Linezolid-resistance Staphylococcus aureus – Prevalence, Emerging Resistance Mechanisms, Challenges and Perspectives

Staphylococcus aureus, an opportunistic pathogen, can root several infections viz skin and tissue infections, bacteraemia, food poisoning, pneumonia, and many other clinical conditions with some variations of virulence factors. In treatment of infections, caused by this Gram-positive pathogen, several antibiotics are being used importantly Methicillin and Vancomycin. This pathogen has high capability of antibiotic resistance development and had evolved new strains such as Methicillin-resistant Staphylococcus aureus (MRSA), and Vancomycin-resistant Staphylococcus aureus (VRSA). Meta-analysis in Ethiopia showed that pooled prevalence of MRSA in environment, food, animal, and human was 54%, 77%, 15%, and 38% respectively (2022). Risk of MRSA isolates from burn ICU was 55 % higher (2018). In Bangladesh, 37.1% isolates from frozen meat chicken (2021) were identified as MRSA. This problem is being dealt with a novel drug called Linezolid which has been proved effective against both MRSA and VRSA. Exacerbating the situation, this pathogen has shown resistance against this unprecedented drug by means of a number of drug resistance mechanisms. Its prevalence has been reporting since the adoption of the drug, but with a minute ratio at one time/place to the very high percentage at another time/place. This inconsistent prevalence must not be ignored, and its surveillance should be augmented as antibiotic treatment is critical for fighting against microbial infections. This review highlights the worldwide reports in which Staphylococcus aureus of either wildtype or Methicillin or Vancomycin resistance that have shown resistance to Linezolid drug for the past 2 decades. At the same time where incidences of Linezolid Resistant Staphylococcus aureus (LRSA) indications are reporting, there is a call for comprehensive strategies to overcome this challenge of antibiotic resistance.

[1]  Ruhul A. Khan,et al.  A review on antibiotic resistance and way of combating antimicrobial resistance , 2021 .

[2]  E. Clementi,et al.  Supra-therapeutic Linezolid Trough Concentrations in Elderly Patients: A Call for Action? , 2020, Clinical Pharmacokinetics.

[3]  M. El-Nakeeb,et al.  Prevalence and mechanisms of linezolid resistance among staphylococcal clinical isolates from Egypt , 2020, European Journal of Clinical Microbiology and Infectious Diseases.

[4]  M. Tsai,et al.  Linezolid as salvage therapy for central nervous system infections due to methicillin-resistant Staphylococcus aureus at two medical centers in Taiwan. , 2020, Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi.

[5]  Tangjuan Liu,et al.  Antibacterial synergy between linezolid and baicalein against methicillin-resistant Staphylococcus aureus biofilm in vivo. , 2020, Microbial pathogenesis.

[6]  C. Cabellos,et al.  Linezolid for therapy of Staphylococcus aureus meningitis: a cohort study of 26 patients , 2020, Infectious diseases.

[7]  Yhu-Chering Huang,et al.  Evolution of Multi-Resistance to Vancomycin, Daptomycin, and Linezolid in Methicillin-Resistant Staphylococcus aureus Causing Persistent Bacteremia , 2020, Frontiers in Microbiology.

[8]  S. Sheppard,et al.  The emergence of plasmid-borne cfr-mediated linezolid resistant-staphylococci in Vietnam. , 2020, Journal of global antimicrobial resistance.

[9]  C. Sola,et al.  Oxidative stress response in reference and clinical Staphylococcus aureus strains under Linezolid exposure. , 2020, Journal of global antimicrobial resistance.

[10]  M. Nawaz,et al.  Incidence of Vancomycin Resistant Phenotype of the Methicillin Resistant Staphylococcus aureus Isolated from a Tertiary Care Hospital in Lahore , 2019, Antibiotics.

[11]  G. I. Makarov,et al.  A noncanonical binding site of linezolid revealed via molecular dynamics simulations , 2019, Journal of Computer-Aided Molecular Design.

[12]  Rui Wang,et al.  Linezolid and Its Immunomodulatory Effect: In Vitro and In Vivo Evidence , 2019, Front. Pharmacol..

[13]  Kanwardeep Singh,et al.  Emerging Antimicrobial Resistance in Staphylococcus and Spectrum of Oral Oxazolidinone Linezolid in Multidrug Resistant Staphylococcus in a Tertiary Care Hospital , 2019, International Journal of Contemporary Medical Research [IJCMR].

[14]  N. Lee,et al.  Linezolid Resistance in Methicillin-Resistant Staphylococcus aureus in Korea: High Rate of False Resistance to Linezolid by the VITEK 2 System , 2019, Annals of laboratory medicine.

[15]  B. Kot,et al.  Antimicrobial Resistance Patterns in Methicillin-Resistant Staphylococcus aureus from Patients Hospitalized during 2015–2017 in Hospitals in Poland , 2019, Medical Principles and Practice.

[16]  G. Igrejas,et al.  First report of linezolid-resistant cfr-positive methicillin-resistant Staphylococcus aureus in humans in Portugal. , 2019, Journal of global antimicrobial resistance.

[17]  S. Hassan,et al.  Evaluation of antibiotic resistance pattern in clinical isolates of Staphylococcus aureus. , 2019, Pakistan journal of pharmaceutical sciences.

[18]  L. A. Vitali,et al.  Staphylococcus aureus carriage among food handlers in a pasta company: pattern of virulence and resistance to linezolid , 2019, Food Control.

[19]  F. Doucet-Populaire,et al.  Emergence and Within-Host Genetic Evolution of Methicillin-Resistant Staphylococcus aureus Resistant to Linezolid in a Cystic Fibrosis Patient , 2018, Antimicrobial Agents and Chemotherapy.

[20]  E. Ishii,et al.  Therapeutic Effect of Linezolid in Children With Health Care–Associated Meningitis or Ventriculitis , 2018, Clinical pediatrics.

[21]  Amira Amine,et al.  Vancomycin resistance among Staphylococcus aureus isolates in a rural setting, Egypt. , 2018, Germs.

[22]  Liang Chen,et al.  Dissemination of cfr-mediated linezolid resistance among Staphylococcus species isolated from a teaching hospital in Beijing, China , 2018, The Journal of international medical research.

[23]  S. Hashemian,et al.  Linezolid: a review of its properties, function, and use in critical care , 2018, Drug design, development and therapy.

[24]  S. Gardner,et al.  Manuka honey and methylglyoxal increase the sensitivity of Staphylococcus aureus to linezolid , 2018, Letters in applied microbiology.

[25]  M. Saeed,et al.  Detection of high levels of resistance to linezolid and vancomycin in Staphylococcus aureus. , 2017, Journal of medical microbiology.

[26]  N. Mbembati,et al.  Prevalence of methicillin-resistant Staphylococcus aureus carriage on admission among patients attending regional hospitals in Dar es Salaam, Tanzania , 2017, BMC Research Notes.

[27]  A. Protti,et al.  Linezolid-induced lactic acidosis: the thin line between bacterial and mitochondrial ribosomes , 2017, Expert opinion on drug safety.

[28]  M. Ahmed,et al.  Nasal carriage of enterotoxigenic Staphylococcus aureus among food handlers in Kerbala city , 2017 .

[29]  T. Lithgow,et al.  Structural Basis for Linezolid Binding Site Rearrangement in the Staphylococcus aureus Ribosome , 2017, mBio.

[30]  M. Pfaller,et al.  Five-Year Summary of In Vitro Activity and Resistance Mechanisms of Linezolid against Clinically Important Gram-Positive Cocci in the United States from the LEADER Surveillance Program (2011 to 2015) , 2017, Antimicrobial Agents and Chemotherapy.

[31]  S. Khan,et al.  Susceptibility profile of methicillin-resistant Staphylococcus aureus to linezolid in clinical isolates , 2017, International journal of health sciences.

[32]  M. Yousefi,et al.  Linezolid: a promising option in the treatment of Gram-positives , 2017, The Journal of antimicrobial chemotherapy.

[33]  K. Hiramatsu,et al.  Rapid Acquisition of Linezolid Resistance in Methicillin-Resistant Staphylococcus aureus: Role of Hypermutation and Homologous Recombination , 2016, PloS one.

[34]  D. Carter,et al.  Therapeutic Manuka Honey: No Longer So Alternative , 2016, Front. Microbiol..

[35]  Abdulrasheed Abdu,et al.  Linezolid and Methicillin Resistances in S. aureus Isolated from the Anterior Nares of Apparently Healthy Undergraduates of the Niger Delta University, Nigeria , 2016 .

[36]  K. Fukuchi,et al.  Linezolid-resistant Staphylococcus aureus isolated from 2006 through 2008 at six hospitals in Japan. , 2015, Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases.

[37]  Vance G. Fowler,et al.  Staphylococcus aureus Infections: Epidemiology, Pathophysiology, Clinical Manifestations, and Management , 2015, Clinical Microbiology Reviews.

[38]  Idoko,et al.  Occurrence and antibiogram profile of Staphylococcus aureus isolated from some hospital environment in Zaria, Nigeria , 2015 .

[39]  M. Gilmour,et al.  Tedizolid: A Novel Oxazolidinone with Potent Activity Against Multidrug-Resistant Gram-Positive Pathogens , 2015, Drugs.

[40]  R. Goering,et al.  Linezolid-Resistant Staphylococcus aureus Strain 1128105, the First Known Clinical Isolate Possessing the cfr Multidrug Resistance Gene , 2014, Antimicrobial Agents and Chemotherapy.

[41]  F. Giampieri,et al.  The Composition and Biological Activity of Honey: A Focus on Manuka Honey , 2014, Foods.

[42]  Hanine Mansour,et al.  Tedizolid: a new oxazolidinone antimicrobial. , 2014, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[43]  J. Rello,et al.  European perspective and update on the management of nosocomial pneumonia due to methicillin-resistant Staphylococcus aureus after more than 10 years of experience with linezolid. , 2014, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[44]  X. Ye,et al.  The Efficacy and Safety of Linezolid and Glycopeptides in the Treatment of Staphylococcus aureus Infections , 2013, PloS one.

[45]  M. Ebrahimi,et al.  Vancomycin and Linezolid Resistant Staphylococcus in Hospitalized Children , 2012 .

[46]  B. Wadher,et al.  Detection of resistance to linezolid in Staphylococcus aureus infecting orthopedic patients. , 2012, Indian journal of pathology & microbiology.

[47]  R. Jenkins,et al.  Synergy between oxacillin and manuka honey sensitizes methicillin-resistant Staphylococcus aureus to oxacillin. , 2012, The Journal of antimicrobial chemotherapy.

[48]  B. Diep,et al.  Linezolid effects on bacterial toxin production and host immune response: review of the evidence. , 2012, Current therapeutic research, clinical and experimental.

[49]  L. Rice,et al.  Emergence of Linezolid-Resistant Staphylococcus aureus after Prolonged Treatment of Cystic Fibrosis Patients in Cleveland, Ohio , 2011, Antimicrobial Agents and Chemotherapy.

[50]  F. Martínez Sagasti,et al.  Clinical outbreak of linezolid-resistant Staphylococcus aureus in an intensive care unit. , 2010, JAMA.

[51]  Gracia Morales,et al.  Resistance to linezolid is mediated by the cfr gene in the first report of an outbreak of linezolid-resistant Staphylococcus aureus. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[52]  S. North,et al.  Linezolid-resistant ST36 methicillin-resistant Staphylococcus aureus associated with prolonged linezolid treatment in two paediatric cystic fibrosis patients. , 2010, The Journal of antimicrobial chemotherapy.

[53]  Ronald N. Jones,et al.  Linezolid surveillance program results for 2008 (LEADER Program for 2008). , 2009, Diagnostic microbiology and infectious disease.

[54]  E. Stobberingh,et al.  The evolution of Staphylococcus aureus. , 2008, Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases.

[55]  H. Rohde,et al.  Emergence of Linezolid Resistance in a Methicillin Resistant Staphylococcus aureus Strain , 2008, Infection.

[56]  T. Wichelhaus,et al.  Linezolid Resistance in Staphylococcus aureus: Gene Dosage Effect, Stability, Fitness Costs, and Cross-Resistances , 2008, Antimicrobial Agents and Chemotherapy.

[57]  M. Furue,et al.  Linezolid versus vancomycin for the treatment of infections caused by methicillin-resistant Staphylococcus aureus in Japan. , 2007, The Journal of antimicrobial chemotherapy.

[58]  Ronald N. Jones,et al.  LEADER surveillance program results for 2006: an activity and spectrum analysis of linezolid using clinical isolates from the United States (50 medical centers). , 2007, Diagnostic microbiology and infectious disease.

[59]  J. Quinn,et al.  Acquisition of a natural resistance gene renders a clinical strain of methicillin‐resistant Staphylococcus aureus resistant to the synthetic antibiotic linezolid , 2007, Molecular microbiology.

[60]  A. Mankin,et al.  The site of action of oxazolidinone antibiotics in living bacteria and in human mitochondria. , 2007, Molecular cell.

[61]  H. K. Tiwari,et al.  Emergence of vancomycin resistant Staphylococcus aureus (VRSA) from a tertiary care hospital from northern part of India , 2006, BMC infectious diseases.

[62]  S. S. Andrade,et al.  Emergence of linezolid-resistant Staphylococcus aureus during treatment of pulmonary infection in a patient with cystic fibrosis. , 2006, International journal of antimicrobial agents.

[63]  M. Kollef,et al.  Linezolid versus vancomycin for Staphylococcus aureus bacteraemia: pooled analysis of randomized studies. , 2005, The Journal of antimicrobial chemotherapy.

[64]  G. Eliopoulos,et al.  Reversion to susceptibility in a linezolid-resistant clinical isolate of Staphylococcus aureus. , 2004, The Journal of antimicrobial chemotherapy.

[65]  S. Kaplan,et al.  Linezolid versus vancomycin for treatment of resistant Gram-positive infections in children , 2003, The Pediatric infectious disease journal.

[66]  Mary Jane Ferraro,et al.  Linezolid resistance in a clinical isolate of Staphylococcus aureus , 2001, The Lancet.

[67]  S. Schwarz,et al.  Identification of a Plasmid-Borne Chloramphenicol-Florfenicol Resistance Gene inStaphylococcus sciuri , 2000, Antimicrobial Agents and Chemotherapy.

[68]  A. Fatima,et al.  In-vitro susceptibility of Methicillin resistant Staphylococcus aureus isolates to linezolid at a tertiary care hospital of Karachi, Pakistan , 2018 .

[69]  R. Humphries,et al.  The emerging problem of linezolid-resistant Staphylococcus. , 2013, The Journal of antimicrobial chemotherapy.

[70]  Y. Nakipoğlu,et al.  Prevalence of phenotypic resistance of Staphylococcus aureus isolates to macrolide, lincosamide, streptogramin B, ketolid and linezolid antibiotics in Turkey. , 2010, The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases.

[71]  K. Fukuchi,et al.  Linezolid-resistant methicillin-resistant Staphylococcus aureus isolated after long-term, repeated use of linezolid , 2009, Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy.

[72]  E. Calderón-Jaimes,et al.  Linezolid diminishes inflammatory cytokine production from human peripheral blood mononuclear cells. , 2006, Archives of medical research.

[73]  J. A. Andrews,et al.  Linezolid resistance in clinical isolates of Staphylococcus aureus. , 2003, The Journal of antimicrobial chemotherapy.

[74]  C. Perry,et al.  Linezolid: a review of its use in the management of serious gram-positive infections. , 2001, Drugs.