Drugs for Bone and soft tissue infections

1. Drugs for Bone and soft tissue infections

2. Principles of antimicrobial therapy Drug Host Microbe

3. Name of the disease Etiological agent (s) Signs and symptoms Treatment (drug of choice and one alternative drug)

4. SkinNormal Flora • Mostly gram-positive bacteria • staphylococci • micrococci • corynebacteria (diphtheroids) • Propionibacterium acnes • Vigorous washing reduces but does not completely eliminate • Sweat glands and hair follicles help to reestablish bacterial flora S. aureus

5. impetigo Ecthyma Erysipelas Cellulitis Panniculitis Necrotizing fasciitis

6. Impetigo (S. pyogenes, S. aureus) Folliculitis: infection of hair follicle (S. aureus) Furuncle: deep inflammatory nodule usually developing from folliculitis (S. aureus) Carbuncle: more extensive than a furuncle with involvement of the subcutaneous fat (S. aureus)

7. 1. 2. 3. 4. 5.

8. Skin and soft tissue IDSA 2005

9. Phenoxymethylpenicillin Flucloxacillin Cloxacillin Dicloxacillin • Similar profile : • Comparable bioavailability after oral administration dicloxacillin /cloxacillin (48.8% and 36.9%) • The elimination rate was similar the urinary recovery of active dicloxacillin was higher in young subjects and that the non-renal • clearance was higher in elderly volunteers. • Dicloxacillin: risk of thrombophlebitis • (NSW advisory, 2000) • better oral absorption (53.7% and 32.9%, respectively) • slower (renal and extra-renal) elimination (T1/2 : 46 and 32 min, respectively). • high risk of cholestatic hepatitis PHP 32

11. Cellulitis: extending subcutaneous tissues (S. aureus, S. pyogenes, anaerobes) Erysipelas: (S. pyogenes) Staphylococcal Toxic Shock Syndrome: (S. aureus) Scalded skin syndrome (S. aureus)

12. Common Antibiotics for skin and soft tissue infections

13. Nafcillin • resistant to inactivation by the enzyme penicillinase (beta-lactamase). • relatively acid-stable and have reasonable bioavailability. • The peak OX levels in serum were at least twice the peak NAF level, but the half-life of NAF in the serum (2.1 hours) was about twice that of OX (1.1 hours). • Nafcillin is associated with neutropenia; oxacillin can cause hepatitis

15. Soft Tissue Infections • Myositis • infection of skeletal muscle (rare) • S. aureus, S. pyogenes (rare), mixed organism

16. Soft Tissue Infections • Necrotizing fasciitis • “flesh-eating disease” • sever infection involving the subcutaneous soft tissue, particularly the superficial and deep fascia • predisposing conditions: diabetes, abdominal surgery, perineal infection, trauma • organisms: S. pyogenes, C. perfringens, mixed aerobic and anaerobic bacteria • treatment surgical debridement, antibiotics, +immunoglobulins

18. Gas gangrene • rapidly progressive, life-threatening, toxemic infection of skeletal muscle due to clostridia

19. Antibiotics for MRSA

20. Why are MRSA important? MRSA: Strains that are oxacillin and methicillin resistant, historically termed methicillin-resistant S.aureus (MRSA), are resistant to all ß-lactam agents, including cephalosporins and carbapenems. • Pathogenicity.MRSA have many virulence factors that enable them to cause disease in normal hosts. • Limited treatment options.Vancomycin and two newer antimicrobial agents, linezolid and daptomycin, are among the drugs that are used for treatment of severe healthcare-associated MRSA infections. • MRSA are transmissible. CDC

21. Linezolid: Prevents bacterial protein synthesis by binding to the 23S ribosomal RNA of 50S subunit fMet - tRNA Initiation Factors 30S + mRNA Linezolid blocks formation of the initiation complex mRNA 30S ribosome 50S ribosome 70S Initiation Complex Elongation Elongation Factors Peptide Product Aminoglycosides Macrolides Streptogramins

22. Linezolid Use: • Works against aerobic gram-positive organisms • Infections caused by MRSA/VRE Pdynamics: • Linezolid is administered by intravenous infusion or orally (100% oral bioavailability) • have significant penetration into bone, fat, muscle, and hematoma fluid • metabolism is non-enzymatic and does not involve CYP450; Non-renal clearance accounts for 65% of an administered linezolid dosage (no adjustment in renal failure)

23. Safety of Linezolid • common adverse events in children are diarrhea, vomiting, loose stools, and nausea • Toxicity: Duration-dependent bone marrow suppression, Thrombocytopenia is the most common manifestation, • non-selective inhibitor of monoamine oxidase (MAO) =neuropathy, and optic neuritis  serotonin-syndrome may occur when coadministered with other serotonergic drugs (eg, selective serotonin reuptake inhibitors); lactic acidosis

24. Daptomycin • Daptomycin is a lipopeptide class antibiotic that disrupts cell membrane function via calcium-dependent binding, resulting in bactericidal activity in a concentration-dependent fashion. • It is a naturally-occurring compound found in the soil microbe Streptomycesroseosporus.

25. Lipopeptides • treatment of complicated skin and soft tissue infections due to gram-positive bacteria (but not anaerobes) • Bacteriocidal against multidrug-resistant, gram-positive bacteria • Methicillin-resistant Staphylococcus aureus • Vancomycin-resistant enterococci • Glycopeptide-intermediate and -resistant S. aureus. • Penicillin-resistant Streptococcus pneumoniae

26. Daptomycin • Post antibiotic effect • Once daily dosing • Elevations Adv events:  in creatininephosphokinase (CPK), rarely treatment limiting muscle pain or weakness; daptomycin-induced eosinophilic pneumonia have been described Excreted mainly through kidneys

31. Types of bone/joint infections • Arthritis (infective/septic) • Osteomyelitis • Prosthetic bone and joint infections

33. Bone Infections • Septic arthritis • infection of joint spaces • hematogenous or contiguous • S. aureus, Streptococcus spp., Gram-negative bacilli • Osteomyelitis • infection of the bone • hematogenous or contiguous • S. aureus, S. pyogenes, H. influenzae, Gram-negative bacilli

34. RISK FACTORS / Manifestations • Pain • Swelling, redness, warmth • Purulent exudate • Systemic • Fever • Chills • Nausea • Malaise • Trauma • Diabetes • Hemodialysis • Splenectomy • Advanced age  Immune function • Poor circulation

35. CAUSES • Direct Contamination/contiguous focus (80% • Most common: S aureus (50%) • Neonatal: grp B streptococci & E.coli • Adults: S. aureus, P. aeruginosa, Serratia, Candida, Tuberculosis • surgical procedures, bites, puncture wounds, open fractures, periph vascular disease • Hematogenous (20%) • tibia, femur and humerus in children • Vertebral bodies in drug users\\\ • and older adults • Polymycrobial; often gram negative and anaerobic bacteria

36. Gonococcal ArthritisTenosynovitis, dermatitis, polyarthralgia syndrome • Typically seen in young adults • Acute illness with fever, chills, malaise. • Tenosynovitis • Generalized arthralgia • Dermatitis: pustular or vesicopustular • Monoarticular or Pauciarticular • Large joint involvement (knees, wrists, ankles) • Most patients are afebrile • Signs of disseminated infection are rare

37. DIAGNOSTIC STUDIES • MRI • CT • Bone Scan • Ultrasound • Labs: • Sed Rate • WBC’s • Cultures

38. Initial empirical antibiotic choice in suspected septic arthritis

39. Duration of treatment • Hematogenous 4-6 weeks • Contiguous focus 2 wks after debridement • Chronic 4-6 wks

40. Diabetic foot infection

42. Management • Surgical debridement (may not be necessary in children) • Antibiotics for 4-6 weeks (at least 2wks IV) – multiple courses may be necessary Rheumatology 2006 45(8):1039-1041;

43. Septic ArthritisEpidemiology Risk factors • Elderly or very young • Underlying chronic illness • Increased incidence with warmer climates and poorer socioeconomic status • 1:10,000 annual incidence in Northern European children • Age > 80 years • Comorbid conditions (especially diabetes) • Joint damage from arthritis • Prosthetic joint • Skin & extraarticular infection • Immune suppression (malignancy or treatment) • Cirrhosis • Chronic renal failure and hemodialysis • IV drug abuse • Prior antibiotic use

44. Pathogenesis • No previous joint disease or illness in 54% • 72% of infections were hematogenous in origin • Staph aureus 37% • Strep pyogenes 16% • Neisseria gonorrhea 12% 1. Hematogenous 2. Dissemination from osteomyelitis 3. Spread from adjacent soft tissue infection 4. Diagnostic or therapeutic measures 5. Penetrating damage by puncture or cutting. • Clinical Features • Joint swelling and pain • Pain with range of motion, immobility • Fever • Signs of sepsis • Distribution usually monoarticular • Large joints most often involved

45. Joint Adults % Children % Knee 55 40 Hip 11 28 Ankle 8 14 Shoulder 8 4 Wrist 7 3 Elbow 6 11 Others 5 3 Multiple joints (12) (7) Septic ArthritisJoints affected (non-gonococcal)

46. Temp < 38.3 in 14/40 • WBC < 15K in 13/38 • ESR < 30 in 4/36 • Synovial fluid WBC < 50K in 8/22 Septic ArthritisNatural History Experimental bacterial arthritis induced Maximal acute arthritis symptoms Chronic or irreversible changes 0 1 2 3 4 5 6 7 8 Time (days)

47. Type Features WBC/mm3 Normal Clear, colorless, Viscous <200 <25% PMNs Non-Inflammatory Clear, Yellow, viscous 200-2000 <25% PMNs Inflammatory Cloudy, Yellow, Watery Glucose may be low 2000-100,000 >50% PMNs Septic Purulent Glucose very low 80,000 >90% PMNs Classification of Joint Effusions

48. Septic ArthritisAdults versus Children

49. Rheumatology 2006;45:1039–1041

50. Viral Arthritis • Inflammatory polyarthritis, similar to early RA • Duration usually < 1 month, self limited illness • Not destructive to joint • Prodromal symptoms • Fever • Rash • Supportive Treatment (NSAIDs, Analgesics) No Antibiotic treatment !!!