Anda di halaman 1dari 76

Treatment for Bone and Joint

Infections
Dr.Irvan
Case 1
A 12 year old female soccer player sustained a
nasty bruise below her R knee during a
particularly physical game. Two weeks later she
complained of increased pain over the area
accompanied by a low grade fever and sweats.
She didnt tell her parents. Her coach told her to
quit complaining. However, her symptoms
persisted and 2 weeks later she went to her
pediatrician. Physical exam revealed a
temperature of 38 C and a slightly swollen and
warm left proximal tibia.
Case 1
What tests would you order?

Plain film, blood culture, ESR
Case 1
www.imc.gsm.com
Case 1
What tests might have been positive 2 weeks
earlier?

Bone scan, WBC scan, AB-CD15 scan, Gallium scan, MRI
Case 1
www.imc.gsm.com
Case 1
What is the most likely organism?

Do you need to perform a needle biopsy for diagnosis?


How would you treat this patient? Does she need
debridement? Which antibiotics and for how long?

S. aureus > streptococci
BC+: no. Needle biopsy culture sensitivity ~ 80%,
Histopathology increases yield
Antibiotics, probably not, many choices; nafcillin,
ceftriaxone. Empiric treatment for MRSA?
Case 1
Would oral antibiotics be acceptable?



YES: Zaoutis T, et.al, 2009, Pediatrics;123:636-42
Retrospective cohort of children 2-17 years old, cared
for at 29 childrens hospitals
N=1969, IV 1021, oral 948
Failure: IV 5%, oral 4%
AEs: 3.4% of children on IV therapy admitted with
catheter complications
Case 2
A 26 year old thrill-seeker suffered an open fracture of his
right tibia and fibula while roller-blading behind a motorcycle
driven by his ex-girlfriend. The fracture was reduced and
fixed with the placement of screws, plates and rods. He did
remarkably well until 4 months later when he noted a pimple
followed by a little drainage from one of wounds. Four days
later he was chasing his ex-girlfriend up some stairs and heard
a loud crack and looked down to find hardware and bone
protruding through his right leg.
Case 2
Why did his leg break (the second time)?

What is the most likely bug?

What specimens do you want sent to the lab?

Can you rely on cultures taken from the sinus tract?


Pathologic fracture
S. aureus, CoNS > GNR
Bone cultures
Generally no
If S. aureus or single organism - some + predictive value
Diagnosis - Culture
Gold standard is open bone biopsy for
histopathology and culture.
Needle biopsy has a sensitivity of 87% and a
specificity of 93%. However, in the post-operative
or post-trauma setting its performance is
compromised.
Histopathology of needle biopsy yields diagnosis
even if a specific organism is not identified
Diagnosis - Culture
Superficial or sinus tract cultures correlate poorly
with bone cultures in most studies (< 50%).
Perry (1991) found a 62% correlation between
wound swab and operative cultures and a 55%
correlation between needle biopsy and operative
cultures. Better correlation demonstrated for
mono-microbial infections (80 and 76%) and S.
aureus infections (69% and 74%).
Bottom line: don't trust sinus cultures unless
the results yields a single organism or S. aureus
Case 2
Should all the hardware be removed or can the leg
be set and he be treated with antibiotics alone?




What antibiotics would you recommend, by what
route and how long would you treat him?


Best: 2 or 3 step procedure: remove hardware,
antibiotics, new hardware later
Some success without removing hardware if infection
detected early, sensitive bug
Vancomycin/rifampin/quinolone
A long time
Case 2



Euba, AAC, 2009;53:2672-2676
Prosepctive, randomized trial of S.
aureus, non-axial osteomyelitis
Randomized to 1) IV cloxacillin for 6
weeks followed by oral cloxacillin for 2
weeks or 2) oral TMPSMX (3 DS bid) +
rifampin 600 mg/d
Results:
Overall cure rate 89.6% (on protocol
92.9%) no difference b/n the groups
Median follow up was 10 years!!
Relapses: at median of 9 months,
associated with FB retention and not
following the protocol

Would oral antibiotics be acceptable?
Cochrane Review: 2009, Issue 3:
Antibiotics for treating chronic
osteomyelitis in adults
8 studies (257 patients), 5 studies
compared IV to oral
No significant difference in outcome
at 12 months
AEs: moderated-severe: IV 15.5%,
oral 4.8%
Clinical Presentation
Cierny-Mader staging
Anatomic stage
Stage 1 medullary infection only, hematogenous
spread or spread through an intramedullary prosthesis
Stage 2 superficial infection, due to a contiguous soft
tissue infection, could also be termed osteotis
Stage 3 localized infection, full thickness infection
(one cortex), bone integrity maintained
Stage 4 diffuse infection (both cortexes), destabilizes
bone (or resection would destabilize bone)
Treatment
Cierny-Mader staging
Stage 1 Antibiotics alone. Patients with rods in
place require removal. Adults without hardware may
require medullary reaming.
Stage 2 Debride to bleeding bone and antibiotics
Stage 3 Follow principles of removal of necrotic
bone, elimination of dead space and soft tissue
coverage plus antibiotics
Stage 4 Same as stage 3 plus fracture stabilization.
Case 3
A 72 yo male who underwent a right THR 6
months ago, then developed an
enterococcal UTI 3 months ago and now
presents with low grade fevers and pain in
the right hip that prevents ambulation.

Case 3
How should he be treated?
Two stage replacement with 2 - 6 wks between surgeries.
Time between operations for tough-to-treat organisms - 6 to 8 wks.
Stop abx 1 -2 wks before 2nd operation - if cultures neg - stop, if
cultures +, continue abx for 3 months (6 months for knees).
Case 3
Imaging reveals a peri-
prosthetic fluid
collection
Culture of this fluid
grows MRSA and
enterococcus
(Lew, Lancet, 2004)
Case 3
If the cultures had been sterile at 3 days,
what would you recommend?
Prolonged incubation for 15 days to identify
Propionibacterium acnes (Zeller, 2007)
Case 3
Are there situations when the prosthesis
can be retained after debridement?

Symptoms < 3 weeks
Stable implant
Easy to treat organism

Success rates 82-100%
Case 3
Are there indications for single stage
replacement?

Symptoms >3 weeks
Soft tissue in good shape
No co-morbidities
Easy to treat organism

Success rates 86-100%
Treatment
Ciprofloxacin/rifampin for
Osteomyelitis (Zimmerli,
1998)
N=33, stable implants
Staphylococcus
All treated with debridement and
2 weeks of rifampin + vancomycin
or flucloxacin
Then either cipro/rifampin or
cipro/placebo
Prostheses retained
Median duration of symptoms 5d
0
10
20
30
40
50
60
70
80
90
100
P
e
r
c
e
n
t

c
u
r
e
d
Cipro Cipro/rif
Treatment
0
20
40
60
80
100
P
e
r
c
e
n
t

c
u
r
e
d
Hips Knees Bone plates Total
Ofloxacin/rifampin for Staphylococcal
Osteomyelitis (N=47)
Prosthesis removed: hips (42%), knees (60%), bone plates (50%)
All 11 failures occurred in patients with retained prostheses (8) or resistant
staphylococcus (8) or both (6) (Drancourt 1993)
Case 4
A 39 year old IVDU reports to the ER with fever and
back pain. He mixes his drugs with dirty tap water
and does not prep his skin before injecting. On exam
his temperature is 39 C, he has a 3/6 holo-systolic
murmur and tenderness over his thoracic spine on
percussion. Neurological exam is initially normal.

Case 4
Diagnoses?

Likely organisms?

Initial antibiotics?

Imaging studies?

Endocarditis, vertebral OM, epidural abscess
Staphylococcus > streptococci > GNR > fungi
Nafcillin and gentamicin or vancomycin and gentamicin
MRI
Case 4
The lab reports that 3/4 blood cultures have turned
positive in 4 hours and are growing a GPC, the
following day the lab reports that 2 blood cultures
are also growing GNR.

Likely organisms?

The patient starts complaining of mid-thoracic
radicular pain. What does this represent?

S. aureus > streptococci; P. aeruginosa > other GNR
Spinal ache - first sign of epidural abscess
Case 4
www.xray.2000
Tomogram CT MRI
Case 4
What do you recommend?

What are indications for debridement of vertebral
osteomyelitis?

MRI, decompression (laminectomy or aspiration)
Instability
Abscess
Cord compression
Cervical infection
Medical failure
Neurological signs or symptoms
Case 4
By what route and for how long should abx be
administered?



What about follow up imaging?

No advantage of IV over oral abx (usually quinolones)
Duration at least 4 weeks
Longer if hardware in place or abscesses are not drained
MR less than 4 weeks into Rx often look worse even in
patients improving dont order!
MR later dont follow bone changes often progress. Focus
on epidural and soft tissue changes if these are equivocal or
progress suggests failure (Kowalski, CID, 2006)
Case 5
A 56 year old diabetic man visits his PCP for a
routine visit. He is noted to have a 2.5 cm ulcer
on the plantar surface of his foot at the first
metatarsal head, extending up to the great toe.
He was unaware of the ulcer although, in
retrospect, he recalls that his socks have been
stained and foul smelling lately. He has not noted
fevers or chills. His physician notes a hard, gritty
surface at the base of the ulcer.
Case 5
Recommended work-up



In this case, plain films, ESR sufficient
Of all imaging modalities - MR is most accurate
(sensitivity > 90%, specificity > 80%)
Combination of WBC scan or ABscan with MRI can
improve specificity
Diagnosis
The gold standard is histopathologic
evidence for osteomyelitis with supporting
microbiologic data
However, in many cases the diagnosis rests
on clinical, laboratory and radiographic
data
Diagnosis
Sometimes its easy:
Compatible history and physical exam, elevated
ESR, elevated WBC (acute osteomyelitis)
Positive blood cultures (50% in cases of acute
osteomyelitis)
Classic radiographic findings
Diagnosis
In many cases the diagnosis is difficult
Atypical presentations
Non-specific symptomatology
Co-morbid local and generalized conditions that
confound and obscure the infection
Diabetic Foot Infections
What are exam findings that predict bone
involvement?
Larger (> 2cm, 92% specificity) and deeper ( >
3mm) associated with osteomyelitis
Probe to bone 66% sensitivity and 85%
specificity, PPV around 55%, NPV 98%
ESR > 70: 100% specificity (only 28%
sensitivity)

(Grayson, JAMA,1995;273:721-3)
(Newman, JAMA, 1991;266:1246-51)
(Kaleta, J Am Pod Med Assoc, 2001;91:445-50)
(Dinh, CID, 2008;47:519-27)
Diabetic Foot Infections
What are the best imaging modalities?
Plain film
CT scan
MRI scan
Nuclear medicine studies


Diabetic Foot Infections
Plain films
Need 30 to 50% mineral loss for x-ray
changes to be evident - takes at least
14 days
Sensitivity 43-75%, specificity 75-83%
Insensitive with acute osteomyelitis
In chronic infection - sclerosis,
periosteal elevation and sequestra.
(www.podiatry.files.wordpress.com)
(Lipsky, CID, 1997;25:1318-26)
Diabetic Foot Infections
CT
Best method for
detecting small areas
of necrosis, gas,
foreign bodies
Metallic foreign bodies
compromise the image

(www.xray.2000)
Diabetic Foot Infections
MRI
Sensitivity 82-100%
Specificity 53-94% (tumors, fractures, post
surgery, sympathetic edema, infarction all
can look the same; light up on T2 weighted
image)
BEST SINGLE TEST
Location important -
Heel and malleoli with ulcer = osteo
Midfoot, joint-centered, no ulcer - Charcot
Combine with Ind-111 WBC scans or
gallium scans to increase specificity
(www.med.harvard.edu)
(Eckman, JAMA, 1995;273:712-20)
(Croll, J Vasc Surg,1996:24:266-70)
(Craig, Radiology, 1997;203:849-55)
(Enderle, Diabetes Care, 1999;22:294-9)

Diabetic Foot Infections
Bone scan (TC-99 labeled
phosphorus)
Soft tissue infection will be
positive in the immediate (blood
flow) and 15 minute (blood pool)
phases while osteomyelitis will be
positive in these 2 plus the
delayed (> 4 hour) images.
Sensitivity 69-100% (> 95% in
acute osteomyelitis), specificity
38-82% (tumors, fractures, post-
surgery, septic arthritis, Pagets
disease, Charcot foot)
(www.postgradmed.com)
(Eckman, JAMA, 1995;273:712-20)
(Enderle, Diabetes Care, 1999;22:294-9)
Diabetic Foot Infections
AB + WBC scan (Ind-111)
Will be positive prior to bone
scan
Useful p-surgery (better than
MRI) which will always be
abnormal
When combined with bone
scan has specificity in the 90%
range, sensitivity in the 70%
range and PP value in the 90%
range
(www.nuclearonline.org)
(Becker, QJ Nuc Med, 1999;43:9-20)
(Unal, Clin Nuc Med, 2001;26:1016-21)
Newer Imaging Tests
Tc-99 monoclonal (Fab fragments) against CD-15:
sensitivity and specificity ~ 85%
IND-111 biotin: used and concentrated in
bacteria: sensitivity and specificity for vertebral
OM ~ 95%
PET: better than WBC scans for chronic vertebral
OM. Limited use in patients with diabetes and
cancer


Case 5
What organisms
are likely
responsible for
this infection?

(www.erc.montana.edu)
Diabetic Foot Infections
Infection Organisms
No infection S. aureus, streptococci
Infected ulcer (abx
nave)
S. aureus, streptococci
Chronically infected
ulcer (often previously
treated)
S. aureus, streptococci, enterococci,
Enterobacteriaceae, Pseudomonas
species and other NLF GNR
Necrotic, malodorous,
fetid foot
S. aureus, streptococci, enterococci,
Enterobacteriaceae, Pseudomonas
species and other NLF GNR +
anaerobes
Case 5
Recommended treatment
Surgical debridement (with bone cultures)
Re-vascularization if needed
Long-term abx

Recent retrospective studies suggest abx alone
may be sufficient treatment in many cases (Jeffcoate, 04)
Diabetic Foot Infections
Which antibiotics
should I prescribe
and for how long?

(www.erc.montana.edu)
Diabetic Foot Infections
Basic principles for choosing antibiotics:
Should always include coverage for Gram-
positive cocci, especially S. aureus
Add Gram-negative coverage for chronic
wounds, for patients previously treated with
abx and for wounds classified as moderate to
severe
Provide anaerobic coverage for obviously
necrotic wounds or those with a feculent odor
Narrow coverage based on culture results
(Lipsky, Clin Micro Infect, 2007;13:351-53)
Diabetic Foot Infections
Basic principles for choosing antibiotics:
Consider risk factors for MRSA when choosing Gram-
positive coverage
Coverage for enterococci usually not necessary unless it is
the only organism isolated
Coverage for Pseudomonas may also not be necessary
unless the wound had been treated with hydrotherapy or
Pseudomonas is present and the patient is not improving
without anti-Pseudomonal treatment
Avirulent organisms (e.g. coagulase negative
staphylococci, Corynebacterium species) may become
real pathogens in immunocompromised hosts with
significant tissue necrosis
(Lipsky, Clin Micro Infect, 2007;13:351-53)
Diabetic Foot Infections
(Lipsky, Clin Micro Infect, 2007;13:351-53)
Infection Pathogen Antibiotics
Mild, no previous Abx, No
MRSA risks
Aerobic GPC Pcns, 1st gen cephalosporins
Mild, no previous Abx, Yes
MRSA risks
Aerobic GPC + MRSA Pcns, 1st gen cephalosporins (+
TMP-SMX or doxy or clinda)
OR Vancomycin OR linezolid
OR daptomycin
Moderate/severe, chronic,
previous Abx
GPC + GNR +/- anaerobes -lactam/-lactamase inhibitor,
2nd or 3rd gen cephalosporin,
carbepenam, FQ
Necrotic, gangrenous wound,
fetid foot
GPC + GNR + anaerobes Clinda + FQ OR metronidazole
+ FQ or -lactam/-lactamase
inhibitor OR carbepenam
Hydrotherapy Pseudomonas Anti-Pseudomonal FQ, Pcn or
Cephalosporin or Carbepenam
Diabetic Foot Infections
Duration of therapy
Mild infections 1-2 weeks
Moderate to severe infections: 2-4 weeks
Osteomyelitis: 4-6 weeks (or longer)
Diabetic Foot Infections
Adjuvant Therapies
G-CSF
Cruciani, Diabetes Care, 2005;28:454460
Meta-analysis of 5 studies including 167 pateints
No effect on wound healing
Did reduce the risk for amputation (RR 0.41) and for any type of
surgery (major debridement, revascularization, angioplasty and
amputation) (RR 0.38)
Hyperbaric Oxygen
Roeckl-Wiedman, Br J Surg, 2005;92:24-32
Meta-analysis of 6 studies, including 5 on patients with DFI (118
patients)
No effect on ulcer healing or minor amputation
Did reduce the risk of major amputation: RR 0.31
Case 6
A 43 year old male immigrant from Pakistan reports
to urgent care complaining of back pain for the last
12 months. He has lost ~15 pounds. During the last
2 weeks he noticed some mild weakness in his right
leg. Examination reveals a thin, stooped, muscular
male with normal vital signs. His back has a tender
deformity at T6. His right knee is tender and swollen.
Plain films of his T-spine show anterior wedge-
shaped collapse of T6.
Case 6
www.imc.gsm
Case 6
Differential


Diagnostic tests:

TB > Staphylococcus > other
MRI spine
PPD and CXR
Blood cultures
Biopsy
HIV
Leg films
Case 6
MRI of his spine reveals complete destruction of
T6, a 20 anterior acute angle deformity and a
large para-spinal fluid collection. Biopsy reveals
granulomas, no AFB.

Does he need anti-tuberculous therapy?

Does he need surgery?
Yes
Yes
Case 6
What are indications for surgery in Potts disease?



What about his knee?

Neurological deficits
Instability
Cervical disease
Medical failure including non-adherence
Needs evaluation
Skeletal TB more common in young people with Potts
Medical treatment alone usually sufficient
If severe destruction with abscess - debride
Skeletal Tuberculosis
Pathogenesis
In developed countries skeletal TB is a disease of
adults and represents reactivation of an old focus of
infection.
In the developing world most cases of skeletal TB
occur in patients who recently acquired TB.
Therefore, most skeletal TB occurs in childhood.
Many patients give a history of recent trauma to the
involved area.
Skeletal Tuberculosis
Clinically
Accounts for 35% of cases of extra-pulmonary TB
and 2% of all cases of TB
Indolent course, average duration of symptoms
prior to diagnosis: 16 to 19 months.
Local swelling, pain, fluctuance; systemic
symptoms (fever, sweats, etc) often absent.
Pulmonary disease present in 30%. PPD+ in > 85%
Skeletal Tuberculosis
Clinically
Potts disease (tuberculous spondylitis)
Responsible for 1/3 of cases of skeletal TB.
Infection begins in the anterior aspect of the vertebral
body leading to anterior collapse and spread of the
infection along the anterior ligament
Most cases involve the lumber and lower thoracic spine
50% of cases have associated abscesses (if calcified is
diagnostic for TB)
Skeletal Tuberculosis
www.imc.gsm.com www.path.sunysb.edu
Skeletal Tuberculosis
Clinically
Potts disease
50% have weakness or paralysis at the time of
presentation or during Rx
50% associated with disc involvement
50% without disc involvement are younger and more
likely to have other skeletal lesions
77% have epidural involvement by MRI (Pertuiset,
1999)
Skeletal Tuberculosis
Clinically
Other bones: any bone; weight bearing, flat, ribs -
relatively unique to TB
Diagnosis
AFB stain and culture of biopsy specimen (sensitivity
~85%)

Skeletal Tuberculosis
Treatment
Chemotherapy: Duration - 9 to 18 months. Although
recent studies suggest that 6 months of treatment,
when combined with surgery, is as effective as longer
course of antibiotics.
Debridement of abscesses will lead to faster
resolution and less kyphosis in those with severe
disease at presentation.
Skeletal Tuberculosis
Treatment
Criteria for surgical intervention in Potts
Neurological deficit
Spinal instability
Cervical spine disease
Failure of medical therapy
Non-adherence to medical therapy.
Case 7
A 43 year old female with a long history of rheumatoid
arthritis requiring multiple joint replacements complains
to her rheumatologist of a flare of her disease with pain
and swelling in one of her IP joints and her right wrist. Her
temperature is 37.5C, her right wrist is warm, swollen and
red as is one of her IP joints on the same hand.
Why isn't this just a flare of her RA?

How would you differentiate infected from non-infected
joint fluid?
Too few joints
Aspiration: Gram stain 50-75%, Culture 90%, BC 50%
Case 7
What is the bug?

Which antibiotics would you use and for how
long?

Do the joints need to be drained? How?





S. aureus - 80% in RA
Anti-staph (anti-MRSA?), 4 to 6 weeks
Yes
Serial aspiration or open procedure
Case 7

What are indications for open drainage?


Hips, shoulders, prosthetic joints
Osteomyelitis with arthritis
GNR
When aspiration fails (thick pus)
Case 8
A 23 year old female reports to the ER with 2 days of
diffuse arthralgias, low grade fever and then the
development of swelling and increased pain in her right
knee and wrist. She has a new boyfriend.

Diagnosis?

What do you find on exam?

Is the patient likely to be menstruating?

GC > reactive arthritis
Skin lesions (< 30), tenosynovitis, additive oligoarthritis
Yes; risks for DGI: certain strains of GC,
F > M, menses, complement deficiency
Case 8
Is she likely to have genital symptoms?

Will BC grow the organism? Joint fluid? Cervical culture?

Should her joints be drained? Open drainage?

Antibiotic therapy: drugs, route, duration?


Should anyone else be treated?
No (strains that dont fix complement - less inflammation)
< 20% ~50% > 80%
Yes, Usually not necessary
Ceftriaxone for 7-10 days
Partner
Case 9
The ex-boyfriend of the last patient is treated as a contact.
Two weeks later he reports to urgent care with pain in his
toes, right knee and left hip area. He also complains of a
little dysuria. Exam reveals 2 sausage digits on his right
foot, a swollen, warm right knee and pain and decreased
range of motion of his left hip.

Differential diagnosis?

Would you order any imaging studies?
GC or reactive arthritis
MRI of hip
Case 9
Would you tap his knee? His hip? His hip and knee?

Antibiotics? Which ones? Until when?

Would you culture anything else?

What makes you think this is not a bacterial infection?
Yes Yes Yes
Anti-staph, strep, GC (e,g., ceftriaxone) - until cultures neg
Urethral and oral cultures
Sausage digits
Multiple sites (RA or GC > strep or staph)
Negative cultures
Case 9
Two days later he is no better and all the cultures are
negative.
How would you treat him now?

How likely is he to HLA-B27 positive?

Is he likely to relapse?

Are antibiotics of any use in this disease?

What are other risk factors for this syndrome?

Anti-inflammatories (sulfasalazine, NSAIDS, steroids)
Post CT: > 90%, post enteric infections: 50-80%
Sure, more common post CT
Doxy or macrolides for RA post CT - maybe, otherwise - No
After any enteric infection, IBD
Case 10
A 37 year old male roofer sustained a T12-S1
fracture/dislocation due to a fall. His spine was initially
stabilized with rods, plates and screws. Eight weeks post-
operation he was diagnosed with osteomyelitis due to S.
aureus and CNS. This infection was treated by
debridement of necrotic tissue and bone, removal of
almost all the original hardware and immediate
replacement with new hardware and a tibial allograft. The
patient also received 3 months of appropriate antibiotics
(vancomycin, ciprofloxacin and rifampin).
He did well for 8 months, joined a wheelchair basketball
team and then began noticing pain in his back, made
worse by a rigorous game of hoops. His surgeon thinks
(hopes) his pain is due to his recent increased activity but
orders an ESR (32 mm/hr) and a CT (lots of post-operative
changes but no obvious osteomyelitis).
Case 10
What diagnostic tests might you order now?


Was it a mistake to replace the infected hardware with
new hardware at the same operation?


What about the placement of the tibial allograft?


What treatment strategy would you recommend at this
point?
MRI-CT with WBC scan: Specificity 90%, PPV ~90%
Best to avoid this but in some cases not avoidable due to
stabilization issues (spine)
Theoretically a bad idea (adding sequestrum!)
Nevertheless, some support in the surgical literature (Shuster)
Remove hardware, antibiotics
Case 10
The patient refuses any further treatment or work-up. A
month later a draining sinus develops at the site of the
original injury. The patient takes some antibiotics he had
stashed at home and the sinus dries up. The infection
intermittently flares over the next 15 years and each time
it does the patient takes a short course of antibiotics that
temporarily solves the problem. However, the most
recent episode of drainage has not responded to his usual
remedy and he comes back to see you. Your examination
of his spine reveals an 8 cm area of tough, indurated skin
with a necrotic, bleeding center draining green, purulent
material.
What are you worried about?

What do you recommend?

Recurrent, resistant infection, squamous cell cancer
Image, debride, biopsy

Anda mungkin juga menyukai