Staph Aureus MC Org for MS Infx

Basic Science

Infection

-Staph aureus MC org for MS infx

Expresses fibronectin that helps adhesion
Toxins that damage cells
Excretion of protein A which inact IgG
Capsular polysacc which reduces opsonization of org
Biofilm

-ESR returns to nl after 3 wks

-CRP returns to nl after 1 wk

-WBC only elevated in 50% of pt

-Indium-111-labeled leukocyte scans dist b/w infx and noninfx etiology

80% sens, 80% spec

-Bone scintigraphy + indium-labeled

90% sens, 85% spec
this combo good in TKR, THA

-PET

100% sens, 90% spec

-MRI

In septic arthritis, 97% sens, 92% spec

-Osteomyelitis

CRP most sensitive
good ind of rx success
Pseudomonas in IV drug users
medial clavicle
Tx: add cipro
Fungus in chronically ill
Brodies abscess
insidious onset
epiphyseal osteo – S. aureus
In children
< 3, S. aureus, strept pneumo and pyogenes
more likely to spread to septic arthritis
sickle cell = Salmonella
S. aureus MC
microinfarcts of bone and bowel
diaphyseal involvement
distinguished from bone infarction w/ bone marrow and bone scintigraphy
MC in legs
group B strep MC in newborn
chronic OM
XX: sclerotic avascular bone
dead bone in compromised soft tissue
SCC (Marjolin’s ulcer)
1% of OM
burns
biopsy edge of lesion
wide excision, skin graft
chronic recurrent multifocal OM
bilateral, usu symmetric
NSAIDs relieve
Antibx not needed if cx neg

-Septic Arthritis

Intra-articular physis
prox femur
prox humerus
radial neck
dist fib
cells > 50 K
N. gonorrhoeae MC pathogen in healthy adults
MC around menses
ceftriaxone
intracell gram - cocci
Clinical: polyarthritis, rash, tenosynovitis
Hip jt MC (kids?)
Knee jt MC
Serratia, pseudomonas in IV drug users
Synovial fluid cx + in 90% pt w/ nongonoccal, 25% w/ gonoccal
Joint is ER, abd, mild flexion to inc jt volume, release tension on capsule
Ant approach preferred to preserve vascularity of fem head
Lyme dz
1st stage – erythema migrans, “bull’s eye”
2nd stage – neuro/cardiac
3rd stage- MS sx in 80% untx pt
Chronic Lyme ass w/ HLA-DRB1*040 (autoimmune)
Single dose of 200-mg doxy can prevent Lyme
spirochete – Borrelia
ixodes – tick
tx: amoxicillin

-DM foot infx

excess glucose red N. fx
autonomic dysfx
Monckeberg’s sclerosis – accelerated arteriosclerotic dz
ischemia = dec tissue O2
TcO2 < 20 prob b/c
prevents fibroblast collagen production
PMNs use O2 to kill bacteria
type I – superficial
total contact cast
type II – deep ulceration
surg debridement, offloading, anbx
type III – extensive ulceration, abscess
surgery, amputation, offloading
gangrene – vascular consult
if feel 5.07, then 90% don’t get ulcer
MC bug – aerobic gram + cocci
vascular consult
ischemic pain
recurrent ulcer
nonhealing ulcer
gangrene

-Paronychia

S. aureus MC acute
candida MC chronic

-Herpetic Whitlow

clear fluid in vesicles
don’t i/d
tzanck test

-AIDS

HIV+ and opportunistic infx or CD4 < 200 (nl > 700)
0.3% risk of transmission w/ needle stick
risk higher
hollow needle
blood on needle
advanced AIDs w/ inc titer
prophy zidovudine after stick
80% dec transmission
transfusion 1 in 500,000

-Hepatitis B

single stick transm 30%

-Hepatitis C

single stick transm 3%
HCC
sex transm not major factor

-cellulitis

group A strep MC
staph less common
erysipelas – sup layers of skin
group pyogenes
can become toxic if elderly, immunocom
tx: diclox or nafcillin

-nec fasc

group A strep MC
spontaneous or can follow trauma, surg
worse in immunocomp (DM, PVD, etOH, IVDA)
spreads faster deep than superf
25% mortality
emergent wide debridement

-gas gangrene

clostridium perfringes
gram + anaerobic rod
shows 6 hr – 5 days after injury
alpha exotoxin lecithinase
sweet smelling d/c
gas in soft tissue
leaves wounds open
bug won’t grow in O2
hyperbaric O2 may help
IV antibx

-Diskitis

S. aureus MC pathogen
Low yield of bx/cx – no bx needed

-SI jt infx

FABER test
S. aureus MC

-Surg Site Infx

> 105 in nl host causes infx
Virulence
abx resistance
toxins
gram - : lipopolysacch capsules
strep pyogenes – M protein superant
staph aureus – TXX toxin-1
clostridia – exotoxin lecithinase

-Toxic Shock Sx

TSS toxin-1
toxemia
fever, hypotension, confusion
desquamating rash
tx: I/D wound, antibx

-Superantigens

reg ant stim 1 of 10,000 T-cells
superant act 1/5 of T-cells
T-lymphocyte toxemia: massive cytokind release, looks like septic shock

-Tetanus

gram + club shaped rod
heat stable exotoxin
M. spasms
potentially lethal
tx: good open wound care
booster every 5-10 yrs
anti-tetanus IgG

-Botulism

gram + spore form rod
endopeptidase exotoxin
blocks acetylcholine

-Bites

Fight bites
Eikenella corrodens, Pasteurella multocida
tx: augmentin
cat
pasteurella
tx: augmentin, cefoxitin
dog
pasteurella, most are mixed
tx: augmentin, cefoxitin
Rabies
acute viral infx
neurotropic virus in saliva of rabid animals
100% fatal if no tx before sx
CNS irritation
Tx: human rabies Ig
Marine
mycobacterium marinum
atypical mycobacteria
cx specimen in cooler temp 30 deg C
long incubation period
noncaseating granulomas
deep infx get surgery
tx: minocycline
Sporotrichosis
fungus: sporothrix
path: asteroid body
tx: amphotericin

-Arthroplasty

Single-dose antibx prophylaxis recommended when dental procedure w/ immunocomp pt w/in 2 yrs from date of arthroplasty
Staph epi, Staph aureus

Antibiotics

-give more when EBL > 1000cc, >80kg, >4hr

-aminoglycosides for grade III open

-comp open fx 48 hrs, o/w 24h

-Penicillin

inh bact peptidoglycan synth
beta-lactam

-glycopeptides

vancomycin
inh bact pept synth

-aminoglycosides

inh prot synth, irreversibly binds 30S ribosomes

-macrolides

clindamycin
inh prot synth by inh dissociation of t-RNA, revers binds 50S ribosomal subunit
clinda best penetration to bone

-tetracycline

inh prot synth blocks binding of tRNA to ribosome (A site)

-rifampin

inh bact RNA synth, binds DNA-dep RNA polymerase

-quinolones

inh DNA gyrase (topoisomerase)

-Rifampin – inh RNA synth

-Aminoglycosides – inh protein synth (cytoplasm rRNA)

-Tetracycline – inh prot synth

-Clindamycin and macrolides – inh diss of peptidyl-tRNA from ribosomes during translocation

Arthritis

-IL-1 stimulates chondrocytes to produce proinflamm mediators such as MMPs

-TGF-B stim chondrocytes to differentiate, produce type II collagen and PG

-IL-4 activated w/ mechanical loading

-Collagen provides tensile strength

-Type II collagen 90% of art cart

Oriented tangentially to art surf in superf zone of art cart

-Proteoglycans

Aggrecan has lon-chain GAG molecules attached covalently to protein core
Itself is attached to hyaluronic acid
Provides elastic strength to art cart

-Obesity not consistently ass w/ hip OA

-Chondrocyte is key in development of OA

In resp to mech stress and cytokines such as IL-1, TNF-alpha – releases MMPs that degrade extracell matrix
In turn, chondrocytes attempt to repair damaged cartilage, but new cart has type I collagen, inc fibronectin

-RA

TNF-alpha and IL-1 involved
Humoral component
Active plasma cells in synovium
B-cell depleting therapy, rituximab – remarkable benefits in RA
Inhibition of TNF-alpha leads to dramatic red in sx of RA, improvement of fx (Etanercept, infliximab)
Infliximab shown to worsen CHF
IL-1 inhibitor (Anakinra)
Less of reduction of inflam as etanercept
Inc in pneumonia, UTI’s
NSAIDs
RA pt more prone to dev sx GI ulcers

-Ankylosing Spondylitis

Major sx are back pain w/ morning stiffness, loss of motion of axial spine
XX findings: sacroilitis, bamboo spine
Diminished chest excursion

-Psoriatic Arthritis

Anti-TNF-alpha tx improve jt pain

Ehlers-Danlos Syndrome

-Classic EDS

former type I and type II subsets
AD
40-50% w/ COL5A1 or COL5A2 mutation of type V collagen
33% have aortic root dilatations
30% w/ scoliosis

-Hypermobility subtype

most debilitating
AD
90% w/ debilitating pain

-Vascular subtype

AD, sometimes AR
90% w/ COL3A1 mutation
aortic root dilatation in 75%
25% women die in pregnancy (uterine rupture)

-Kyphoscoliosis

AR
def in lysyl hydroxylase (enz that modifies collagen)
scoliosis – double thoracic curves

-Arthrochalasis

AD
def in pro-alpha I or II chains at N-terminal end
bilateral DDH

-Dermatosparaxis

AR
def of procollagen I N-term peptidase

Osteogenesis Imperfecta

-mutations in COL1A (pro-alpha1 protein chain) or COL2A (pro-alpha2 protein)

-basilar invagination in 3rd/4th decades

tx: transoral approach, w/ PSF, instrumentation

-bisphosphonates – improves bone mass

pamidronate dec fx, relieve pain, inc act levels, dec mobility aids, inc height of vert bodies
no dec in scoliosis

Marfan Syndrome

-AD

-mutation on fibrillin-1 (FBN1) gene on chrom 15q21

-pectus excavatum, planovalgus, long thin feet, long great toe, scol in 65% pt, spondylolisthesis

right thoracic lordotic curves MC
success rate for bracing lower than AIS
curves > 25deg w/ Risser grade II will req surg
inc pseudarthrosis in PSF

-severe neonatal form – serious cardiac abn, contractures

-dural ectasia in 60%

-medical tx: B-blockers

Bone

-lamellar (nl cortical, cancellous)

more organized, less cellularity, stress-oriented
cortical bone
composed of osteons
high torsional resistance
cancellous
less dense
high turnover rate
more elastic
smaller Young’s modulus

-woven (immature, pathologic)

weak, random organization, inc turnover, more cellularity, not stress oriented

-Osteons – Fx unit of bone

Volkmann’s canals (vessels)
Interstitial lamellae
Cement lines
Canaliculi (spaces in b/w osteons)

-Osteoblasts

Bone forming cells
Derived from undifferent mesenchymal cells
Synthesize Type I collagen
High alk phos act
Osteoblast receptors
PTH – releases secondary messenger to stim osteoclastic activity
1, 25 vit D – stim matrix, alk phos synthesis, osteocalcin
glucocorticoids – inh synth of DNA, prod of collagen, synth of osteoblastic proteins
PG – act adenylate cyclase mediated bone resorption
Estrogen – anabolic anc anticatabolic

-Osteocytes

Maintain bone
90% of cells in mature skeleton
cont extracell conc of calcium and phosphorus
directly stimulated by calcitonin and inh by PTH

-Osteoclasts

Resorb bone
Multinucleated
Originate from monocytes
“ruffled” border – inc S.A. for resorption
bone resoprtion @ Howship’s lacunae
synthesize TRAP – break down mineral/osteoid
bind to bone surface via integrins
receptors for calcitonin
IL-1 – potent stimulator for osteoclastic bone resorption – found in membranes of loose THA

-Organic components

Collagen
Tensile strength of bone
Type I collagen – 90% of org matrix
Triple helix = fibril
Mineral deposition in pores and hole zones
Cross-linking dec solubility and inc tensile strength
Proteoglycans
Compressive strength of bone
Consist of GAG-protein complexes
Osteocalcin
Most abundant noncaollagenous matrix protein
Produced by osteoblasts
Attract osteoclasts
Reg bone density
Inh by PTH and stim by 1,25 vit D
Can be measured in serum/urine as marker of bone TO (Paget’s)
Osteonectin
Secreted by plt, osteoblasts
Matrix mineralization

-Inorganic components

Calcium hydroxyapatitie
Compressive strength of bone
Ca10 (PO4)6 (OH)2

-Cortical bone remodeling

Osteoclastic tunneling (cutting cones)
Capillaries, osteoblasts

-Bone Circulation

3 sources to long bones
nutrient artery system
enters diaphysis through nutrient foramen and enters medullary canal
2/3 of cortex
metaphyseal-epiphyseal sys
periosteal sys (capillaries)
outer 1/3 of diaphyseal cortex
Fx Healing
Initial response – decreased flow
Blood flow inc w/in hours and peaks at 2 wks
Flow returns to nl 3-5 mo

-Periosteum

Resp for growth in bone diameter
Inner (cambium) layer
Vascular
Contain osteoblastic progenitor cells

-Bone Marrow

Red marrow – hematopoietic
40% water, 40% fat, 20% protein
Yellow marrow – inactive, aged
15% water, 80% fat, 5% protein

Bone formation

-Enchondral

Bone replaces a cartilage model
E.g.
Embryonic long bone form
Mesenchymal anlage (6 wks in utero)
Vasc buds invade mesench model
Cells diff into osteoblasts
Form primary centers of ossification (8 wks)
Secondary centers of oss dev @ bone ends
Cartilage model grows by apposition
Longitudinal growth (physis)
Fracture callus

-Physis Zones

Reserve
Matrix production
Cells store lipids
Low oxygen tension
Proliferative
Longitudinal growth
Arranged in columns
Increased oxygen tension
Hypertrophic
Maturation zone
Degeneration zone
Provisional calcification zone
Cells inc in size,
Osteoblasts migrate from vessels and use cartilage as scaffold
Metaphysis
Primary spongiosa mineralized to form woven bone, remodeled to form secondary spongiosa according to stress
Periphery of physis
Groove of ranvier – lateral growth
Perichondrial ring of LaCroix – fibrous tissue anchors and supports physis

-Physeal abnormalities

Reserve zone
Gaucher’s, Diastrophic dwarfism, Kneist sx, pseudoachondroplasia
Proliferative zone
Achondroplasia, gigantism
Hypertrophic Zone
Rickets, osteomalacia
Enchondromas
Mucopolysaccharidoses
SCFE
Physeal fractures (zone of provisional calcification)

-Intramembranous Ossification

Occurs w/o cartilage model
Mesench cells in layers and differentiate into osteoblasts that deposit org matrix
Embryonic flat bone formation
Distraction osteogenesis
Blastema bone (young children w/ amputations)

-Appositional Ossificaiton

Osteoblasts align on existing bone surfaces and lay down new bone
Periosteal bone enlargement (width)
Bone formation phase of bone remodeling

Fracture repair

-Primary callus repair occurs w/in 2 wks

-Bridging soft callus converted to hard by enchondral ossification

-Primary cortical healing – resembles nl remodeling (Haversion remodeling) – no visible callus

-cast – enchondral

-compression plate – Haversian remodeling

-IMN – endochondral

-Ex-Fix – periosteal

-Inadequate – failed enchondral ossification (Type II collagen – no convert to Type I)

-Biochemistry of fx healing

Mesenchymal – collagen I, II, (III, V)
Chondroid – collagen II, IV
Chondroid to Osteoid – collagen I, II, X
Osteogenic – collagen I

-Collagen X is involved in mineralization

expressed by hypertrophic chondrocytes as ECM calcifies

Growth Factors

-BMP

Causes mesenchymal cell differentiation to osteoblasts
Target cell for BMP – undifferentiated perivascular mesenchymal cell

-TGF-beta

Induces mesench cells to prod tpe II collagen and PG
Present in fx callus
Regulates cart and bone formation in fx callus

-IGF-II

Stim type I coll, cell prolif, cart matrix synthesis

-PDGF

Chemotactic – attracts inflam cells to fx site

-BM cells of bone allograft – incite greatest immunogenic resp compared to others

Least immunogenic – hydroxyapatite

-Cortical BG

Slow incorporation
Remodeling of existing haversian systems via resorption followed by deposition of new bone
Weak during resorption phase (fatigue fx)

-Cancellous BG

Osteoblasts lay down newbone on old trabeculae (creeping substitution)

-Synthetic BG

Calcium phosphate grafts are incorporated (not sulfate ?)

Heterotopic Ossification

-Common in CHI, THA in Paget’s (50%)

-Irradiation prevents proliferation and differentiation of mesenchymal cells

-Diphosphonates – inh mineralization but not osteoid formation (not a tx)

Bone Metabolism

-Calcium

Important in muscle, nerve, clotting fx
absorbed in duodenum by active transport, jejunum by passive transport
resorbed in prox tubules of kidney
750 mg/day – adult men
1500 mg/day – pregnant women
2000 mg/day – lactating women

-Phosphate

85% of body’s stores in bone
reabsorbed in prox tubules of kidneys
Diet requirement – 1500 mg/day

-PTH

secreted from chief cells of the 4 parathyroid glands
directly activates osteoblasts which stimulates osteoclasts through secondary messenger
decreased calcium levels stimulate PTH release which acts at intestines, kidneys, and bone
intestinal effect is by stim prod of 1,25 dihydroxycholecalcife

-Vitamin D

hydroxylated in liver
25-(OH)2 vit D3
hydroxylated again in kidney
1,25-(OH)2 active form
24,25-(OH)2 inactive form
active form (1,25) works at intestine, kidney, & bone
inc serum calcium
inc serum phosphate
dilantin impairs metabolism of vit D

-calcitonin

made by clear cells in parafollicles in thyroid gland
inhibits of osteoclastic bone resorption – decreases serum calc levels
stimulated by inc serum calcium

-Estrogen

inhibits bone resorption
supplementation helpful in postmenopausal women – only if started w/in first 5-10 yrs
progesterone added to prevent inc risks of breast/uterine ca

Bone Loss

-peak bone mass 16-25 yo

-decreases by .3-.5%/year

-decreases 2-3%/year for untx women during 6-10 yrs after menopause

-osteoporosis

markers of bone reosrption
urinary hydroxyproline
pyridoline cross-links
markers of bone formation
serum alk phos

-Hypercalcemia

from malignancy
multiple myeloma, lung CA
tx: hydration, diuretics, dialysis, mobilization, bisphosphonates
clinical: M. weakness, anorexia, resorption of phalanges, metastatic calcif

-Primary HyperPTH

overproduction of PTH
net increase in plasma calcium
decrease in plasma phosphate
inc osteoclastic resorption
bony changes (osteitis fibrosa cystica, brown tumors, chondrocalcinosis)
labs
inc serum calcium, PTH, 1,25Vit D, urinary calc, alk phos
dec phos
nl vit D
histo: osteoblasts and osteoclasts active on both sides of trabeculae

-Hypocalcemia

low PTH or Vit D
tetany, seizures, cataracts, prolonged QT interval
from renal osteodystrophy, rickets, hypoPTH
HypoPTH
decreased PTH, inc plasma phosphate, diminished plasma Ca
iatrogenic hypoPTH results from thyroidectemy
labs:
dec calcium, PTH, 1,25 Vit D, urinary Ca
inc phos
nl alk phos
pseudohypoPTH
rare genetic d/o caused by lack of PTH effect on target cells (resistance to PTH)
Albright Hereditary Osteodystrophy
short 1st, 4th, 5th MC, MT, obesity
labs:
dec calcium, 1,25 Vit D, urinary Ca
nl PTH, alk phos, 25 Vit D
inc phos

-renal OD

impaired renal fx compromises mineral homeostasis
high turnover dz – from chronically elevated PTH
elevated BUN/Cr, low GFR – giveaway
secondary hyperPTH
dec Ca, 1,25 Vit D, GFR
inc Phos, Alk phos, PTH, Bun/Cr
nl 25 Vit D
low turnover dz – reduced levels of PTH
results from aluminum tox
no secondary hyperPTH
labs: nl PTH, Ca, Phos

-aluminum

impairs prolif of osteoblasts
inh release of PTH
disrupts mineralization process

Rickets

failure of mineralization leading to changes in physis, cortical bone
physis – increased width
bone – cortical thinning
Vit D deficient
rare in U.S.
Tx: Vit D 5000 IU/day
labs
rachitic rosary
bowing of knees
pathologic fx (Looser’s Zone)
dec Ca, Phos, 25 Vit D, 1 25 Vit D, urin calcium
inc PTH, alk phos
Calcium def rickets
hypocalcemia leads to inc in PTH
Tx: oral calcium 700 mg/day
osteomalacia in adults
inc PTH = 25 Vit D conversion to 1,25 Vit D
labs
dec Ca, Phos, urinary Ca
inc PTH, 1, 25 Vit D, Alk Phos
Phosphate def rickets
dec serum phosphate – inc in 1,25 Vit D
Labs
nl Ca, PTH, 25 Vit D, urinary Ca
dec phosphate
inc 1,25 Vit D
Tx: oral phosphate
Hereditary Vit D-dependent rickets
Type I
defect in renal 25(OH)2 Vit D alpha hydroxylase
inh of inactive form to active form of Vit D
AR
Gene on chrom 12q14
Tx: oral 1,25 Vit D
worse than Vit D
labs
dec Ca, Phos, 1,25 Vit D
inc alk phos, PTH, 25 Vit D
Type II
defect in intracell receptor for 1,25 Vit D
no response to active form of Vit D
more severe ppt than Vit D def
tx: high dose Vit D and Ca
labs
dec Ca, Phos, Urinary Ca
inc PTH, 1,25 Vit D, 25 Vit D, alk phos
Familial hypophosphatemic rickets
aka vit D resistant rickets and «phosphate DM»
x-linked dominant d/o
impaired renal tub resorption of phosphate
MC form of rickets
Tx: phosphate and Vit D replacement
vit D to negate hypocalcemic effect of phosphate supp
labs
dec phos
nl ca, PTH, 25 Vit D, 1, 25 Vit D (low for phosphate level), urinary Ca

-hypophosphatasia

AR
inborn error that leads to low levels of alk phos
features similar to rickets, osteomalacia
dx: inc urinary phosphoethanolamine
labs
dec alk phos
inc ca, phos, urinary ca
nl PTH, 25 Vit D, 1,25 Vit D

Osteoporosis

-age related dec in bone mass