1. Management of clinically important Gram positive MDRO in skin, soft tissue and bone infections
Dr (Prof) RAJU VAISHYA (MS, MCh Orth, FRCS Eng) President, Arthritis Care Foundation & Sr. Consultant Orthopaedic & Joint Replacement Surgeon Indraprastha Apollo Hospitals, New Delhi

2. What is MDRO?
Microorganisms that have developed resistance to multiple types of antibiotics.
These bacteria are present on the bodies of many people, including on the skin, in the nose or other moist areas of the body, and in secretions.
Antibiotic resistance often occurs following frequent antibiotic use or frequent exposure to a health care setting. For most healthy people, these bacteria don’t cause a problem.
MDRO can enter the body and cause infection. MDRO are most likely to enter the body if:
- There is an open wound in the skin
- There is an IV, catheter or other invasive device in place
- The person has a suppressed immune system.

3. Epidemiology
Infections caused by Gram positive organisms have a poorer prognosis when the infecting strain is multidrug resistant.
These strains have been progressively causing increased mortality, morbidity, and health care costs with bone, skin and soft tissue infections.
About 40% of S. aureus infections acquired in large hospitals (500 or more beds) are methicillin-resistant.
Reports of emergence of vancomycin resistance in Gram positive bacteria from India are ever increasing.
In many Indian hospitals, the percentage of MRSA has ranged from 29% to 35% of all clinical isolates.

4. Pathogenesis of MDRO
These microorganisms employ several mechanisms in attaining multi-drug resistance:
Alteration of the peptidoglycan synthesis pathway
Acquisition of extrachromosomal genetic elements containing resistance genes
Enzymatic deactivation of antibiotics
Decreased cell wall permeability to antibiotics
Altered target sites of antibiotic
Efflux mechanisms to remove antibiotics
Increased mutation rate as a stress response.

5. Potential sites for MDRO
Biomaterial or allograft surfaces present free energy sites which are available for occupation by protein (fibronectin), thus forming a biofilm.
The production of slime by some strains of Staphylococcus epidermidis reduces antibiotic penetration and may aid their colonization of such surfaces.

6. Musculoskeletal infections by MDRO
1) Acute bacterial arthritis
2) Septic bursitis
3) Osteomyelitis
4) Prosthetic Joint Infections (PJI)
5) Skin & Soft tissue infections

7. ACUTE BACTERIAL ARTHRITIS
Diagnosis : Patient’s demographics, clinical history, physical exam, laboratory and imaging.
Synovial fluid examination – cell count, crystal examination under polarized light, gram stain, aerobic/anaerobic bacterial cultures.
Gram positive isolates in bacterial arthritis :
MRSA (Methicillin Resistant Staphylococcus aureus)
Coagulase negative Staphylococci
Streptococcus pyogenes
Streptococcus pneumoniae
Streptococcus agalactiae

8. Other Streptococci
Streptococcus pneumoniae is a relatively rare cause of septic arthritis and raises the question of underlying immunosuppression.
β-Haemolytic streptococci are also responsible for bone infection, e.g. Lancefield group B osteomyelitis in neonates and Group A septic arthritis in other age groups.

9. Management: Prompt joint drainage + antimicrobial therapy
Gram positive cocci in stain – Vancomycin mg/kg IV daily administered q 8-12 hours is the empiric therapy (Linezolid or Daptomycin, if patient intolerant of Vancomycin)
MSSA in culture – anti-staphylococcal Penicillin or first generation cephalosporin.
MRSA in culture – Vancomycin mg/kg IV (Linezolid or Daptomycin, if patient intolerant of Vancomycin)
VISA (Vancomycin Intermediate Staphylococcus aureus) in culture – Linezolid or Daptomycin.
Septic arthritis & no other viable treatment for MRSA- Quinupristin-dalfopristin and Tigecycline.

10. SEPTIC BURSITIS
Causative agent : 80% Staphylococcus aureus and Streptococcus species
Diagnosis : Aspirated fluid examination for cell count, crystals, Gram stain and culture
Management : Daily aspiration + antimicrobial therapy.
CA-MRSA : Clindamycin, trimethoprim-sulfamethoxazole, and minocycline

11. Coagulase negative Staphylococci
OSTEOMYELITIS
Microbiology of Osteomyelitis:
Common (>50% of cases)—
MRSA
Coagulase negative Staphylococci
Occasionally encountered (>25% of cases)—
Streptococci
Enterococci

12. Microorganisms First choice Alternative choice
Antimicrobial therapy of Osteomyelitis
Microorganisms
First choice
Alternative choice
Staphylococci
MSSA
MRSA
Nafcillin sodium or Oxacillin sodium g IV or Cefazolin 1-2 g IV
Vancomycin 15 mg/kg IV or Daptomycin 6mg/kg IV
Vancomycin 15mg/kg IV
Linezolid 600mg PO/IV or Levofloxacin 500mg PO/IV + Rifampin 600mg PO
Penicillin sensitive Streptococci
Aqueous penicillin G 20×106 U/24 hr IV or Ceftriaxone 1-2g IV or IM or Cefazolin 1-2g IV
Enterococci or Streptococci
Aqueous crystalline penicillin G 20×106 U/24 hr IV or Ampicillin sodium 12g/24 hr IV

13. Prosthetic Joint Infection (PJI)
Diagnosis : Clinical, Laboratory, Radiological
Aspirated joint fluid for cell count, ESR, CRP, crystals, protein content, glucose content, gram stain.
Operative specimens of tissue and fluid for culture.
Diagnostic value of Number of Positive Operative Cultures
Number positive
Probability of Infection (%) 3
94.8 2
20.4 1
13.3
3.4

14. Biofilm
An assemblage of surface-associated microbial cells that is enclosed in an extracellular polymeric substance matrix. Staphylococcus aureus and Staphylococcus epidermidis are the most common biofilm-forming bacteria.
In prosthetic joint infection (PJI), biofilm bacteria can attach to hardware components, cement, bone and fibrous tissue, and detached clumps of biofilm can also be found in the joint fluid.

15. Higher accumulation of biofilms are found on Cobalt-Chromium based materials, polystyrene, porcelain, silicon, and polycarbonate surfaces than that on titanium or zirconia that are used for prosthetic structures.
Polymerase chain reaction (PCR) assays – to detect presence of infections, particularly within BIOFILMS.

16. Bacteriology of PJI Pathogens Frequency (%)
Coagulase negative staphylococci 22
MRSA
Alpha-hemolytic streptococci 9
Beta-hemolytic streptococci A, B, G 5
Enterococci 7

17. Management :
Complete removal of all foreign materials (metallic prosthesis, cement, and any accompanying biofilm), followed by a 6 week course of antimicrobial therapy.
Streptococci– Aqueous penicillin G 20×106 U/24 hr IV or Ceftriaxone 1-2g IV or IM or Cefazolin 1-2g IV
Enterococci – Aqueous crystalline penicillin G 20×106 U/24 hr IV or Ampicillin sodium 12g/24 hr IV
MSSA – anti-staphylococcal Penicillin or first generation cephalosporin.
MRSA – Vancomycin mg/kg IV (Linezolid or Daptomycin, if patient intolerant of Vancomycin)

18. Future prospects:
Surface-tethered antibiotics and metal oxide nanoparticle prosthetic coatings for the prevention of biofilm formation.
Local antibiotic delivery from absorbable bone cements with no permanent surface for biofilm formation.
Vaccines targeting biofilm-specific components, such as the EPS
Dispersal agents as antibiotic adjuvants that attack the EPS matrix, breaking up biofilms and releasing bacterial cells.

19. SKIN AND SOFT TISSUE INFECTIONS
Infections caused by Gram positive Organisms :
Impetigo
Staphylococcal Scarlet fever
Toxic Shock Syndrome
Folliculitis
Furuncles & Carbuncles
Ecthyma
Erysipelas
Cellulitis
Paronychia
Necrotizing fasciitis
Pyoderma

20. SKIN AND SOFT TISSUE INFECTIONS
Diagnosis : Gram-stained smears, cultures, anti-streptolysin O titer.
Management :
Primary therapy – Dicloxacillin or Amoxicillin-clavulanate or Cephalexin or Cefadroxil
CA-MRSA – Co-trimoxazole, Clindamycin and macrolides.
MRSA- topical antibiotics like Mupirocin, Retapamulin; oral therapy like Co-trimoxazole, Clindamycin or Linezolid; intravenous like Vancomycin or Daptomycin.

21. New resistance patterns :
Methicillin resistant Staphylococcus aureus (MRSA) Community acquired MRSA (CA-MRSA) Hospital acquired MRSA (HA-MRSA) Vancomycin-intermediate Staphyloccus aureus (VISA) Vancomycin resistant Staphylococcus aureus (VRSA) Vancomycin-resistant Enterococcus (VRE)

22. New drugs to fight Gram positive MDROs :
Linezolid, Tedizolid Daptomycin Vancomycin Ceftaroline, Ceftobiprole Tigecycline Telavancin,Dalbavancin, Oritavancin Quinipristin-Dalfopristine

23. Linezolid, Tedizolid Linezolid:
Blocks the protein synthesis providing broad activity against Gram-positive bacteria (with little to no Gram-negative activity)
High oral bioavailability (approximately 100%)
Indicated for vancomycin-resistant Enterococcus faecium (VRE)
Tedizolid:
* Offer advantages over Linezolid to include coverage of Linezolid-resistant isolates and once daily dosing.

24. Daptomycin
A bactericidal concentration-dependent lipopeptide that promotes the efflux of potassium out of bacterial cells,
leading to cell death.
It is indicated for the treatment of SSTIs (6 mg/kg) and other infections caused by Gram-positive bacteria.

25. Vancomycin
A glycopeptide antibiotic with a number of labeled indications for use against GPC, primarily MRSA.
It includes complicated infections in seriously ill patients, SSTIs, prosthetic joint infections.

26. Ceftaroline, Ceftobiprole
Ceftaroline & Ceftobiprole are anti-MRSA cephalosporins that were approved by the FDA in 2010 for the treatment of community acquired bacterial pneumonia (CABP) and acute bacterial skin and soft structure infections (ABSSSI).
Ceftaroline works by binding to penicillin-binding proteins (PBPs) inhibiting their ability to function as transpeptidases in cell wall synthesis.
It is unique for its affinity for PBP2a and PBP2x providing activity against MRSA and MDRSP including ceftriaxone resistant strains.

27. Tigecycline
A glycylcycline, an analog of tetracyclines with an extended spectrum of activity to include:
- Resistant Gram-positive organisms such as MRSA
- Specific resistant Gram-negative bacteria
- Extended spectrum β-lactamase producing Enterobacteriaceae
- As salvage therapy for susceptible strains of Acinetobacter
- Multi-drug resistant (MDR) pathogens.

28. Telavancin, Dalbavancin, Oritavancin
These are novel lipoglycopeptide antibiotics approved for the treatment of acute bacterial skin and skin structure infections due to Gram-positive pathogens and has recently received approval for the treatment of HAP caused by these pathogens.
Unlike other glycopeptides, telavancin maintains its antimicrobial activity against pathogens with decreased susceptibility to glycopeptides, including VISA and hVISA strains, and exhibits more rapid concentration-dependent bactericidal activity against susceptible organisms.

29. Quinupristin-Dalfopristin
Quinupristin-Dalfopristin is a combination of steptogramins for use in the treatment of serious or life-threatening infections associated with vancomycin-resistant Enterococcus faecium bacteraemia and complicated skin and skin structure infections caused by methicillin susceptible Staphylococcus aureus and Streptococcus pyogenes (group A streptococcus).
The combination of Quinupristin-Dalfopristin and synergistic and bactericidal.

30. Conclusion
Proper sample collection technique is of paramount importance to rule out any false positive growth of multidrug resistant microorganisms.
Active screening rather than passive surveillance is recommended for high-risk specialties.
Contact precautions must be applied for those patients who present an infection risk. Where possible, single-room isolation should be provided for these patients.
Use Personal Protective Equipment (PPE) like disposable gloves and gowns or aprons to care for patients with MDR Gram-positive bacteria. Hand hygiene is required before and after direct patient contact.
Environmental screening should be considered. Respiratory and other contaminated equipment should be decontaminated.
Appropriate antibiotics with broad spectrum & good anti-staphylococcal activity is recommended.