and several other studies.[28],[29],[30] As is evident from this result, MRSA infection is associated with an increased incidence of patient morbidities such as bacteremia, septic shock, amputation, and finally, mortality.[31],[32],[33],[34]

This study is the only reported prospective observational study with proven MRSA infections. More than 100 patients with proven MRSA infection enrolled into the study, out of which 56 patients met all the criteria clinically and microbiologically. The two treatment groups consisted of matched demographics. MRSA comprised almost 65% of all the S. aureus isolates in the laboratories, consistent with the National Nosocomial Infection Surveillance System that indicate MRSA in hospitals continue to rise and is now nearly 60% which is a stark increase from 54.5% as reported in 1999.[6] Conventionally, vancomycin has been the drug of choice for the treatment for MRSA strains with multidrug resistance. Among the newer drugs, linezolid is the forerunner to replace vancomycin.[35]

Surprisingly, although several studies describe linezolid to be more potent over vancomycin, IDSA/ATS guidelines equate the efficacy of both the antibiotics.[36],[37] Therefore, the safety differences between linezolid and vancomycin as reported previously were evaluated in this study, including all the adverse events and treatment failures. The results were as expected-vancomycin showed more adverse events per say (64 events in 16 patients), including local pain (9 [14.0%]) and thrombophlebitis (11 [17.1%]) [Table 6], as compared to linezolid (79 events in 40 patients), which characteristically included thrombocytopenia and bleeding tendencies (10 [12.6%]). There was no serious life-threatening anaphylactic reaction reported from either group. Oral linezolid preparations were very popular among the clinicians due to their 100% oral bioavailability. Vancomycin was a drug given only via intravenous route, still the incidences of GI disturbances were more with its use (20 [31.25%]).

Our initial hypothesis could be proven practically with the increased preference for linezolid in the treatment of MRSA, but statistically our study was not able to prove it conclusively (P = 0.095 i.e., <0.05 for clinical cure of linezolid vs. vancomycin). This might primarily be due to the limited sample size (n = 56) and the short normal duration of therapy for either drug to effectively correlate the late effects such as thrombocytopenia and other such events that might have occurred after the study was completed, although an effort was made to follow-up the discharge records and contact the enrolled patients even at the time of analysis to include any significant events. Apart from the two deaths in the vancomycin group, there were no fatalities reported to date in the study population. The treatment duration was similar in both cases. More epidemiological, drug-related studies such as this are needed to establish the trend of multidrug-resistant nosocomial infections such as MRSA and to evaluate the most appropriate drug therapy for the patients with a view of both clinical cure and monetary and time considerations. The indiscriminate use of broad-spectrum antimicrobial agents in hospital setups coupled with the limited choices of antimicrobials to specifically treat multidrug resistant nosocomial infection is of great concern.[38],[39] Antibiotic policy of the healthcare establishments should ideally make continual analyses to determine and practice uniformly the drug protocols. The results of this study demonstrate that linezolid therapy is safer, better tolerated, and as effective as vancomycin in the treatment of MRSA infections.


  Conclusion Top


The results were consistent with our hypothesis that linezolid remains an effective option as an antimicrobial agent when used in the treatment MRSA. Linezolid treatment as oral and intravenous preparations is as effective as vancomycin with fewer adverse events and better result with cent percentage cure rates in the treatment of MRSA-induced nosocomial infection. The availability of linezolid as oral preparation is deemed desirable.

Acknowledgment

We would like to express our sincere gratitude to faculty members and staffs of Department of Pharmacology, Biochemistry, JSS medical college, JSS Academy of Higher Education and Research (JSS AHER) Mysore – 570015, Karnataka, India, for their time and corporation in completing this work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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