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Los antibiticos orales para el tratamiento de la osteomielitis adulto: una pldora difcil de golondrina

Kirsten Roberts, Pharm.D.PGY2 medicina interna residente de farmacia

Familia salud SetonAustin, Texas

26 de septiembre de 2014

ObjetivosRevisar las limitaciones en la literatura actual de osteomielitis, las directrices nacionales y prctica.Evaluar la literatura mdica investigando las modalidades del tratamiento de la osteomielitis y la comparacin de los antibiticos orales a los regmenes tradicionales.Comparar las propiedades farmacocinticas de antibiticos parenterales y orales y su eficacia en el tratamiento de la osteomielitis.Desarrollar la conclusin basada en pruebas para el papel de los antibiticos orales en osteomielitis.

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FondoRelevancia prctica

Terapia basada en la evidenciaNo hay alimentos y Drug Administration (FDA) aprob los antibiticos para la osteomielitis en ltimos 15 aos

II. No hay normas "Orientacin para la industria" para osteomielitis estudios iii.

IV.Escasez de las recomendaciones de las directricesVarias limitaciones de estudio en la literatura actual

RepeticinAltas tasas de fracasos de tratamiento y la recurrencia de ~ 20% de los casos1

Problemas con los regmenes tradicionalesPaciente comodidad y calidad de vida

II. Complicacin de la terapia intravenosa (IV)Mecnica: obstruccin, trombosisInfecciosasVeterans Affairs reciente estudio tasa de complicaciones de lnea inform de ~ 6% en su poblacin de pacientes adultos2

III. Costo Cargos mdicos directos por episodio de los cargos de instalaciones de hospital, honorarios y costos extrahospitalaria, fue estimada en

Estafiloccica osteomielitis, incluyendo promedio

$35.000 en 1995 en un hospital de Nueva York; ninguna especificacin de IV o terapia oral (PO)3$135-263/ da para terapia antimicrobiana intravenosa ambulatoria versus costo de antibiticos orales4

II. Definicin de osteomielitisInflamacin del hueso debido a un organismo patgeno lleva a la destruccin del hueso III.

EpidemiologaRara en adultos; No bien descrito en la literaturaOcurre en el 3-25% de las fracturas abiertas, dependiendo del grado de trauma5La incidencia anual de osteomielitis vertebral es 2.4/100.000 6Osteomielitis pueden estar presente en hasta un 20% de infecciones leves de pie diabtico (DFI) y 50-60% de heridas gravemente infectadas7

FisiopatologaEstructura sea

Cortical: hueso denso exteriorEsponjoso: hueso esponjoso interiorPeriostio: membrana fibrosa densa cubre hueso

Mecanismos de infeccin5,8II.Adherencia

Se adhieren microorganismos fibronectina receptores u otras protenas de la destruccin del hueso de la mdula

Las citoquinas inflamatorias en curso conducen a ii de destruccin del hueso.Isquemia debido a la compresin de canales vasculares y la necrosis de hueso posterior

hueso necrticoHueso atrapado rpidamente se convierte en inviable

Formacin de secuestro Los organismos pueden vivir aos en secuestroFormacin del involucro nuevo, viviendo alrededor de secuestro

BiofilmsComunidad microbiana que muestran fenotipos alterados ii.Comunicacin bacteriana a travs de qurum sensing

III.IV.

Cubierta de fibringeno evade los mecanismos de defensa del husped y las bacterias permite penetracin antimicrobiana para ocultar intracelular y lograr lenta tasa metablicaComn: Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa

K. Roberts 2

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Poblacin peditrica 9,10Bacteriemia transitoria comn en Pediatra

II. Las bacterias tienen acceso a hueso largo a travs de las ramas de las arterias nutrientes iii.Periostio libremente se une a la corteza; abscesos subperisticos considerables pueden formar y

ampliar para las largas distancias a lo largo de la superficie del hueso III.

Tabla 1. Organismos por frecuencia encontradosAgentes patgenos

8

Comn> 50% de los casos

Encontrado ocasionalmente> 25% de los casos

Rara< 5% de los casos

aureusEstafilococos coagulasa negativos

Los estreptococos sppEnterococos spp

No-tuberculosis del MycobacteriumHongos dimrficos(CoNS)

Pseudomonas sppEnterobacter spp

Candida sppCryptococcus spp

Proteus sppEscherichia coli

Aspergillus sppMycoplasma spp

Serratia sppAnaerobios

Tropheryma whippleiBrucella spp

Tuberculosis del Mycobacterium Salmonella spp

La tabla 2. Organismos aislados en la poblacin de pacientes selecto7,8Poblacin de pacientes Organismos

Todas las poblaciones de pacientesCuerpo extranjero asociado a infecciones

aureusContras, Enterobacteriaceae P. aeruginosa Candida

Propionibacterium,

sppInfecciones NoscomialLas lesiones del pie diabtico y lceras de decbito

, Los estreptococos spp, E. coli, K. neumona, Proteus spp,

sppbacterias anaerobias

Virus de inmunodeficiencia humana (VIH)Pacientes inmunocomprometidos

Bartonella henselae o Aspergillus spp,

B quintanaCandida albicans, o Micobacterias spp

IV.Tabla 3. Mtodos de clasificacin de osteomielitis

Sistemas de clasificacin11,12,13

Waldvogel" Hematgena

A menudo secundaria a la siembra de bacteriemia; Comn en Pediatra

" CrnicaFormacin de hueso necrtico

" ContiguoLocal de contaminados de origen - ninguna enfermedad vascular generalizada-enfermedad vascular generalizada

Cierny-Mader" Puesta en escena

Etapa 1: medular; Etapa 2: superficial; Etapa 3: localizada; Etapa 4: difusoHost

ooSaludableComprometida

" BS: sistmicos:Desnutricin, insuficiencia renal / heptica, diabetes, edad extrema inmunocomprometidos

BL: LocalLinfedema, estasis venosa, cicatrices extensas, enfermedad de pequeos vasos, neuropata

BLS: Locales y sistmicasCronicidad

" Sincronizacino Aguda: signos y sntomas < o 2 semanas

Crnica: signos y sntomas 2 semanas

" Presentacino Inicialo Posterior

K. Roberts 3

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DiagnosisDiagnostic testing

LaboratoryWhite blood cell count (WBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)

ii. Blood cultures, bone biopsyImaging

Initial: conventional radiography; commuted tomography (CT) imaging often unnecessaryii. Standard of care: magnetic resonance imaging (MRI)more specific and sensitive1

OtherDoppler ultrasonography

TreatmentTreatment based on chronicity 8

AcuteAntibiotics +/- surgical debridement

ChronicAntibiotics + surgical debridement

Surgical debridement and abscess drainageII.Goal of debridement is to reach viable, healthy tissue and to remove biofilm Livorsi and colleagues, 200814

Significantly higher failure rates have been reported in patients with vertebral osteomyelitis who do not receive drainage of abscess, (P

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TreatmentLack of data suggesting any specific antibiotic, route or duration of therapy is superior

ii. Initial parenteral antibiotics may be beneficial, but predominantly oral antibiotic therapy with high bioavailability is probably adequate

Spellberg B, Lipsky B. Clinical Infectious Diseases, 2012.16IV.Are certain antibiotics preferred? Data does not suggest that parenteral antibiotics are superior to oral antibiotics for osteomyelitisAre oral antibiotics acceptable in certain cases? Oral agents with high bioavailability acceptable alternative in most cases How long should antibiotics be given?

InconclusiveIs surgical debridement always necessary for cure? Surgical resection with antibiotic therapy appears to increase cure rate

Cochrane Review, 2013.5Objectives: to determine the effects of different systemic antibiotic treatment regimens for treating chronic osteomyelitis in adultsInclusion: randomized controlled trials (RCTs) and quasi-RCTs addressing effects of antibiotics after surgical debridementResults

8 trials, 282 participants; All high risk of bias ii. No difference found in four trials comparing parenteral to oral antibiotics (CI: 0.92-1.18)

ConclusionsLimited evidence suggests route does not affect rate of disease remission

ii. The main finding was lack of evidence to guide practice

Pharmacokinetics available antibioticsIV. Background

Bone less vascularized than tissue; cancellous bone achieves higher concentration than cortical bone 18Few reports of higher antimicrobial concentration in inflamed bone16,19Goal: bone concentration>MIC16

Table 4. Pharmacokinetics of Oral Antibiotics1,16,20,21Antibiotic Serum level g/mLb

(Free drug)% Bone

ConcentrationMIC90 MSSAc CLSI Breakpointsd E. coli

Amoxicillin (500mg )aAmox/clav (875mg)

5.5-7.52.2-11.6

3-31%3-30%/1-14%

--1

88/4

Cephalexin (500mg)Cefpodoxime (400mg)

12-304.5-7

18%15-30%

44

2 (cefazolin)2

amilligram; micrograms per milliliter; minimum inhibitory concentration that inhibits 90% of isolates; CLSI: Clinical Laboratory Standard Institute b c d

Figure 1. Human bone:serum ratios for various groups of antibacterials.20

*Lines indicate the group medians, and each symbol indicates the median concentration ratio of one study.

K. Roberts 5

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Table 5. Pharmacokinetics of Oral Antibiotics 1,16,20,21Antibiotic Serum level g/mL

(Free drug)4.3

% Bone Concentration

MIC90 MSSA CLSI Breakpoints E. coli

Ciprofloxacin (750mg)TMP-SMX (160mg)

27-48%50%/15%

12/38

12/381.72

11-21.1Linezolid (600mg)Clindamycin (600mg)

40-50%40-67%

40.5

----7.5

2.6Doxycycline (100mg) 2-86% 4 4

Evidence Supporting Use of Oral antibioticsEvidence supporting early parenteral to oral transition

Table 6. Daver N, et al. Oral step-down therapy is comparable to intravenous therapy forosteomyelitis. J Infection. 2007.22

Staphylococcus aureus

Study objective " Evaluate osteomyelitis cure with early switch from parenteral to oral therapy o Apparent cure: no signs/symptoms 6 months after completion

o Relapse: infection occurring at same site requiring antibiotics or surgery

Study designPatient population

""

Retrospective chart review72 adults

""

Do not specify chronic versus acute Mostly following trauma

Intervention ""

IV group received >4 weeks of IV therapyPO group received

I.

Treatment by individual antibiotics

Ciprofloxacin LiteratureTable 7. Ciprofloxacin Randomized and Nonrandomized Studies

Greenberg et al. 200023Study DesignProspective,

Baseline Characteristics" N: 5 "

InterventionCiprofloxacin 750mg BID or

Source/Organism" Bone biopsy or

Follow-up14-36 months

Clinical ResponseCiprofloxacin: 40% (2/5)

nonblinded, RCT

""

Chronicity: ChronicMean age: 38 years

lomefloxacin 800mg BID" Debridement: Not reported" Mean duration therapy:

60.6 days (28-110)

aspirate

S. aureusS. epidermis

(4),(1)

Lomefloxacin: 71% (5/7)

ConclusionsAuthors conclusions:" Oral quinolone therapy may offer an alternative option in some patients

for quinolone susceptible gram-positive organismsComments:" All patients who failed were treated for Staphylococcus spp infections

Limitations:" Do not specify etiologies" Several patients lost to follow-up" Small patient population

Greenberg et al. 198724Study DesignProspective,

Baseline Characteristics" N: 30 "

InterventionCiprofloxacin 750mg BID

Source/Organism" Blood or from site of

Follow-up Clinical response

nonblinded, RCT

""

Chronicity: ChronicMean age: 52 years

versus appropriate therapy for 6 weeks

""

Debridement: Not reportedMean duration therapy:

"

Ciprofloxacin group: 56 days (44-73)Alternative antibiotic group: 43 days (19-150)

infectionPrimarily obtained from biopsy

Enterobacteriaceae spp(18),P. aeruginosa aureus(4)

(16), S.

1-13 months Ciprofloxacin: 50% (7/14)

Alternative antibiotic group: 69% (11/16)

ConclusionsAuthors conclusions:" Oral ciprofloxacin therapy for chronic osteomyelitis appears to be as

effective as other antibiotic therapiesComments:" Failures were due to noncompliance, foreign body infection,

immunosuppression, and superinfection" More failures with ciprofloxacin over alternative antibiotic group with

P. aeruginosa

"""

" Alternative antibiotic group often combination therapy of broad- spectrum antibiotics

Strengths:" Randomized

Comparator group"Limitations:" Did not include etiology infection

Exclusion was severity of disease requiring parenteral therapy Debridement not reportedNo standardized comparator

K. Roberts 7

Gentry et al. 199025Study DesignProspective,

Baseline Characteristics" N: 67 "

InterventionCiprofloxacin 750mg BID

Source/Organism" Bone biopsy

Follow-up Clinical Response

RCT ""

Chronicity: ChronicMean age: 37 years

versus ceftazidime or nafcillin plus aminoglycoside (AMG)Duration:"Oral: at least 6 weeks Parenteral: at least 4 weeks, not to exceed 6 weeks

" Mean duration of therapy: Ciprofloxacin group: 56 days Alternative antibiotic group: 47 daysDebridement: Required"

S. aureus E. faecalis

(20)(7)

, ,

P. aeruginosa P. mirabilis (8),

(17),

K. pneumonia (7)S. marcescens

, ,(7)

Enterobacter spp (5), E. coli M. morganii

(2), (2)

Providencia spp, (2), (2)Acinetobacter spp

1 year Ciprofloxacin: 77% (24/31)

Ceftazidime or nafcillin plus AMG: 79% (22/28)

ConclusionsAuthors conclusions:" Oral ciprofloxacin is as safe and effective as parenteral antibiotics in

chronic osteomyelitis" Debridement is the most important factor for clinical success Comments:" Ciprofloxacin group treated 10 days longer on average Failure rates high with P. aeruginosa in both groups" S. aureus as a single pathogen 0/8 cures in ciprofloxacin group

Strengths:" Sufficient follow-up

Bone biopsy"" Included patients with DM, foreign body infections Limitations:" Small patient populationstated 6,000 cases to achieve 80% power

Swedish Study Group, 198826Study DesignProspective,

Baseline Characteristics" N: 34 "

InterventionCiprofloxacin 500-1500mg BID

Source/Organism" Bone biopsy or

Follow-up Clinical Response

NR, open- label, non- comparative

" Chronicity: Acute, chronic

" Etiology: Trauma, DFI, PAD, hema- togenousMean age: 65 years "

" Mean duration of therapy: 139 days (15-476 days)

" Debridement: Not reported, likely as majority of patients had bone biopsies

fistula secretion(28), P. aeruginosa

Enterobacter spp (2), E. , coli

S. aureus,S. epidermis,(1), P. mirabilis (2)

B. fragilis

2 months 65% (22/34)

ConclusionsAuthors conclusions:" Ciprofloxacin offers an oral treatment alternative in patients with acute

and chronic osteomyelitis caused by gram-negative pathogensComments:" Resistance developed in 4 patients; 3/20 P. aeruginosa

Strengths:" Bone biopsy in most patientsLimitations:""

Small patient populationShort follow-up time

K. Roberts 8

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Hessen et al. 198727Study DesignProspective,

Baseline Characteristics" N: 23 "

InterventionCiprofloxacin 750mg BID for

Source/Organism" Bone or deep soft

Follow-upMean: 43 weeks

Clinical Response86% (19/22)

non- randomized (NR)

" Chronicity: Acute, chronic

" Etiology: Surgery, trauma, DFI, decubitus ulcer Mean age: 58 years "

duration determined on individual basis

" Additional antibiotics acceptable

" Mean duration of therapy: 62 days

" Debridement: 22/23 patients

tissue biopsyP. aeruginosa (15),S. marcescens (5), S. aureus (3), S. epidermis (3), E. coli (3), P. mirabilis (1), K. pneumoniae (1)

"

ConclusionsAuthors conclusions:" Ciprofloxacin was effective and well-tolerated for the treatment of gram-

negative bacillary osteomyelitisComments:" One failure likely due to non-compliance; another secondary to

S. marcescens resistance

Strengths:" Majority of patients with bone biopsies Debridement performed in most patients"Limitations:

Reasonable follow-up time

""

Excluded patient with severe acute underlying disease No standardized length of treatment

Lesse et al. 198728Study DesignProspective,

Baseline Characteristics" N: 23

InterventionCiprofloxacin 750mg BID

Source/Organism" Bone biopsy or

Follow-up Clinical Response100% (14/14)

NR, non-comparator, on-going at time of publication

""

14 completed therapy Chronicity: Acute, chronic, recurrent Etiology: post-surgical "(9), post-traumatic (3), DM (2), alcoholism (2),

"

sickle cell disease (1)" Mean age: 51 years

"for 6-24 weeksMean duration of therapy: "110 days (41-191) Debridement: Performed as indicated

joint aspirate(18), P. aeruginosa

S. marcescens (2)Enterobacter spp

, (2),

M. morganii coli (1)

(2), Proteus spp

, E.

CoNS Streptococcus spp

(6), S. aureus (3)

,

2-14 months

Mean: 6.1 months(1-13 months)

"

" Discontinued (D/C) in two patients due to adverse drug reactions (ADRs) (urticaria, depression)

ConclusionsAuthors conclusions:" Ciprofloxacin efficacious for gram-negative osteomyelitis

Strengths:" Included MICs

Reasonable follow-up time"" Majority of patients with bone biopsies Limitations:""

Small patient populationNo standardized length of treatment

K. Roberts 9

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II. Ciprofloxacin summarySeveral studies from 1980-1990 provide positive evidence for the use of oral ciprofloxacin for the treatment of gram negative osteomyelitis Largest study showing positive results was randomized, included debridement, and obtained bone biopsy cultures 25

ii. All of the studies were small sample sizes iii. Cure percentages ranged from 40-100% (40% outlier)

Study with the lowest cure rate was primary treating S. aureus23P. aeruginosaiv. Several of the studies showed high rates of failure with

between IV and PO, however, in comparator study, rate of failure were similar

Important to consider collateral damage of increased resistance with use of ciprofloxacin29Favorable pharmacokinetic profile16,20

Oral bioavailability: 60-80%ii. Bone penetration: 37-60%

Ciprofloxacin is an efficacious agent in the treatment of gram-negative acute and chronic osteomyelitis

III.Table 8. Trimethoprim-Sulfamethoxazole Randomized and Nonrandomized Studies

Trimethoprim/sulfamethoxazole Literature

Saengnipanthkul, et al. 198830Study DesignProspective,

Baseline Characteristics" N: 88 "

InterventionTMP-SMX 1 DS tablet BID

Source/Organism" Unspecified

Follow-up Clinical ResponseTMP-SMX: 30/66 (45%)

NR " 66 in TMP-SMX group, 22 in penicillin (PCN)/ erythromycin group

""

Chronicity: ChronicEtiology: unspecified

" Mean age: 25.4 years TMP-SMX group, 19.1 years PCN/erythromycin group

versus dicloxacillin, cloxacillin, or erythromycin

" Debridement: 54% in TMP/SMX group, 56% in penicillin/erythromycin group

" All patients received at least 4 weeks therapyTreatment duration 0.05

ConclusionsAuthors conclusions:" TMP-SMX should be another antimicrobial choice in chronic osteomyelitis

because low cost, convenient administrationComments:""

Do not address how organisms like PCN/erythromycin not recommended for osteomyelitis

P. aeruginosa were treated

Strengths: " Comparator group

Statistical analysis"Limitations:""

Do not specify etiologyDo not specify culture sources

" Only half received debridement

K. Roberts 10

Nguyen, et al. 200931Study DesignRetrospective,

Baseline Characteristics" N: 56 "

InterventionLinezolid 600mg BID plus

Source/Organism" Intra-operative

Follow-up12 months; most

Clinical ResponseCure: linezolid 89.3%, TMP-

NR " 28 in linezolid group, 28 in TMP-SMX groupChronicity: Chronic"

" Etiology: 36 orthopedic device-related, 6 DFIMean age: 58.5 (22-"83)

rifampicin 10mg/kg BID versus TMP-SMX (TMP 8mg/kg/day) BID plus rifampicin 10mg/kg BID

" Lead-in of IV antibiotics for 5-7 days

" Debridement: not reported; all patients with foreign body (FB) had surgical intervention

samples or joint aspiration

Linezolid: MRSA (11, 34%), MSSA (4, 13%), MRCoNS (9, 28%), Enterococcus spp (5, 16%)TMP-SMX: MRSA (10, 22%), MSSA (7, 16%), MRCoNS (9, 20%)

patients with 2 year follow-up

SMX 78.6%, (P=0.47)

ADRs Linezolid 42.9%, TMP-SMX 46.4%, (P=1)

ConclusionsAuthors conclusions: " Oral linezolid/rifampicin and oral TMP-SMX equally efficacious in

treatment osteomyelitisComments:" No differences in cure based on surgical intervention, organisms

"

"

Strengths:" Comparator

Statistical analysis"Sufficient follow-up

Limitations:Small sample size

32Euba et al. 2009Study DesignProspective,

Baseline Characteristics" N: 50 "

InterventionIV cloxacillin 2gm q4h for 6

Source/Organism" Bone biopsy

Follow-upMedian: 10 years

Clinical responseOverall cure rate

randomized " 22 IV group, 28 PO group

""

Chronicity: chronic Etiology: 34 post- surgical, 9 hematogenous, 4 trauma, 3 contiguous

" Mean age: 47.7 years (18.3) cloxacillin group; 41.7 years (21.1) TMP-SMX+rifampin

weeks plus oral cloxacillin for 2 weeks versus oral TMP-SMX (TMP 7- 8mg/kg/day) plus rifampin 600mg/day for 8 weeks

" Debridement: all patients

MSSA(IQR 4-13)

"89.6%(43/48)Cure rate difference "between the groups was 1.6% (CI -15.7-33.3)

" 3 failures per protocol: 1/18 in cloxacillin group, 2/24 in rifampin-TMP-SMX group

K. Roberts 11

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Euba et al. 2009 (Authors conclusions:

continued Conclusions

" Oral rifampin-cotrimoxazole therapy is a good alternative in the treatment of chronic staphylococcal osteomyelitis

""

Comments:" 2 patients with HIV

1 patient with bacteremia"" No factor associated with failure

Strengths:Defined etiologyDefined organisms

""

All bone biopsyAll received debridement

"Limitations:

Long follow-up time

" Unblinded

IV. TMP-SMX SummaryTMP-SMX is a potentially useful option in the treatment of chronic, gram-positive osteomyelitis Cure percentages ranged from 45-89.6%

The study with the lowest cure rate by Saengnipanthkul, et al. included patients with only P. aeruginosaii. Treatment with TMP-SMX was generally well-tolerated

osteomyelitis30

iii.Favorable pharmacokinetic profile

All studies had long follow-up times which increases the strength of this recommendation 16,20

Oral bioavailability: 90-100%ii. Bone penetration: 50% TMP, 15% SMX

The MRSA Guidelines give TMP-SMX with rifampin combination a B-II recommendation17

Linezolid LiteratureTable 9. Linezolid Randomized and Nonrandomized Studies

Nguyen et al. 200931Study DesignRetrospective,

Baseline Characteristics" N: 56 "

InterventionLinezolid 600mg BID plus

Source/Organism" Intra-operative

Follow-up12 months; most

Clinical ResponseCure: linezolid 89.3%, TMP-

NR " 28 in linezolid group, 28 in TMP-SMX groupChronicity: Chronic"

" Etiology: 36 orthopedic device-related, 6 DFIMean age: 58.5 (22-"83)

rifampicin 10mg/kg BID versus TMP-SMX (TMP 8mg/kg/day) BID plus rifampicin 10mg/kg BID

" Lead-in of IV antibiotics for 5-7 days

" Debridement: not reported; all patients with FB had surgical intervention

samples or joint aspiration

Linezolid: MRSA (11, 34%), MSSA (4, 13%), MRCoNS (9, 28%), Enterococcus spp (5, 16%)TMP-SMX: MRSA (10, 22%), MSSA (7, 16%), MRCoNS (9, 20%)

patients with 2 year follow-up

SMX 78.6%, (P=0.47)

ADRs Linezolid 42.9%, TMP-SMX 46.4%, (P=1)

K. Roberts 12

Nguyen et al. 2009 (Authors conclusions:

continued) Conclusions

" Oral linezolid/rifampicin and oral TMP-SMX equally efficacious in treatment osteomyelitis

""

Comments:" No differences in cure based on surgical intervention, organisms

""

Strengths:Included patients with comorbiditiesComparatorStatistical analysisSufficient follow-up

Limitations:" Small sample size

33Lipsky et al. 2012Study DesignProspective,

Baseline Characteristics" N: 371 "

InterventionLinezolid 600mg q12h

Source/Organism" Suitable tissue

Follow-up15-21 days following

Clinical responseLinezolid group: 27/44

RCT " 241 in linezolid group

" Total 77 patients with osteomyelitis

""

Etiology: DFIMean age: 63 years old

either IV or PO versus ampicillin-sulbactam (1.5- 3gm q6h) or amoxicillin- clavulanate (500-875mg q12-8h)

Could add vancomycin for "MRSA infections in amino- penicillin/-lactamase inhibitor groupCould add aztreonam for "gram-negative infections in linezolid group

" Median duration: 19 (9) days for osteomyelitis

" Debridement: Not required, but wounds with necrotic areas were sharply debrided

wound specimens

Staphylococcus aureus (158 isolates), Staphylococcus epidermis (60 isolates),

(59 Enterococcus sppisolates), Streptococcus

(52 isolates)agalactiae

treatment"

(61%)Amino-penicillin/-"lactamase inhibitor: 69% (11/16)

" CI: -34.3-19.5

ConclusionsAuthors conclusions: " Oral linezolid equally efficacious to IV amino-penicillin/-lactamase

inhibitor combination in treatment osteomyelitisComments:""

Most common ADRs were thrombocytopenia, anemia, nausea Shorter duration of treatment

Strengths:" Prospective, randomizedLimitations:""

Did not require debridementDid not include patients with critical ischemia or foreign bodies

""

Could use additional antibioticsShort follow-up time

K. Roberts 13

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b.i.

c.

Rayner et al. 200434Study DesignProspective,

Baseline Characteristics" N: 55 "

InterventionLinezolid 600mg BID IV or

Source/Organism" 49 had surgically

Follow-upShort-term

Clinical ResponseShort-term follow-up

NR, open-label

" Chronic; 53% long bone, 18% DFI, 15% vertebral osteo- myelitis

" Included 3 immuno-suppressed patients

""

Compass-ionate use All failed prior treatmentMean age: 58 year "(30-81)

PO19 received IV lead-in period "(34.5%)27 received PO only (49.1%)"

" Duration 5 days to 3 months" 13 (23.6%) received 28 "daysDebridement: not required"

obtained positive cultures (89% bone, remaining aspirate)

MRSA (25; 45.5%), vancomycin-resistant faecium30.9%), MSSA (3, 5.5%),

(VRE) (17,

MRSE (2), VRE faecalis (2), VRE spp. (1), other

"follow-up median:21.5 days (5-31)Long-term "follow-up median: 195 days (31-540)

"cure: 79% (38/48)Long-term follow-up cure: "81.8% (18/22) 2 patients with failure of "oral

ConclusionsAuthors conclusions:" Oral linezolid efficacious in treatment of chronic, MDR osteomyelitis Comments:" Most common ADR was GI disturbances; 10 patients developed anemia-6

requiring D/C; 9 decrease PLT counts-7 requiring D/C

""

""

No specific factor was more likely to result in failure 63.6% (7) cure with MRSA

Strengths:" Defined etiology

Defined organisms Majority bone biopsy

Limitations:""

Non-comparatorMany patients did not receive long-term follow-up

VI. Linezolid SummaryBased on these three small studies, linezolid is a potential option in the treatment of gram-positive osteomyelitis Rayner et al. and Nguyen et al. included several patients with multi-drug resistant (MDR) organisms

ii. Cure percentages ranged from 61-89.3%The study with the lowest reported cure rate was in osteomyelitis secondary to diabetic foot infections33Patients were treated for a median duration of 19 days (9 days) Comparator group had similar rates of cure

iii.iv.

Small sample sizes weaken the strength of this recommendationAdverse drug reactions may limit use, although this was not significant in the trials presented

Favorable pharmacokinetic profileOral bioavailability: 100%

ii.The MRSA Guidelines give linezolid a B-II recommendation

Bone penetration: 40-51%

K. Roberts 14

VII.Table 10. Clindamycin Randomized and Nonrandomized Studies

Clindamycin Literature

Pontifex et al. 197335Study DesignNR, case-

Baseline Characteristics" N: 12 "

InterventionClindamycin 150mg q6h

Source/Organism" Source unspecified

Follow-up Clinical Response

series " Chronicity: chronic, refractory to other therapyEtiology: unspecified"

" Mean age: 47 years

" Surgical debridement: not required

" Mean duration of therapy: 124 days (48-288)

S. aureus micrococcus (1), others

(7), CoNS (1),

unidentified

Not specified " Cure: 5/12 (41.7%)

ConclusionsStrengths:Authors conclusions:

" Clindamycin would appear distinctly inferior to lincomycin and cloxacillin Comments:" Likely underdosed

"Limitations:

Reported organisms

""

Did not require debridementDid not specify follow-up

Petola et al. 199736Study Design

Prospective, RCTBaseline Characteristics" N: 50 "

Intervention150mg/kg/d cephadrine

Source/Organism" Bone biopsy or

Follow-up1 year (Median 27

Clinical responseCure: 100% (50/50) patients

""

Pediatric patientsChronicity: acute

" Etiology: hematogenous; 8 had joint involvement

" Median age: 9 years old

""

divided q6h vs 40mg/kg/day clindamycin divided q6h

" Treatment initiated IV, but switched to oral within 4 days in most cases (85%) Mean duration: 23 days Debridement: ~50% of patientspurposefully kept at a minimum

Treatment Duration: 3-4 "weeks

blood cultures

S. aureus

months)"

ConclusionsAuthors conclusions:" Treatment of pediatric acute S. aureus

cost reduced by keeping surgery at a minimum, shortening the course of osteomyelitis can be simplified and "

"antimicrobials, and switching quickly to the oral route

Comments:" No mention MRSA

Strengths:Well-designedLong-term follow-up

Limitations:" Homogenous patient population" Bone biopsy not required" Surgical intervention discouraged

K. Roberts 15

a.i.

b.i.

c.

Petola et al. 201037Study Design Prospective, RCT

Baseline Characteristics" N: 131 "

Intervention Source/Organism" Bone biopsy and

Follow-up1 year follow-up in

Clinical Response"

" 67 patients in the short-term treatment group; 64 in the long-term group

Pediatric patients"" Chronicity: acute

Etiology: "hematogenous

Median age: 9 years

Clindamycin (40 mg/kg per day divided q6h) or first-generation cephalosporin Randomized to 20

"or 30 days, including an IV phase for the first 2 to 4 day

Debridement: purposefully kept at a minimum

blood cultures

MSSA

126/131 patientsCure: 122/131 (93%)

" 5 modifications to therapy made in short-term group

4 modifications to therapy made in long- term group

ConclusionsAuthors conclusions:" Most cases of childhood acute hematogenous osteomyelitis can be treated

for 20 days with large doses of a well-absorbed antimicrobial, such as clindamycin or a first-generation cephalosporin, provided the clinical

""

response is good and CRP normalizes within 7 to 10 days Comments:" Did not consider modifications in therapy failure

Strengths:Well-designedLong-term follow-up

Weaknesses:" Homogenous patient population" Bone biopsy not required" Surgical intervention discouraged

VIII. Clindamycin SummaryStrong data supporting the use of clindamycin in pediatric populations with acute, hematogenous osteomyelitis

The cure percentage was 41.7%, however, clindamycin was likely under-dosed and surgical debridement was not required Favorable pharmacokinetic profile 16,20

Oral bioavailability: 90%ii.

The MRSA Guidelines give clindamycin a B-III recommendationBone penetration: 40-67%

17

IX. Tetracycline Literature

Table 11. Tetracycline case reportsReport Patient Intervention

Oral doxycycline Etiology/ChronicityChronic/contiguous

OrganismsKytococcus

ResponseInflammatory

CommentsOral doxycycline Chan et al. 201238 45 year old,

Chinese male, Shoulder w/ implant placement

100mg BID x6 weeks from implant- related septic arthritis

schroeteri markers resolved after 1 week; no relapse at 3 years

potentially effective for osteomyelitis w/ surgical intervention

K. Roberts 16

).

X.a.b.c.

i.

d.

Table 11. Tetracycline Case Reports (Report Patient

continuedInterventionMinocycline 600mg

Etiology/ChronicityUnknown source

OrganismsMycobacterium

ResponsePain/leg swelling

CommentsOptimal therapy for Gupta et al. 199239 31 year old female,

HIV, lower extremity osteomyelitis

qday and rifampin 600mg qday

possibly hematongenous

haemophilum improved with 6 weeks of minocycline Radiographs continued to show lucencies

M haemophilum is unknown; empiric treatment with minocycline could be considered

Preininger 197340 33 year old, male with spinal fusion with intermittent drainage from his left iliac crest

Wound debrided 3 months prior to antibiotic therapy

Unsuccessful Initial trial with erythromycin Successful Minocycline 100mg BID x unknown duration (recurrence) Minocycline 100mg BID x7 weeks

Surgical procedures 2 separate species resistant to

S. aureus

penicillin and ampicillin

Drainage ceased, wound closed, and patient reported no signs/symptoms osteomyelitis

Response was rapid with both treatment courses of minocycline

No imaging reported

Minocycline may be a useful agent for S. aureus osteomyelitis

Tetracyclines SummaryTetracyclines use in osteomyelitis is not well-reported in the literature Based on available case reports, it may be an effective option Favorable pharmacokinetic profile16,20

Oral bioavailability: 90%ii.

The MRSA Guidelines do not give specific recommendations for tetracyclines, but do mention its use in the narrativeBone penetration: 2-86%

17

XI. Metronidazole Literature

Table 12. Metronidazole case reportsReport Patient Intervention

Metronidazole Etiology/chronicityAcute osteomyelitis

Organisms Response2 months following

CommentsOral metronidazole Chazan et al. 200141 17 year old, male,

vertebral osteomyelitis

500mg q8h x8 weeks Anal dilation

Disc biopsy

B. fragilistreatment patient without back pain, decrease ESR, and imaging showed arrest of destructive process

may be effective for the treatment of acute, vertebral osteomyelitis

K. Roberts 17

)a.b.c.

i.

Table 12. Metronidazole case reports (Report Patient

continuedIntervention Etiology/chronicity

Acute osteomyelitisOrganisms

Blood culturesResponse Comments

No follow-up; Al-Tawfig, 2008.42 18 year old F with sickle cell disease & osteomyelitis

Ceftriaxone + gentamicin initially, then metronidazole 500mg q8h x6 wks B. fragilis

NScannot assess outcomes

XII. Metronidazole SummaryThe use of oral metronidazole is not well-reported in the literatureBased on available case reports, it may be an effective option anaerobic infections Favorable pharmacokinetic profile16,20

Oral bioavailability: 80%ii. Bone penetration: >100%

XIII.Table 13. Antibiotic Summary

Summary Oral Antibiotics7,16,20

Antibiotic Organisms* Doses Oralbioavailability

Bone:SerumConcentration

Bone penetration(ug/g)

Supporting Literature

ADRs/Comments

Ciprofloxacin Gram-negative 750mg BID 60-80% 0.27-1.2

0.42 (osteomyelitis)

0.1-1.4

1.4 (cortical);2 (medullary)

+++ ADRs: QTc prolongation, peripheral neuropathies Resistance

TMP/SMX S. aureus,CoNS

7-10mg/kg/d TMP 90-100% TMP: 0.5 3.7 +++ ADRs: rash, agranulocytosis

Clindamycin S. aureus 450mg q6h-600mg q8h 90% 0.21-0.45(IV data only)

2.63-5 +++ ADRs: Increased risk of C. difficile

Linezolid S. aureus,Streptococci agalactia,CoNS,Enterococci spp

600mg BID 100% 0.37-0.51

0.23(infected bone)

4-9 +++ ADRs: Anemia, thrombocytopenia peripheral neuropathy, optic neuritis, serotonin syndromeMonitoring of CBC with >2 weeks useADRs: erosive Doxycycline S. aureus,

Brucella spp100mg BID 90% 0.13-2.6

(IV data only)0.13-2.6 +

esophagitisADRs: Peripheral Metronidazole B. fragilis 500mg q8h 80% .79-1

(IV data only)14-27 +

neuropathy, leukopeniaEvidence supporting use: +++ Randomized controlled studies; ++ Non-randomized studies; + Case report *Could expect coverage of additional organisms with antimicrobials listed, but not present in current literature

K. Roberts 18

I.a.

a.i.

b.

i.

1.2.

I.a.

b.c.

i.

d.i.

a.b.c.d.e.f.

a.b.

a.b.c.

V.a.

i.b.c.

Future directionsStandards for Industry

Need for FDA Guidance for Industry standards to lead to new drug approval II. Current ongoing studies

Dellitt and collegues, 201143Oral TMP-SMX versus IV vancomycin for the treatment of osteomyelitis

ii. Study no longer ongoing secondary to poor enrollment in vancomycin IV groupEfficacy of Oral Antibiotic Therapy Compared to Intravenous Antibiotic Therapy for the Treatment of Diabetic Foot Osteomyelitis (CRO-OSTEO)44

Randomized, phase II trialii. Patients will receive six weeks of IV or oral antibiotic therapy depending upon their

randomization group. Primary outcomes at six months clinical follow-up will include:No evidence of bone infection Resolution of ulcer

IV antibiotics: piperacillin/tazobactam, cefepime, metronidazole, aztreonam, vancomycin, iii.daptomycin, linezolid, meropenem

iv. PO antibiotics: sulfamethoxazole/trimethoprim, clindamycin, linezolid, moxifloxacin, ciprofloxacin, metronidazole

ConclusionsSummary

Osteomyelitis is a difficult to treat disease state secondary to the complex pathogenesis and scarcity of literature to guide practiceTraditional treatment with only parenteral antibiotics is not well-supported by the literature Advantages oral antibiotics

Patient convenienceii. Eliminates risk of line complications (infection, thrombosis)

Decreased costiii.Disadvantages oral antibiotics

Possibility for decreased complianceii. Potentially less predictable antimicrobial bone concentrations

II. Flaws in study design and literatureUnclear definition of acute versus chronic Several studies do not identify etiology of osteomyelitis Many studies did not require bone biopsy or surgical debridement No standardized follow-up timesMostly small sample sizeEndpoints, such as remission and cure, not well defined

III. Patient populations in which oral antibiotics may be appropriateChronic osteomyelitis in immunocompetent patientsAcute osteomyelitis the data is less clear, but looking at the chronic data and MRSA guidelines, it is likely a suitable alternative

IV. Patient populations in which oral antibiotics may not be appropriateUnderstudied populations: immunocompromised, patients with critical ischemia, patients with gangrene Patients who may not have adequate gastrointestinal absorptionPatients with history or potential for noncompliance

Final RecommendationsSimilar rates of cure regardless of route of administration

RCT suggest percentage cure rate with IV antibiotics to be 67-90% 16Pharmacokinetic data supports use of select oral antibioticsImmunocompetent patients with either acute or chronic osteomyelitis should be considered for 4-8 weeks of oral antibiotics if no contraindications exist

K. Roberts 19

1.

2.

3.4.5.6.7.

.8.9.

5.

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Portada hasta tablas 9 24Cipro combinado tablas a travs de abx Resumen con cabecera 9 24Direcciones futuras y conclusiones 9 24Referencias 9-24