Uso de Linezolida en Perros

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Use of Linezolid to Treat MRSP Bacteremia and Discospondylitis in a Dog

Article  in  Journal of the American Animal Hospital Association · November 2013


DOI: 10.5326/JAAHA-MS-5947 · Source: PubMed

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CASE REPORTS

Use of Linezolid to Treat MRSP Bacteremia and


Discospondylitis in a Dog
Jonathan D. Foster, VMD*y, Lauren A. Trepanier, PhD, DVM, DACVIM, DACVCP, Jennifer A. Ginn, DVM, DACVIMx

ABSTRACT
A 1.5 yr old male German shepherd dog was evaluated for recurrent intermittent episodes of fever and lethargy. Clinicopath-
ologic abnormalities were suggestive of a discospondylitis at the seventh and eighth thoracic vertebrae. Blood and urine cul-
tures yielded growth of methicillin-resistant Staphylococcus pseudintermedius (MRSP) that was resistant to all commonly
used antibiotics. Extralabel antibiotic susceptibility testing demonstrated susceptibility of both blood and urine isolates to
linezolid. The prescribed dose was extrapolated from pharmacokinetic (PK) studies and the isolate’s plasma minimum
inhibitory concentration (MIC). Linezolid was administered for 23 wk and resulted in successful resolution of bacteremia,
bacteriuria, and discospondylitis. When justified, linezolid should be considered to treat methicillin-resistant infections. (J Am
Anim Hosp Assoc 2014; 50:53–58. DOI 10.5326/JAAHA-MS-5947)

Introduction use” drugs such as linezolid. Despite the controversy, there are no
Methicillin-resistant Staphylococcus infections are challenging uniform prescribing guidelines for tertiary antibiotic use in vet-
diseases to treat. Often, the only suitable antibiotics are not erinary medicine. The purpose of this case report is to provide
commonly used, and there is frequently a lack of evidence for some clinical evidence regarding drug dosage, expected plasma
their efficacy in companion animals. The following case demon- concentrations, and possible side effects of linezolid.
strates the successful use of linezolid to treat methicillin-resistant
Staphylococcus pseudintermedius (MRSP) bacteremia, bacteriuria, Case Report
and discospondylitis in a dog. The dose regimen was extrapolated A 1.5 yr old male intact German shepherd dog weighing 33 kg
from pharmacokinetic (PK) studies, and designed to reach ade- was evaluated at the University of Wisconsin Veterinary Medical
quate plasma concentrations to inhibit further growth of the or- Teaching Hospital for progressive fever and lethargy over the
ganism isolated in this dog. Plasma drug linezolid levels were also previous 3 mo. The patient had been diagnosed with steroid-
measured to assess the efficacy of the prescribed linezolid dosage responsive meningitis arteritis 4 mo earlier and was currently
in reaching targeted drug concentrations. receiving 0.45 mg/kg/day of prednisone per os (PO), which had
This case also exemplifies the ongoing debate regarding been tapered from an initial dose of 2 mg/kg/day. In the 3 mo
proper antibiotic use in animals, particularly regarding “tertiary prior to evaluation, the patient had developed recurrent episodes

From the Department of Medical Sciences, School of Veterinary Med- ALT alanine aminotransferase; AUC area under the concentration-time
icine, University of Wisconsin, Madison, WI. curve; CLSI Clinical and Laboratory Standards Institute; MIC minimum in-
hibitory concentration; MRSA methicillin-resistant Staphylococcus aureus;
Correspondence: [email protected] (J.F.)
MRSP methicillin-resistant Staphylococcus pseudintermedius; PK pharma-
cokinetic; PO per os

*J. Foster’s updated credentials since article acceptance are VMD, DACVIM.

J. Foster’s present affiliation is Matthew J. Ryan Veterinary Hospital of the
University of Pennsylvania, Philadelphia, PA.
x
J. Ginn’s present affiliation is Wheat Ridge Animal Hospital and Veterinary
Specialists, Wheat Ridge, CO.

ª 2014 by American Animal Hospital Association JAAHA.ORG 53


of fever and leukocytosis, for which he was prescribed multiple
courses of empirical antibiotic therapy (5 mg/kg enrofloxacin PO
q 24 hr for 10 days, 15 mg/kg ciprofloxacin PO q 12 hr for 10
days, 8.6 mg/kg metronidazole PO q 12 hr for 7 days, ampicillin
Na/sulbactam Naa 17/8.6 mg/kg IV once, amoxicillin trihydrate/
clavulanate potassiumb 10.3/2.6 mg/kg PO q 12 hr for 10 days,
and 9.4 mg/kg clindamycin PO q 12 hr for 14 days); however, no
diagnostics were performed to investigate the source of the fever.
Two mo prior to presentation, azathioprine was added at 1.7 mg/kg FIGURE 1 Initial lateral spinal radiograph showing collapse of
PO q 48 hr due to the concern for relapsing steroid-responsive the seventh to eighth thoracic intervertebral disc space and sclerosis of
meningitis arteritis. Despite the numerous antibiotics adminis- the surrounding endplates.
tered, the patient continued to have recurrent episodes of fever
and lethargy that typically improved within 2–3 days. patient was discharged from the University of Wisconsin Veteri-
A complete blood count and biochemical analysis were nary Medical Teaching Hospital with a prescription for cephalexin
performed by the primary care veterinarian 1 wk prior to pre- (22 mg/kg PO q 12 hr) pending final culture results. The dose of
sentation. The total white blood cell count was elevated (26 3 109/L; prednisone was decreased to 0.3 mg/kg PO q 24 hr, with the in-
reference range, 6–17 3 10 /L) due to a mature neutrophilia
9
tention of tapering and discontinuing that medication over the
(22.5 3 109/L; reference range, 3–12 3 109/L ). The platelet count subsequent few weeks. The azathioprine was promptly dis-
was normal. The biochemical analysis demonstrated increased continued.
alkaline phosphatase (8.4 mkat/L; reference range, 0.34–2.55 mkat/L) The patient’s urine and aerobic blood cultures both grew
and alanine aminotransferase (ALT) activities (6.99 mkat/L; . 100,000 colony-forming units/mL of a b-hemolytic Staphylococcus
reference range, 0.17–2.01 mkat /L), and increased blood urea spp., belonging to the MRSP group. The isolates shared the same
nitrogen (12.9 mmol/L; reference range, 2.5–8.9 mmol/L). Uri- susceptibility panel. Based on Clinical and Laboratory Standards
nalysis revealed a pH of 7.5, specific gravity was 1.025, there were Institute (CLSI) standard antibiotic minimum inhibitory concen-
1–5 white blood cells/high-power field, and 20–50 red blood cells/ tration (MIC) breakpoints, both isolates were resistant to all reported
high-power field, with no bacteria observed. antibiotics (i.e., chloramphenicol, ciprofloxacin, clindamycin,
At the time of referral, the dog was febrile at 39.58C, and erythromycin, gentamicin, oxacillin, penicillin, rifampin, tetra-
mentally dull but responsive. Postural reactions were normal in cycline, trimethoprim/sulphamethoxazole), except nitrofurantoin.
the thoracic limbs, but absent in the pelvic limbs. A mild paraparesis Methicillin resistance was determined due to both isolates’ resis-
and ataxia were also present. Spinal reflexes were normal. Marked tance to oxacillin. Because approximately 50% of the total dose
pain was elicited upon midthoracic spinal palpation. Cranial of nitrofurantoin is excreted in its active form into the urine,
nerve examination was normal. The remainder of the physical nitrofurantoin would have likely been efficacious to treat the
examination was within normal limits. MRSP bacteriuria, but likely ineffective to achieve adequate con-
Neuroanatomic localization was supportive of a third thoracic centrations within blood and bone to treat discospondylitis.1 That
vertebra to third lumbar vertebra myelopathy. Spinal radiographs is why nitrofurantoin is not indicated for the treatment of any
were obtained and demonstrated collapse of the seventh the eighth vancomycin-resistant Enterococcus spp. infections other than lower
thoracic vertebral disc space, with endplate sclerosis and vertebral urinary tract infections.2 Therefore, MICs were requested for
body lysis of both the seventh and eighth thoracic vertebrae, additional antimicrobials.
suggestive of discospondylitis (Figure 1). To identify the causative MIC breakpoints were determined via serial broth dilution for
organism of the discospondylitis, a urine sample was collected via tigecycline, quinupristin/alfopristin, vancomycin, daptomycin, and
cystocentesis and submitted for aerobic culture and susceptibility, linezolid, with CLSI susceptibility standards extrapolated from
and blood was collected for culture using aseptic technique from human performance standards.3 An MIC was reported for tige-
the left jugular and right medial saphenous veins (20 mL/site), cycline; however, that drug had not been included in the CLSI
c
and inoculated into aerobic and anaerobic blood culture bottles . standards since 2009. Therefore, its efficacy was uncertain. Both
Because the patient’s clinical signs had not changed since evalu- MRSP isolates were reported to be sensitive to quinupristin/
ation by the referring veterinarian 1 wk earlier, a complete dalfopristin, vancomycin, and linezolid based on the published
blood cell count and biochemical analysis were not repeated. The human breakpoints. Susceptibility for quinupristin/dalfopristin

54 JAAHA | 50:1 Jan/Feb 2014


Linezolid Treatment of MRSP Infection

applies only to methicillin-susceptible Staphylococcus aureus, not Three wk later (7 wk into therapy), another complete blood
to MRSP, and vancomycin has published standards against count showed a persistent but mild thrombocytopenia (114 3 109
Staphylococcus aureus and coagulase-negative Staphylococcus spp., /mL; reference range, 175–500 3 109/mL) with an increased mean
but not to Staphylococcus pseudintermedius.3 Because those anti- platelet volume (15.4 fL; reference range, 7.9–14.4 fL). The total
biotics did not have MIC data for Staphylococcus pseudintermedius white blood cell count was normal, with a continued mild nor-
or even a genus-wide Staphylococcus susceptibility, their efficacy mocytic normochromic anemia (hematocrit was 34%; reference
was also uncertain. In addition, quinupristin/dalfopristin and range, 40–59%). Because linezolid had been associated with lactic
vancomycin both require IV administration. Prolonged IV cath- acidosis in human patients, a venous blood gas was also per-
eterization posed a risk for creating a nidus of infection due to the formed.6 That test demonstrated a normal blood pH (7.41; ref-
MRSP bacteremia, and the long-term duration of therapy re- erence range, 7.38–7.45), with a compensated lactic acidosis.
quired to treat discospondylitis made IV antimicrobial therapy Lactate was 4.9 mmol/L (reference range, 0–2.9 mmol/L), the
impractical. An MIC was also reported for daptomycin, which was partial pressure of CO2 was 22.7 mm Hg (reference range, 26–
relevant for genus-wide Staphylococcus susceptibility; however, 40.1 mm Hg), bicarbonate was 14.7 mmol/L (reference range, 20–
only IV pharmacokinetic data for that drug were available for 24 mmol/L), and the base excess was 210.1 mmol/L (reference
dogs. 3,4
range, 24–2 mmol/L). The patient had not been involved in any
As for linezolid, which is in the oxazolidinone class of anti- strenuous exercise for at least 24 hr prior to testing and was
biotics, the MIC data were applicable to genus-wide Staphylococcus clinically hydrated; therefore, the compensated lactic acidosis was
susceptibility, which was relevant to the dog’s infection.3 Impor- considered to be a possible linezolid side effect.
tantly, linezolid can be administered orally, and pharmacokinetic At the same 7 wk recheck appointment, peak and trough
data for oral administration were available in dogs.5 Therefore, serum linezolid levels were submitted to the National Jewish
that drug was chosen for treatment. The recommended dose of Health Laboratorye to assess the linezolid dose regimen. The
linezolid in humans is 600 mg PO q 12 hr (approximately 8.5 mg/kg trough level, obtained 12 hr after the previous dose (6.3 mg/mL),
q 12 hr for a 70 kg person), with reported mean peak steady was within the expected steady-state range established for humans
state concentrations of 21 mg/mL.6 Multiple dose administration (2–9 mg/mL)f. The measured peak serum concentration, obtained
of linezolid in dogs (20 mg/kg of linezolid PO q 12 hr) resulted 2 hr after chronic oral dose administration, was 9.6 mg/mL, which
in plasma peak and trough concentrations of 19.7 mg/mL and was slightly below targeted peak concentrations in humans (12–26
2.14 mg/mL, respectively, with steady state reached by at least mg/mL). However, that concentration was still predicted to be
15 days of dosing.5 This dose in dogs was predicted to provide effective in treating the MRSP isolated from the patient based on
plasma concentrations greater than twice the reported MIC for the isolates’ MIC of # 1 mg/mL.5 The serum concentrations
the MRSP isolated in this dog (# 1 mg/mL), even at trough observed in the patient were above the MIC at both trough and
concentrations. Based on those calculations, the dog was started peak concentration times, correlating to a time . MIC index of
on linezolidd at 20 mg/kg PO q 12 hr and the cephalexin was 100%.
discontinued. Blood work was repeated 14 wk after initiation of linezolid
Within 2 wk of initiation of treatment with linezolid, clinical therapy. The complete blood count showed resolution of the
signs of pain and lameness were completely resolved. Further anemia and thrombocytopenia, despite no changes in linezolid
clinical and biochemical monitoring in the dog was based on dosing regimen. A serum biochemical analysis showed only a
reported side effects of linezolid in humans, which included static, mildly increased ALT (2.29 mkat/L; reference range, 0.085–
myelosuppression (i.e., anemia, leukocytosis, thrombocytopenia), 1.82 mkat/L), and the venous blood gas showed resolution of the
lactic acidosis, serotonin syndrome, convulsions, and gastroin- compensated lactic acidosis (lactate was 1.8 mmol/L; reference
testinal upset.6 A complete blood count was rechecked 1 mo into range, 0–2.9 mmol/L). At each of those follow-up appointments,
therapy and revealed a moderate normocytic, normochromic the patient was afebrile and strongly ambulatory.
anemia (hematocrit was 31.5%; reference range, 37–55%) and Spinal radiographs were performed 8 wk and 14 wk into
thrombocytopenia (slide estimated to be between 50 and 120 3 treatment with linezolid and showed static vertebral lysis with
109/L; reference range 164–510 3 109/L). The previously observed progressive bone remodeling consistent with healing dis-
increases in alkaline phosphatase and blood urea nitrogen had cospondylitis.7 Linezolid treatment was continued for a total of
normalized, and the ALT had improved (2.36 mkat/L; reference 23 wk. The decision to discontinue antibiotics was based on
range, 0.085 to 1.82 mkat/L). complete recovery of clinical signs of discospondylitis and static

JAAHA.ORG 55
radiographic changes observed at the site of vertebral infection at clinical diagnosis of discospondylitis due to MRSP, similar to
23 wk (Figure 2). Blood and urine cultures were found to be accepted guidelines in humans.10 MRI is considered the best
negative at 2 wk, 12 wk, and 32 wk after discontinuation of imaging modality in humans, with a sensitivity and specificity of
linezolid therapy. The patient remained asymptomatic 36 mo after 96% and 93%, respectively.11 However, radiographs and clinical
drug discontinuation. response were consistent with the diagnosis in the patient de-
scribed herein, so MRI was not pursued. Computed tomographic-
Discussion guided vertebral biopsy for tissue culture can be performed in
This case represents the first report of discospondylitis attributed to humans if blood cultures are negative.12 Fluoroscopic-guided
MRSP in a dog, and highlights the risks of empirical use of multiple percutaneous fine-needle aspiration of the intervertebral disc
antibiotics, without a definitive diagnosis, in potentially selecting space has been reported in dogs, with positive cultures obtained
for antibiotic-resistant strains of bacteria. In a previous report, two in 75% of samples; however, that approach was not considered
dogs developed iatrogenic methicillin-resistant Staphylococcus necessary given the dog’s positive blood and urine cultures.13
aureus (MRSA) discospondylitis following hemilaminectomy for Standard therapy for MRSA spondylodiscitis in humans
thoracolumbar intervertebral disc protrusion.8 However, both involves initial treatment with IV antibiotics (typically vancomy-
MRSA isolates were sensitive to other commonly used first line cin) for 2–8 wk, followed by oral therapy (i.e., linezolid, cipro-
veterinary antibiotics. The original source of infection in the dog floxacin, rifampin) for another 2–12 wk; however, specific
in this report was unknown and was complicated by the 3 mo guidelines for antibiotic duration have not been established.10
delay between the onset of clinical signs and diagnosis of bac- Reported criteria for discontinuation of antibiotic treatment in
teremia. Prior to the initiation of antimicrobial therapy in febrile humans include resolution of clinical signs, normalization of
animals, an appropriate work-up is necessary to localize and acute phase proteins (such as C-reactive protein), or a reduction
further characterize the presence of an actual bacterial infection, in erythrocyte sedimentation rate.14 A retrospective study of dogs
particularly in patients that are receiving immunosuppressive with discospondylitis described a mean antibiotic duration of 54
therapy. The administration of six different antibiotics to this wk, wherein those dogs documented to have Staphylococcus
patient within the 2 mo preceding the diagnosis of bacteremia infections had a mean duration of 74 wk.15 However, those dogs
likely contributed to the selection of antibiotic resistant bacteria. were treated until no further radiographic changes were observed,
Carriage of MRSP in the nasopharynx and skin of dogs is asso- a treatment endpoint that is not used in humans. Reported ra-
ciated with previous hospitalization and antibiotic administration diographic signs of infection resolution in canine discospondylitis
(and to a lesser extent, previous glucocorticoid therapy); however, include disappearance of vertebral lysis and either replacement
9
not all dogs carrying the organism will develop clinical infections. with bridging or fusion of the involved vertebrae.16 In adult dogs,
The patient in this report had all three risk factors. radiographic signs can lag behind clinical signs by 3–9 wk, and
In humans, the comparable disease, infectious spondylodiscitis, due to the variability in radiographic changes seen in successfully
is typically diagnosed by a combination of imaging and blood treated cases of discospondylitis, treatment efficacy is often based
culture results. The radiographic findings and positive blood and on clinical response rather than on radiographic findings.7 At this
urine culture results in the dog described in this report led to the time, there are no established standard criteria for duration of
antibiotic therapy in canine discospondylitis.
Linezolid belongs to the oxazolidinone class of antibiotics,
which are bacteriostatic through inhibition of protein synthesis via
binding to the 50S subunit.17 Linezolid has adequate penetration
into lung and other soft issues at concentrations above the MICs
for most susceptible pathogens, including MRSA.18 Based on the
demonstrated efficacy of linezolid for MRSA spondylodiscitis in
humans and previously reported pharmacokinetic data for this
drug in dogs, the study authors found linezolid to be an attractive
FIGURE 2 Lateral radiograph obtained after 23 wk of linezolid antibiotic choice for the patient described herein, given that the
therapy showing smoothly marginated sclerosis of vertebral endplates MRSP isolated was reported to be resistant to all other lower
and smooth osseous proliferation bridging the ventral aspect of the category antibiotics with anticipated efficacy.19 It is important to
seventh to eighth intervertebral disc space. L, left lateral radiograph. note that the MIC breakpoints for many antibiotics in veterinary

56 JAAHA | 50:1 Jan/Feb 2014


Linezolid Treatment of MRSP Infection

use are actually adapted from human studies rather than based on used for more serious infections in people. Those drugs often
species-specific pharmacokinetic PK data. Therefore, it is possible have a broader spectrum of activity, and their use should be based
that some of the antibiotics reported as resistant based on human- on culture and susceptibility results. Linezolid would qualify as
adapted MIC standards might actually have been effective in this a “tertiary use” antibiotic (i.e., used for very resistant human
patient if significant PK differences exist for each antibiotic be- infections). The same consensus statement concludes “tertiary
tween dogs and humans. However, in the absence of canine PK use” drugs “should not be employed in patients that are likely to
data for most antibiotics tested and given the patient’s bacteremia, recover without treatment, in patients that are as likely to be
the authors could not risk the choice of an ineffective antibiotic. helped through treatment with lower category drugs, or in
Of all the other antibiotics for which this patient’s isolates were patients that are unlikely to survive regardless of the therapeutic
tested against, only daptomycin and linezolid were suggestive of regimen.”21 Because the dog described herein showed progressive
being efficacious based on human MIC breakpoints that included clinical signs for 3 mo despite multiple antibiotic regimens, had
Staphylococcus pseudintermedius. Linezolid was chosen because a documented resistant MRSP bacteremia, and had a disease with
previously reported PK data after oral administration were a good prognosis for recovery with appropriate treatment, the
available to assist in dose calculation and the patient’s blood and study authors elected to use a “tertiary use” antibiotic, but only
urine isolates were found to be susceptible with a low MIC based after careful consideration.15,22 Despite the apparent efficacy of
on data extrapolated from human performance standards. linezolid in successfully treating the dog’s MRSP discospondylitis,
PK and pharmacodynamic data should be considered when the study authors do not advocate the empirical use of the drug
choosing and dosing any antibiotic, particularly nontraditional under any circumstances. Ideally, the decision to use linezolid or
antibiotic choices. Indices such as area under the concentration- other “tertiary use” antibiotics should be guided by hospital-wide,
time curve (AUC) over 24 hr at steady state divided by the MIC evidence-based infectious disease control programs that are de-
(AUC/MIC), and the cumulative percentage of a 24 hr period that veloped for each institution.
the drug concentration exceeds the MIC under steady-state PK
conditions (percent time of dosing interval . MIC) are useful in Conclusion
predicting the efficacy of an antibiotic. For linezolid, clinical cure This report documents the successful use of linezolid for clinical
and bacterial eradication in human patients were associated with resolution of MRSP bacteremia, bacteriuria, and discospondylitis
a linezolid AUC/MIC of . 100 and percent time of dosing in- in a dog. To the authors’ knowledge, this is the first report of the
terval . MIC of . 85. 20
In the absence of canine data, those use of linezolid to treat naturally occurring disease in a dog. The
criteria were used to support the dosage prescribed to this dog. linezolid dose of 20 mg/kg PO q 12 hr was effective to treat the
Linezolid treatment was successful in resolving the bacter- MRSP isolate with a linezolid MIC of , 1 mg/mL. For Staphy-
emia, bacteriuria, and clinical signs of discospondylitis in this dog. lococcus pseudintermedius infections that are resistant to all “pri-
Anemia, thrombocytopenia, and lactic acidosis, all of which are mary use” and “secondary use” antibiotics, linezolid should be
reported side effects of linezolid in humans, were observed considered as a treatment option when its use if justified, as
transiently in the first several weeks of linezolid therapy; however, outlined above in the American College of Veterinary Internal
all of those abnormalities resolved without any change in linezolid Medicine consensus statement.
dose. The use in dogs of extralabel antibiotics that are typically This case underscores the importance of performing a thor-
reserved for resistant human bacterial infections (i.e., “tertiary ough evaluation for infectious etiologies in febrile immunosup-
use” antimicrobials) is controversial. Some physicians, public pressed patients, as well as considering the risks that may
health specialists, and even veterinarians might advocate for eu- accompany empirical use of antibiotics. It is possible that the
thanasia of a veterinary patient with a resistant infection rather patient’s broad antibiotic resistance would not have been selected
than administer one of those antimicrobials. However, the for if the patient had not received six different antibiotics without
American College of Veterinary Internal Medicine consensus appropriate diagnostics. Tests such as a complete blood count,
statement on antibiotic use advises that “veterinarians are ethi- biochemical analysis, urinalysis, blood and urine cultures, as well
cally obligated to use antimicrobial drugs, when indicated, to aid as imaging (thoracic radiographs, spinal radiographs, abdominal
21
in the promotion of the health and well-being of animals.” ultrasound, echocardiography, MRI, etc.) should be considered
Efforts should be made to choose “primary use” antibiotics when part of the diagnostic regimen for investigation of the cause of
possible. Those are older antibiotics with a narrower spectrum of fever. Antibiotic administration should be based on culture sus-
activity. “Secondary use” antibiotics are typically newer and are ceptibility results, where use of “secondary use” and “tertiary use”

JAAHA.ORG 57
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are available. Staphylococcus pseudintermedius among dogs admitted to a small
animal hospital. Vet Microbiol 2011;150(1–2):191–7.
10. Al-Nammari SS, Lucas JD, Lam KS. Hematogenous methicillin-
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BD Bactec Plus Aerobic/F and BD Bactec Plus Anaerobic/F; BD assessment using MR. Radiology 1985;157(1):157–66.
Diagnostic Systems, Franklin Lakes, NJ 12. Cottle L, Riordan T. Infectious spondylodiscitis. J Infect 2008;56(6):
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f
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National Jewish Health Pharmacokinetics Laboratory, Denver, CO Intern Med 1997;11(5):284–7.
14. Gouliouris T, Aliyu SH, Brown NM. Spondylodiscitis: update on
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58 JAAHA | 50:1 Jan/Feb 2014

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