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MEDICAL GRANDROUNDS
July 3, 2008
Abigail Cruz-Zaraspe M.D.
OBJECTIVES
 To present a case of bacteremia in aplastic
anemia
 To discuss salmonella nontyphi bacteremia
and myositis manifestations, diagnosis and
treatment
 To discuss briefly the treatment of aplastic
anemia
IDENTIFYING DATA




A.R.
42/M
Married
Real-estate broker
CHIEF COMPLAINT
 Right thigh pain
HISTORY OF PRESENT ILLNESS
 5 weeks PTA
 4 weeks PTA
Easy fatigability, SOB,
(+) melena, (+)
abdominal pain,
(+)palpitations
sought consult, CBC
Pancytopenia
admitted for the first
time for transfusion
HISTORY OF PRESENT ILLNESS
 First admission
blood transfusions
BMA-hypocellular BM
Dx: Aplastic anemia
treatment options
were discussed
(discharged-platelet ct 44k)
HISTORY OF PRESENT ILLNESS
 3 weeks PTA
intermittent fever
(390C),body malaise,
nose bleeding
Consult: WBC 1860,
PLT 10k
Tx: Co-amoxyclav
625mg TID x7d,
tranexamic acid 500mg
TID
GCSF 300mcg
HISTORY OF PRESENT ILLNESS
 3 weeks PTA
 2nd admission
generalized petechial
rashes & gum
bleeding and was
admitted
CBC- pancytopenia
Tx: blood & PC
transfusions
CBC on SECOND ADMISSION
hgb
hct
wbc
stabs
segmenter
lymphocyte
platelet ct
anc
22-Mar
8.5
25.5
1850
24-Feb
8
24.4
2960
25-Mar
10
30.5
2190
54
40
5000
999
72
23
2000
2131
48
45
14000
1051
HISTORY OF PRESENT ILLNESS
 2nd admission
Initially given
Cefepime 1gm Q12
HISTORY OF PRESENT ILLNESS
 2nd admission
+ right thigh & hip
pain 5/10 (dull, aching
constant)
+direct tenderness
no swelling
no limitation in ROM
no paresthesia
Hip & Thigh pain
Compartment
syndrome
Avascular
necrosis
neuropathy
infection
fracture
NEUROPATHY
 Severe intractable pain
 Unusual burning, tingling or shocklike quality
 Triggered by light touch
 Sensory deficit on area of pain
Hip & Thigh pain
Compartment
syndrome
Avascular
necrosis
neuropathy
infection
fracture
COMPARTMENT SYNDROME





Pain
Parasthesia
Pulselessness
Pallor
pressure
Hip & Thigh pain
Compartment
syndrome
Avascular
necrosis
neuropathy
infection
fracture
HISTORY OF PRESENT ILLNESS
 2nd admission
Pelvis and Right hip
xray: no pathologic
finding
Hip & Thigh pain
Compartment
syndrome
Avascular
necrosis
neuropathy
infection
fracture
HISTORY OF PRESENT ILLNESS
 2nd admission
Blood CS: Salmonella
enteritidis Grp C
Sensitive: Ceftriaxone
Chloramphenicol
Ciprofloxacin
shifted to Ciprofloxacin
500mg/tab, 1 tab
BID
HISTORY OF PRESENT ILLNESS
 2nd admission
Dx: Aplastic anemia
Salmonella nontyphi
bacteremia
Advised treatment w/
Anti-thymocyte globulin /
cyclosporine
HISTORY OF PRESENT ILLNESS
 2nd admission
THM:
Ciprofloxacin 500mg/tab, 1
tab BID to complete 7
days
Prednisone 30mg BID,
Tranexamic acid &
Omeprazole
HISTORY OF PRESENT ILLNESS
 Since discharge
episodes of fever &
progression R hip &
thigh pain on
movement & palpation
unable to stand
admitted 3rd time
REVIEW OF SYSTEMS
 (-) headache
 (-) loss of
consciousness
 (-) cough or colds
 (-) weight loss
 (-) chest pain
 (-) dyspnea
 (-) palpitations
 (-) abdominal pain
 (-) nausea or
vomiting
 (-) LBM/
constipation
 (+) melena
 (-) hematochezia
 (-) dysuria
 (-) hematuria
PAST MEDICAL HISTORY
 Non-hypertensive
 Non-diabetic
 No known allergies
FAMILY HISTORY





No
No
No
No
No
hypertension
diabetes
asthma
blood dyscrasias
cancer
PERSONAL AND SOCIAL HISTORY
 Previous smoker, stopped in late ‘90s
 Occasional beer drinker
 Lived near an electroplating
factory
 Previously worked as a cashier in
a gasoline station
 Real estate broker
PHYSICAL EXAMINATION
 General:
conscious, coherent, bed-bound
 Vital signs: BP 130/80, HR = 103 bpm,
reg, RR = 22/min, T = 390C
 HEENT:
Pale conjunctivae, icteric
sclerae, no tonsillopharyngeal
congestion, no
cervical lymphadenopathy
PHYSICAL EXAMINATION
 Chest/Lungs:
Symmetrical chest
expansion, no retractions,
clear breath sounds
Adynamic precordium,
tachycardic with regular
rhythm, no murmurs
PHYSICAL EXAMINATION
 Abdomen:
Flabby, normoactive bowel
sounds, soft, non-tender,
no hepatomegaly
no splenomegaly
PHYSICAL EXAMINATION
 Extremities:
(+) erythema and
hyperemia, right thigh
extending to mid-leg
area
No discharge, no open
wounds
no sensory deficit
Left leg was grossly normal
pulses: full and equal
SALIENT FEATURES
 42/M
 Known case of aplastic anemia
 Known case of non-typhi salmonella
bacteremia
 Treated with ciprofloxacin 500mg BID x 1 week
 Still febrile
 Right thigh and hip pain
 Erythema and swelling of right lower extremity
Hip & Thigh pain
Compartment
syndrome
Avascular
necrosis
neuropathy
infection
fracture
AVASCULAR NECROSIS
 results from infarction of bone trabeculae
and marrow cells
 equal frequency in the femoral and humeral
heads
 The femoral heads more commonly
undergo progressive joint destruction as a
result of chronic weight bearing. The
changes are best detected by MRI
AVASCULAR NECROSIS
 Most studies have found that the risk is low
(< 3 percent) in patients treated with doses
of prednisone less than 15 to 20 mg/day
 In one series, the prednisone dose in the
highest month of therapy exceeded 40
mg/day in 93 percent, and 20 mg/day in
100 percent of patients with osteonecrosis.
Hip & Thigh pain
Compartment
syndrome
Avascular
necrosis
neuropathy
infection
fracture
 150 patients with aplastic anemia treated at
Clinical Hematology Branch of the National Heart,
Lung and Blood Institute (NHLBI) between 1978
and 1990
 Infection was documented in 47% of cases
 respiratory tract (32 percent)
 soft tissues (24 percent)
 blood (22 percent)
 gastrointestinal tract (17 percent)
 urinary tract (6 percent).
IMPRESSION
 Aplastic anemia
 Salmonella non-typhi bacteremia with
secondary myositis
 r/o Avascular necrosis,
osteomyelitis
COURSE IN THE WARDS
 On admission
 CBC, PT, PTT, UA, CXR, crea, BUN,
K, Na were requested. He was
placed on a neutropenic diet.
 He was started on Piperacillintazobactam 4.5mg/IV x 1dose then
2.25mg q8 hours
LABS APRIL 12, 2008
hgb
hct
rbc
wbc
metamyelocytes
stabs
segmenter
lymphocyte
mono
platelet ct
anc
12-Apr
8.5
24.9
2.9
2880
1
67
25
7
6000
1929
12-Apr
na
k
bun
crea
CXR- normal
134
4.2
21
1.2
12
-A
p
17 r
-A
22 pr
-A
pr
27
-A
pr
2-M
ay
7-M
12 ay
-M
a
17 y
-M
22 ay
-M
a
27 y
-M
ay
1-J
un
temperature (celsius)
41 Piperacillin-tazobactam
40
39
38
37
36
35
Febrile
COURSE IN THE WARDS
 2nd hospital day
 + severe leg pain, unrelieved by
Tramadol.
 referred to Orthopedic service
 Impression: t/c pathologic
fracture vs. avascular necrosis, R
hip; aplastic anemia.
 Tx: Ketorolac and Morphine.
COURSE IN THE WARDS
 2nd hospital day
 Pelvic MRI was requested
 Myositis with fasciitis involving
the right gluteal and right thigh
muscle and the right obturator
internus muscle.
 Avascular necrosis of the right
femoral head considered
COURSE IN THE WARDS
 2nd hospital day
 still with fever and leg pain
 Blood CS:
 Salmonella Enteritidis Group C
 sensitive to Ceftriaxone and
Ciprofloxacin
 resistant to Co-trimoxazole and
Ampicillin.
COURSE IN THE WARDS
 5th HD
 referred to Infectious Disease service.
 Impression: Salmonella nontyphi
bacteremia with secondary myositis.
 Tx: shift Piperacillin-tazobactam to
Ciprofloxacin 500mg/tab 2x a day &
ceftriaxone 2g/IV OD
12
-A
p
17 r
-A
22 pr
-A
pr
27
-A
pr
2-M
ay
7-M
12 ay
-M
a
17 y
-M
22 ay
-M
a
27 y
-M
ay
1-J
un
temperature (celsius)
41
P
40 T
39
38
37
36
35
CP & CT
Febrile
COURSE IN THE WARDS
 11th HD
 patient was still febrile (Tmax400C)
 endovascular Salmonella was
considered
 Ceftriaxone was discontinued
 Piperacilin-Tazobactam was
resumed & increased to 4.5 IV Q8
 dexamethasone 4mg/tab 12 hrs
12
-A
p
17 r
-A
22 pr
-A
pr
27
-A
pr
2-M
ay
7-M
12 ay
-M
a
17 y
-M
22 ay
-M
a
27 y
-M
ay
1-J
un
temperature (celsius)
41
P
40 T
39
38
37
36
35
CP+CT
CP
CT
dexa
Febrile
COURSE IN THE WARDS
 13th HD
 Afebrile
 pain decreased
 Dexamethasone was tapered to
4mg/tab bid.
COURSE IN THE WARDS
 18th HD
 Cyclosporine (Neoral)100mg/cap
BID
 ATG 1000mg in PNSS x 4 hrs, once
daily until D11 ( 5/9/08)
12
-A
p
17 r
-A
22 pr
-A
pr
27
-A
pr
2-M
ay
7-M
12 ay
-M
a
17 y
-M
22 ay
-M
a
27 y
-M
ay
1-J
un
temperature (celsius)
41
40
39
38
37
36
35
P
CP T
dexa
ATG
Febrile
Cyclo
COURSE IN THE WARDS
 21st HD
 patient was afebrile,
Piperacillin-tazobactam was
discontinued
12
-A
p
17 r
-A
22 pr
-A
pr
27
-A
pr
2-M
ay
7-M
12 ay
-M
a
17 y
-M
22 ay
-M
a
27 y
-M
ay
1-J
un
temperature (celsius)
41
40
39
38
37
36
35
P
CP T
P
T
Febrile
ATG
ATG
Cyclo
COURSE IN THE WARDS
 38th HD




fever recurred
Increased severity of R thigh pain
Blood CS: negative after 5 days
CBC still showed pancytopenia.
12
-A
p
17 r
-A
22 pr
-A
pr
27
-A
pr
2-M
ay
7-M
12 ay
-M
a
17 y
-M
22 ay
-M
a
27 y
-M
ay
1-J
un
temperature (celsius)
41
40
39
38
37
36
35
CP
Febrile
Cyclo
COURSE IN THE WARDS
 41st HD
 persistence of fever
 CXR,urinalysis,CBC were requested
 CXR & urinalysis were normal
 CBC still showed pancytopenia.
 Piperacillin-tazobactam 4.5g/IV q8
was resumed
12
-A
p
17 r
-A
22 pr
-A
pr
27
-A
pr
2-M
ay
7-M
12 ay
-M
a
17 y
-M
22 ay
-M
a
27 y
-M
ay
1-J
un
temperature (celsius)
41
40
39
38
37
36
35
CP
P
T
Febrile
Cyclo
COURSE IN THE WARDS
 46th HD
 BMA: beginning bone marrow
recovery. Some section shows
good cellularity with myeloid
and erythroid precursors,
although megakaryocytes are
still decreased but present
12
-A
p
17 r
-A
22 pr
-A
pr
27
-A
pr
2-M
ay
7-M
12 ay
-M
a
17 y
-M
22 ay
-M
a
27 y
-M
ay
1-J
un
temperature (celsius)
41
40
39
38
37
36
35
CP
BMA
ATG
Febrile
Cyclo
BMA
ATG
DATE
platelet ct
/0
8
5/
27
/0
8
5/
22
/0
8
5/
17
/0
8
5/
12
08
5/
7/
08
5/
2/
/0
8
4/
27
/0
8
4/
22
/0
8
Cyclo
4/
17
/0
8
80000
75000
70000
65000
60000
55000
50000
45000
40000
35000
30000
25000
20000
15000
10000
5000
0
4/
12
PLATELET COUNT
PLATELET COUNT
date
6/1/08
5/27/08
5/22/08
5/17/08
5/12/08
5/7/08
5/2/08
6000
5500
5000
4500
4000
3500
3000
2500
2000
1500
1000
500
0
4/27/08
4/22/08
4/17/08
4/12/08
anc
anc
ATG
Cyclo
anc
COURSE IN THE WARDS
 47th HD
 again had febrile episodes
 Blood culture: negative
 MRI of R leg: myositis, fasciitis &
avascular necrosis of the R thigh
12
-A
p
17 r
-A
22 pr
-A
pr
27
-A
pr
2-M
ay
7-M
12 ay
-M
a
17 y
-M
22 ay
-M
a
27 y
-M
ay
1-J
un
temperature (celsius)
41
40
39
38
37
36
35
CP
Febrile
Cyclo
COURSE IN THE WARDS
 53rd HD
 sent home
 afebrile
 medications:
 Tranexamic acid, Cyclosporine
100mg BID, ciprofloxacin 500mg
BID
FINAL DIAGNOSIS
 Aplastic anemia
 Salmonella enteritides myositis
 Avascular necrosis, femoral head
DISCUSSION
SALMONELLA: MICROBIOLOGY
Gram-negative
non-spore forming
Facultatively anaerobic bacilli
Produce acid on glucose fermentation
Motile
Do not ferment lactose (99%)
Differential metabolism of sugars is used to
distinguish serotypes
 S. typhi does not produce gas on sugar
fermentation







NON-TYPHOIDAL SALMONELLA:
EPIDEMIOLOGY
 1996-1999 estimated 1.4M cases of NTS in
US
 2004 – 14.7/100,000 persons
 Typhimurium – 20%
 Enteritidis – 15%
 Newport – 10%
NON-TYPHOIDAL SALMONELLA:
EPIDEMIOLOGY - HOST FACTORS
Impaired cell-mediated immunity
 AIDS
 Corticosteroid use
 Malignancy





Impaired phagocytic function
Hemoglobinopathies
Chronic granulomatous disease
Schistosomiasis
Histoplasmosis
Malaria
NON-TYPHOIDAL SALMONELLA:
EPIDEMIOLOGY - HOST FACTORS
 Neonates
 Elderly
Extremes of ages
Decreased gastric acidity
 achlorhydria
 Antacids or suppression of gastric acidity
Altered intestinal function
 IBD
 Prior antibiotic therapy
NON-TYPHOIDAL SALMONELLA:
EPIDEMIOLOGY
 Small but significant number
 Associated with food products (meat,
poultry, eggs or dairy products)
 Associated with shell eggs
 Associated with exotic pets, especially
reptiles
NON-TYPHOIDAL SALMONELLA:
EPIDEMIOLOGY
NON-TYPHOIDAL SALMONELLA:
PATHOGENESIS
 Ingestion from contaminated food/water
 Infectious dose: 103-106 CFU
 Gastric acidity is the initial barrier
 Bacteria mediated endocytosis
NON-TYPHOIDAL SALMONELLA:
PATHOGENESIS
 Innate immune system
 May be determining factor for severity
 Depressed PMN function increases incidence
 Cell-mediated immunity
 Role in clearing infection and protecting against
subsequent Salmonella infection
 Humoral immune responses
 Protective immunity
NON-TYPHI SALMONELLA CLINICAL
MANIFESTATIONS
•
•
•
•
Gastroenteritis
Bacteremia and vascular infection
Localized infection
Chronic carrier state
 Clinically useful, have no pathogenic nor
prognostic significance
NON-TYPHI SALMONELLA
BACTEREMIA AND VASCULAR
INFECTIONS
 5% of patients with NTS
 Infants, elderly and immunocompromised
 Salmonella has high propensity for infection
of vascular sites
 10-25% in persons > 50
 Aorta
 Venous septic thrombophlebitis
NON-TYPHI SALMONELLA :
LOCALIZED INFECTION
 Occurs in 5-10% of patients with NTS
bacteremia
NON-TYPHI SALMONELLA :
LOCALIZED INFECTION
NON-TYPHI SALMONELLA :
LOCALIZED INFECTION
NON-TYPHI SALMONELLA SPECIAL
POPULATIONS







Immunosuppression
Biliary and urinary tract abnormalities
Hemoglobinopathies
Malaria
Schistosomiasis
Histoplasmosis
AIDS
NON-TYPHI SALMONELLOSIS
TREATMENT
 Neonates, >50 years of age and in
patients with immunosuppresion or
valvular/endovascular abnormalities
 Oral or IV antimicrobial for 48 to 72
hours or until patient is afebrile
SALMONELLA NON-TYPHI
BACTEREMIA TREATMENT
 Empiric: 3rd generation cephalosporin and
a fluoroquinolone
 Low-grade: 7-14 days of Tx
 High-grade: 6 weeks IV therapy with ßlactam (ampicillin or ceftriaxone) is
recommended to treat documented or
suspected endovascular infection
 IV Ciprofloxacin, followed by prolonged oral
therapy
SALMONELLA NON-TYPHI
LOCALIZED INFECTION
TREATMENT
 Ceftriaxone 2g/d or Cefotaxime 2g q8h
 Ciprofloxacin 500mg/tab BID or 400mg/IV
BID
 Ampicillin 2g/IV q6h
SALMONELLA: ANTIMICROBIAL
RESISTANCE
 Widespread use of “over-the-counter” antibiotics
 Plasmid-encoded resistance
 Empirical treatment of febrile syndromes and as
growth promoters in animal production
 DT104:
 resistant to ACSSuT: ampicillin,
chloramphenicol, streptomycin, sulfonamides
and tetracyclines
 Acquired from plasmids in Pseudomonas species
SALMONELLA: ANTIMICROBIAL
RESISTANCE
 Increase in ceftriaxone and fluoroquinolone
resistant nontyphoidal Salmonella
SALMONELLA: PREVENTION AND
CONTROL
 Hand washing
 Safe drinking water and effective
sewage treatment
 Improved food safety practices
 Good personal hygiene
 Prudent antimicrobial use
TREATMENT OF APLASTIC ANEMIA
 Hematopoietic stem cell transplantation
 Immunosuppression
 Anti-thymocyte globulin – induces hematologic
recovery
 Addition of cyclosporine increases response rate
up to 70% esp. in children
 Improvement in leukocyte count apparent
within 2 months
TREATMENT OF APLASTIC ANEMIA
(IMMUNOSUPPRESSIVE THERAPY)
 improvement in blood counts occurred in 60
percent of patients after three months
 The actuarial risk of relapse was 35 percent
at five years.
 Most of the relapsing patients responded to
additional courses of immunosuppression,
and relapse was not associated with a
significant survival disadvantage..
Rosenfeld, SJ, Kimball, et.al Intensive immunosuppression with antithymocyte globulin and cyclosporine as treatment forsevere
acquired aplastic anemia. Blood 1995; 85:3058.
Treatment of aplastic anemia with antilymphocyte
globulin and methylprednisolone with or without
cyclosporine. The German Aplastic Anemia Study Group
 antilymphocyte globulin,
methylprednisolone, and cyclosporine
appears to be more effective than a
regimen of antilymphocyte globulin and
methylprednisolone without cyclosporine
 may thus represent a treatment of choice
for patients who are not eligible for bone
marrow transplantation
Frickhofen N, Kaltwasser JP, Schrezenmeier H, Raghavachar A, Vogt HG,
Herrmann F, Freund M, Meusers P, Salama A, Heimpel H
THANK YOU!
CBC
12-Apr
13-Apr
15-Apr
17-Apr
19-Apr
23-Apr
25-Apr
26-Apr
28-Apr
30Apr
hgb
8.5
8.6
9.4
6.4
8.2
9.6
6.8
8.5
9.8
9.3
hct
24.9
26.3
27.7
19.3
24.4
29
20.7
25.8
30
28.5
rbc
2.9
2.9
3.1
2.26
2.9
3.4
2.46
3.24
3.98
3.75
wbc
2880
1360
3700
2860
2570 2,000 2,690
3200
4290 1940
Seg
67
25
45
42
34
35
46
50
29
59
Lym
25
73
50
50
60
56
42
37
63
28
Mon
7
2
5
8
6
9
11
13
8
13
Plate
6k
16k
10k
15k
20k
9k
24k
10k
20k
10k
1929
340
1665
1200 873.8
774
1237
1600
Anc
1154 2212
CBC
1May
2May
4May
6May
7May
11May
13May
14May
19May
22May
hgb
9.3
9
8.8
9.6
10.4
9.8
8.1
11.1
9.8
9.1
hct
29.1
27
26.3
28.6
31
27.2
25.3
33.5
29.5
27.4
rbc
3.8
3.54
3.94
3.64
4.55
4.02
3.67
wbc
4.06
2940 5840 4150 8420 4500 5520 4400 4400 4400 4900
Seg
57
80
61
65
45
45
42
44
45
56
Lymph
26
37
30
28
40
46
47
42
43
30
Mono
7
11
11 .
PC
Anc
14k
51k
39k
11k
22k
10k
28k
29k
14
7k
74k
1675 4192 2531 5473 2025 2484 1848 1936 1980 2744
TREATMENT OF APLASTIC ANEMIA
(IMMUNOSUPPRESSIVE THERAPY)
 Horse ATG at a dose 40 mg/kg per
day in 500 mL of saline given over
four to six hours for four consecutive
days.
Rosenfeld, SJ, Kimball, et.al Intensive immunosuppression with antithymocyte globulin
and cyclosporine as treatment forsevere acquired aplastic anemia. Blood 1995; 85:3058.
TREATMENT OF APLASTIC ANEMIA
(IMMUNOSUPPRESSIVE THERAPY)
 Prednisone or methylprednisolone in
divided doses of 1 mg/kg per day.
Steroids were given for two weeks,
with the dose tapered so that the
corticosteroids were discontinued by
day 30.
Rosenfeld, SJ, Kimball, et.al Intensive immunosuppression with antithymocyte globulin
and cyclosporine as treatment forsevere acquired aplastic anemia. Blood 1995; 85:3058.
TREATMENT OF APLASTIC ANEMIA
(IMMUNOSUPPRESSIVE THERAPY)
 Cyclosporine, 10-12 mkd, in two equally
divided doses,
 aiming for trough levels of 100 to 200 ng/mL of
serum or 500 to 800 ng/mL in whole blood.
 Cyclosporine is generally continued for about
six months, although the dose may be tapered
after one month to trough whole blood levels of
200 to 500 ng/mL.
Rosenfeld, SJ, Kimball, et.al Intensive immunosuppression with antithymocyte globulin and cyclosporine as treatment forsevere
acquired aplastic anemia. Blood 1995; 85:3058.