Drugs for Bone and soft tissue infections

Principles of antimicrobial therapy

Drug

HostMicrobe

Name of the diseaseEtiological agent (s)Signs and symptoms Treatment (drug of choice and one alternative drug)

Skin Normal 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

impetigo

Ecthyma

Cellulitis

Panniculitis

Necrotizing fasciitis

Erysipelas

Folliculitis: infection of hair follicle (S. aureus)

Impetigo (S. pyogenes, 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)

1.2.

3.

4.5.

Skin and soft tissue

IDSA 2005

• 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

PhenoxymethylpenicillinCloxacillin Dicloxacillin

Flucloxacillin

PHP 32

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)

Cloxacillin Dicloxacillin Oxacillin FlucloxacillinR: ClR1: H

R: ClR1: Cl

R: HR: H

R: ClR1: F

Bioavailability % 6.0 3.1 6.9 5.3Protein binding % 94.7 96.9 93.1% 94.7Cost 28.50 na 212/vial 32.35Indications (Need) Staphylococcal skin infections and cellulitis

Pneumonia (adjunct) / Osteomyelitis, septic arthritis Septicaemia / Empirical treatment for endocarditis Surgical prophylaxis

Cellulitis: extending subcutaneous tissues (S. aureus, S. pyogenes, anaerobes)

Erysipelas: (S. pyogenes)

Staphylococcal Toxic Shock Syndrome: (S. aureus)

Scalded skin syndrome (S. aureus)

Common Antibiotics for skin and soft tissue infections

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

Soft Tissue Infections• Myositis

– infection of skeletal muscle (rare)– S. aureus, S. pyogenes (rare), mixed organism

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

Gas gangrenerapidly progressive, life-threatening, toxemic infection of skeletal muscle due to clostridia

Antibiotics for MRSA

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

Linezolid :Initiation Factors

30S ribosome

mRNA50S

ribosome

30S + mRNA

fMet - tRNA

Elongation Factors

70S Initiation Complex

Peptide Product

Elongation

AminoglycosidesMacrolides Streptogramins

Linezolid blocks formation of the

initiation complex

Prevents bacterial protein synthesis by binding to the 23S ribosomal RNA of 50S subunit

LinezolidUse:• Works against aerobic gram-positive organisms• Infections caused by MRSA/VREPdynamics:• 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)

•

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

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 Streptomyces roseosporus.

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

Daptomycin

• Post antibiotic effect• Once daily dosing• ElevationsAdv events:

in creatinine phosphokinase (CPK), rarely treatment limitingmuscle pain or weakness; daptomycin-induced eosinophilic pneumonia have been described

Excreted mainly through kidneys

Types of bone/joint infections

• Arthritis (infective/septic)• Osteomyelitis• Prosthetic bone and joint infections

Bacteria Acute Septic Arthritis

Prosthetic Joint Infection Septic Bursitis Osteomyelitis

Staphylococcus aureus +++ +++ +++ +++Coag negative Staph +++

Hemolytic Streptococcus ++ ++ ++ ++Other Streptococci + + +

Skin anaerobes + +++ +Gram-negative cocci + +

Hemophylus influenza + + +Gram-negative anaerobes + ++ + +Pseudomonas aeruginosa + + +

Salmonella + + +Intestinal anaerobes +

Mycobacteria + +

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

RISK FACTORS / Manifestations Trauma Diabetes Hemodialysis SplenectomyAdvanced age Immune function

Poor circulation

Pain Swelling, redness,

warmth Purulent exudate Systemic

Fever Chills Nausea Malaise

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

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

DIAGNOSTIC STUDIES

MRI CT Bone Scan Ultrasound Labs:

Sed Rate WBC’s Cultures

Initial empirical antibiotic choice in suspected septic arthritis

Patient group Antibiotic choice

No risk factors for atypical organisms Penicillin 3-4 u IV q 8 (pen sensitive)Nafcillin or oxacillin 2 g IV q 4hFlucloxacillin 2 g qds i.v. Local policy may be to

add gentamicin i.v.If penicillin allergic, clindamycin 450–600 mg qds i.v. or 2nd or 3rd generation cephalosporin (Cefazolin 1 g q 8)

High risk of Gram-negative sepsis (elderly, frail, recurrent UTI, and recent abdominal surgery)

2nd or 3rd generation cephalosporin eg cefuroxime 1.5 g tds i.v. Local policy may be to add flucloxacillin i.v. to 3rd generation cephalosporin. Discuss allergic patients with microbiology—Gram stain may influence antibiotic choice

MRSA risk (known MRSA, recent inpatient, nursing home resident, leg ulcers or catheters, or other risk factors determined locally)

Vancomycin i.v. plus 2nd or 3rd generation cephalosporin i.v.

Suspected gonococcus or meningococcus Ceftriaxone i.v. or similar dependent on local policy or resistance

Pseudomonas Extended B lactam: Piperacillin 3-4g Ivq 4-6h; Ceftazidime 2 g IV q 12h

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

Diabetic foot infection

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;

Septic ArthritisEpidemiology Risk factors

Elderly or very youngUnderlying chronic illnessIncreased incidence with warmer climates and poorer socioeconomic status1:10,000 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

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.

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%Clinical Features• Joint swelling and

pain• Pain with range of

motion, immobility• Fever• Signs of sepsis• Distribution usually

monoarticular• Large joints most

often involved

Septic ArthritisJoints affected (non-gonococcal)

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 ArthritisNatural History

0 1 2 3 4 5 6 7 8

Time (days)

Experimental bacterial arthritis induced

Maximal acute arthritis symptoms

Chronic or irreversible changes

• Temp < 38.3 in 14/40

• WBC < 15K in 13/38• ESR < 30 in 4/36• Synovial fluid WBC <

50K in 8/22

Classification of Joint Effusions

Type Features WBC/mm3

Normal Clear, colorless, Viscous <200<25% PMNs

Non-Inflammatory Clear, Yellow, viscous 200-2000<25% PMNs

Inflammatory Cloudy, Yellow, WateryGlucose may be low

2000-100,000>50% PMNs

Septic PurulentGlucose very low

80,000>90% PMNs

Septic ArthritisAdults versus Children

Adults % Children %

Gram positive cocci

Staph aureus 35 27

Strep (pyogenes, pneumonia, viridans) 10 16

Gram negative cocci

Neisseria (meningitidis and gonorrhea) 50 8

Hemophilus influenzae <1 40

Gram negative bacilli

E. coli, Salmonella and Pseudomonas sp. 5 9

Mycobacteria and Fungi <1 <1

Rheumatology 2006;45:1039–1041

Viral ArthritisInflammatory polyarthritis, similar to early RA

Duration usually < 1 month, self limited illness

Not destructive to joint

Prodromal symptoms◦ Fever◦ Rash

Supportive Treatment (NSAIDs, Analgesics)

Definite Possible Hepatitis (B & C) Rubella Parvovirus Mumps Arbovirus Variola

Vaccinia Varicella Rubeola Echo EBV Adenovirus

No Antibiotic treatment !!!

Suspected MRSA

Drugs for MRSAIDSA, 2011

a. Name of the diseaseb. Etiological agent (s)

c. Treatment (drug of choice)

d. Alternative drug)

1.

2.

3.