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Vive La OVIVA: The Start of Something New

Evaluating the Role of Oral Antibiotics as an Alternative to Intravenous Antibiotics in the Treatment of Bone and Joint Infections

Lindsey A. Lu, PharmD. PGY1 Pharmacy Resident

Department of Pharmacy, South Texas Veterans Health Care System University of Texas at Austin College of Pharmacy

February 14, 2020

Learning Objectives: 1. Understand the pathophysiology behind bone and joint infections2. Identify important factors to consider when selecting antibiotic therapy3. Formulate appropriate antibiotic regimens by considering properties of pharmacokinetics and bone

penetration of antibiotics4. Evaluate literature reviewing route of administration osteomyelitis treatment to help with future

treatment decisions

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Background I. Epidemiology

a. OM: approximately 21.8 cases per 100,000 persons per year1 b. Native vertebral OM: 5.4 cases per 100,000 persons each year3 c. Diabetic foot osteomyelitis (DFO) present in4,5,6,7

i. 20% of mild and moderate diabetic foot infections ii. 50% to 60% of severe diabetic foot infections

d. Prosthetic joint infections (PJI)2 i. 0.5 to 2 percent occurrence in all knee replacements

ii. 0.5 to 1.0 percent occurrence in all hip replacements iii. <1 percent occurrence in all shoulder replacements

e. In the US, average hospital admission cost due to bone and joint infections estimated to be $35,000

II. Definitions a. Osteomyelitis (OM): inflammation which occurs in the bone as a result of

i. Native vertebral osteomyelitis (NVO): Infection of the vertebra or intervertebral disc space3 ii. Diabetic foot osteomyelitis: soft tissue infection, chronic wounds, or ulcers that spread into

the bone, causing infection of the bone5 b. Prosthetic joint infection (PJI): infection involving the joint prosthesis and adjacent tissue2

III. Pathophysiology

a. OM: (Figure 1; Figure 2) i. Hematogenous spread: transmission of bacteria to bone through the bloodstream

ii. Contiguous Spread 1. Without vascular insufficiency: due to surgical inoculation or adjacent skin and soft

tissue infection 2. With vascular insufficiency: diabetic foot infection

iii. Direct inoculation following trauma or surgery b. PJI:

i. Hematogenous spread: transmission of bacteria to joint space through the bloodstream ii. Direct inoculation of microorganisms at the time of surgery either through direct contact or

aerosolized contamination of the prosthesis c. Common pathogens and risk factors by infection type (Table 1)

IV. Classifications of OM11 (Appendix A)

V. Guideline recommended diagnostic criteria of bone and joint infections (Table 2)

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Figure 1. Review of bone anatomy12 Figure 2. Pathophysiology of osteomyelitis1

Table 1: Common causative organisms and risk factors by infection type9,10

Hematogenous OM Vertebral OM Contiguous focus OM

Prosthetic joint infections

Population and risk factors

• Most common in children

• IVDU

• Most common in adults

• UTI

• IVDU

• Spinal surgery

• Infections of intravascular devices

• Diabetes mellitus

• Vascular insufficiency

• Contaminated open wound with fracture

• Puncture wounds on the foot with nails

• Revision of prior arthroplasty

• Previous PJI occurrence at that site

• Tobacco abuse

• Obesity

• Rheumatoid arthritis

• Malignancy

• Immunosuppression

• Diabetes mellitus

• Active infection at remote location during joint implantation

• Prolonged procedures

• Bilateral joint replacements

• Impaired wound healing

• Co-morbid conditions that prolong hospitalization

Organisms Staphylococcus aureus

Pseudomonas aeruginosa

Enterococcus spp.

Coagulase-negative staphylococci

Aerobic gram-negative bacilli

β-hemolytic streptococci

β-hemolytic streptococci

Enterobacteriaceae Haemophilus influenzae group B

Brucella spp. Stenotrophomonas maltophilia Nocardia spp. Pasteurella multocida

Cutibacterium acnes

Abbreviations: IVDU: Intravenous drug users; UTI: Urinary tract infections

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Table 2. Guideline recommended diagnostic criteria of bone and joint infections14,15,16 Diagnostic criteria

OM NVO PJI

• Presence of ulcer and visible bone

• Bone present upon instrument probing

• Obtain ESR and CRP

• Gold standard: bone biopsy with histopathologic examination and tissue culture

• Blood culture (usually positive in up to ½ of children with acute osteomyelitis)

• Blood cultures always obtain when OM is suspected (usually negative in adults)

• Imaging: plain radiographs initially to detect bony abnormalities. MRI is recommended for patient who require further more specific imaging

• Perform medical and motor/sensory neurologic examination

• Obtain 2 sets of blood cultures and baseline ESR and CRP

• Imaging: spine MRI is diagnostic imaging of choice*

• Presence of sinus tract that communicates with prosthesis

• Presence of acute inflammation (per histopathologic exam from surgical debridement)

• Presence of purulence without another known etiology surrounding prosthesis

• 2 or more intraoperative cultures or combination of preoperative aspiration and intraoperative cultures that yield the same organism.

• Growth of a virulent microorganism in a single specimen of a tissue biopsy or synovial fluid

• Imaging: Plain radiograph should be performed in all patients. Bone scans, and PET scans are not routinely recommended for diagnosis

Abbreviations: CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; PET: positron emission tomography *NVO: Combination spine gallium /Tc99 bone scan, or computed tomography scan or a positron emission tomography scan recommended in patients whom MRI cannot be obtained

VI. Risk factors for recurrence13,14

a. Bone and joint infections are difficult to cure and are associated with high relapse rates b. Factors contributing to risk of recurrence (Figure 2)

Figure 2: Predisposing factors to relapse and recurrence

VII. Treatment15

a. Goals of therapy i. Achieve source control

ii. Resolution of symptoms (fever, pain, inflammation) iii. Salvage limb and function

b. Surgical management (Table 3) c. Pharmacologic management (Table 3)

i. Therapeutic success depends upon 1. The antibiotic effect on the infecting pathogen 2. Extent of antibiotic penetration into the bone

ii. Guideline recommendations for bone and joint infections16,17,18 iii. Considerations of pros and cons of oral vs. IV antibiotics (Table 4)

d. Factors to consider when selecting antimicrobial therapy for bone and joint infections (Figure 3) i. Pharmacokinetics and bioavailability (Table 5)

ii. Pharmacodynamics (Table 6) iii. Clinical considerations (Table 7)

Persistent skin

infections

Uncontrolled diabetes

Poor blood circulation

Immunodeficiency Prosthetic joints IV drug use

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Table 3. IDSA Guideline Recommendations NVO guidelines Diabetic foot osteomyelitis (from

DFI guidelines): PJI guidelines

Recommendations for surgical management

• Progressive neurologic deficits

• Progressive deformity

• Spinal deformity with or without pain despite adequate abx therapy

• Persistent sepsis

• Patient unable to tolerate abx therapy

• Progressive deterioration of bone

• Prolonged abx are contraindicated

Susceptible to oral agents:

• Debridement and retention Not susceptible to oral agents:

• Removal of prosthesis Patients with PJI who have a well-fixed prosthesis without a sinus tract who are within approximately 30 days of prosthesis implantation or <3 weeks of onset of may be considered for

• Debridement and retention of prosthesis strategy

Recommended therapies (tailored to cultured organism)

IV:

• Nafcillin

• Cefazolin

• Ceftriaxone

• Vancomycin

• Penicillin G

• Cefepime PO:

• Metronidazole

• Moxifloxacin

• Linezolid

• Levofloxacin

• Ciprofloxacin

• TMP/SMX

• Clindamycin

• Doxycycline

No specific antibiotic regimen defined

IV:

• Nafcillin

• Cefazolin

• Ceftriaxone

• Vancomycin

• Penicillin G

• Ampicillin

• Cefepime

• Meropenem

PO companion drugs:

• Rifampin (combination therapy)

• Ciprofloxacin

• Levofloxacin

• Minocycline

• Doxycycline

• Cephalexin

• Dicloxacillin

Route (IV vs PO)

Optimal route of administration not specified (except for DFO)

IV or PO

• No residual infected tissue post-amputation

• Residual infected soft tissue (but no bone)

Initial IV then consider PO switch:

• Residual infected (but viable) bone

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Duration 6 weeks*

No residual infected tissue post- amputation: 2-5 days Residual infected soft tissue (but no bone): 1-3 weeks Residual infected (but viable) bone:4-6 weeks No surgical treatment, or residual post-operative dead bone present: >3 months^

Retained hardware or 1-stage exchange: Staphylococcal PJI

• 2-6 weeks of pathogen specific therapy + PO rifampin¥ followed by:

• Rifampin +oral companion drug¥ (THA:3 months; TKA: 6 months total antibiotic therapy)

PJI due to other organisms:

• 4-6 weeks of pathogen-specific IV or highly bioavailable PO therapy

2-stage exchange:

• 4–6 weeks of intravenous or highly bioavailable oral antimicrobial therapy between resection arthroplasty and reimplantation

Abbreviations: Abx: Antibiotics; THA: Total hip arthroplasty; TKA: Total knee arthroplasty; TMP/SMX: Trimethoprim/sulfamethoxazole *NVO duration: Exception 3 months recommended for Brucella infections

^MRSA infections duration: Unknown minimum of 8 weeks is recommended ¥Rifampin dose: 300-450 mg PO BID €Oral companion drugs choices: Ciprofloxacin A-I; levofloxacin A-II;cotrimoxazole A-II;minocycline/doxycycline:C-III;cephalexin C- III; dicloxacillin C-III).

Table 4. Pros and cons of oral vs. IV antibiotics (19,20,21)

Clinical Question:

When would early oral antibiotic therapy be an appropriate alternative to intravenous antibiotics when treating bone

and joint infections?

Pros Cons

Oral antibiotics • Ease of administration

• More affordable

• Slow absorption

• Unpredictable absorption

• Potential tolerability concerns

• Risk of nonadherence

IV Antibiotics • Reliable systemic absorption

• Achieve peak levels more rapidly

• Risk of line infection, occlusion, or accidental removal

• Potential vesicants

• May require therapeutic drug monitoring

Inpatient or Skilled Nursing Facility

• More frequent monitoring

• Ability to ensure compliance

• May be more appropriate for IVDU

• May prolong duration of inpatient stay

• Financial burden to healthcare system

• Potential for placement issues

OPAT (Outpatient Parenteral Antibiotic Therapy)

• More cost-effective than prolonged IV course in hospital

• Patients have freedom to return to normal activities and are in control of their own therapy

• Decrease risk for hospital acquired infections

• Requires frequent lab monitoring, home health visits, and coordination of care

• Not appropriate for patients with visual impairment, problems with manual dexterity, dementia, uncontrolled mental illness or substance abuse

• Questionable safety in IVDU

• Need refrigeration, electricity, running water

• Possible insurance barriers

• Must consider the stability of antibiotic

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Abbreviations: IVDU: Intravenous drug users

Abbreviations: PK: pharmacokinetic; PD: pharmacodynamic

Figure 3: Pathway for selecting antimicrobial treatment

Table 5. Pharmacokinetics and bioavailability22,23 PK and bioavailability considerations

Bioavailability • Affects volume of distribution (Vd)

• Cancellous bone allows better antibiotic penetration than cortical bone

• Agents with high bioavailability are optimal for long-term oral therapy in OM (fluoroquinolones, metronidazole, clindamycin, sulfonamides, tetracyclines, macrolides, rifamycins, oxazolidinones)

Protein binding • Only free unbound drug has antimicrobial effects

Clearance mechanism • Renal failure: enhanced exposure to antibiotic

• Augmented renal clearance: reduced exposure

Table 6. Pharmacodynamics24,25

PD considerations

Time course of bacterial killing • Concentration-dependent (aminoglycosides, fluoroquinolones, metronidazole, daptomycin). Will need higher dosing to achieve adequate peak levels

• Time-dependent (β-lactams and vancomycin). Will need to be dosed more frequently to achieve efficacy

Post-antibiotic effect • Suppression of bacterial growth that remains after a brief exposure of antibiotics (antibiotics with no post-antibiotic effect may require more frequent dosing administration)

• Ex: aminoglycosides, clindamycin, macrolides, tetracyclines, rifampin

• Infusion plan needs to be simple enough for patient to administer at home

• If given in infusion center, once daily dosing is preferable

PK considerations

• Solubility

• Protein binding

• Clearance mechanism

PD considerations

• Time course of

bacterial killing

• Post-antibiotic effect

Clinical considerations

• Site of infection

• Severity of illness

• Body composition

• Pathogen

characteristics

Antibiotic

Regimen:

• Dose

• Frequency

• Duration

• Route

Clinical

Evidence

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Abbreviations: Vd: volume of distribution Table 7. Clinical considerations24,25,26

Clinical considerations

Site of infection • Certain antibiotics don’t reach adequate concentrations in bone or joint and may make it hard for drug to reach site of infection

• Ex: ertapenem, meropenem, cefazolin, vancomycin

Severity of illness • Help to determine agent of choice: bactericidal vs. bacteriostatic

Body composition • Bone: presence of ischemic, calcified, arthritic tissues, or bone cysts destroys bone tissue, affecting blood perfusion and ability of antibiotic to reach the site

• Obesity: increased Vd particularly for lipophilic antibiotics because of increased lean body mass and increased adipose tissue; may lead to decreased serum antibiotic levels

Pathogen characteristics • Resistance mechanisms

• Local resistance patterns

VIII. Literature Review

a. PK studies and early clinical data (Table 8) b. Collection of studies comparing PO fluoroquinolones vs IV therapy (Table 9) c. Randomized controlled trials

i. Greenberg (2000): Comparing PO vs PO therapy (Table 10) ii. Euba (2009): Comparing PO vs IV+PO sequential therapy (Table 11) iii. Li (2019): Comparing PO vs IV (Table 12)

Table 8. PK studies and early clinical data27,28,29:

Antibiotic penetration and cure rates in bone and joint infections

PK/PD studies • PK analysis: calculated by concentration ratios between bone and serum

• Bone penetration studies o Good penetration for FQ, linezolid, penicillin, and cephalosporins (in order

from highest to lowest bone-to-serum concentration ratios) o Most antibiotics achieved concentrations exceeding MIC90 and or MIC

breakpoints of the infecting pathogens

Animal studies (most widely studied rabbit Staphylococcus aureus model)

• Rifampin: o Higher bone concentrations than clindamycin, azithromycin, vancomycin,

trimethoprim, and ciprofloxacin o Not synergistic and even antagonistic to the above agents in vitro

• Ciprofloxacin: monotherapy showed good in vitro activity against S. aureus OM, but had limited in vivo activity

Conclusion:

• Difficult to predict in vivo activity of antibiotics based on animal in vitro studies

• Ciprofloxacin monotherapy should be used cautiously in S. aureus osteomyelitis

Non-randomized human studies

IV

• β-lactams: 4-6 weeks of therapy; 60-90% cure rates (didn’t report if there was surgical debridement)

• Vancomycin: low cure rates for chronic OM

• P. aeruginosa cure rates lower than for other pathogens PO

• FQ: 60-80% cure rate

• SMX/TMP: 45% cure rate

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Abbreviations: FQ: Fluoroquinolones; SMX/TMP: Sulfamethoxazole/trimethoprim Table 9. Comparing PO fluoroquinolones to IV antibiotics30,31,32

Trial Design Intervention Duration Results

Gentry (1990) Prospective Randomized controlled trial (RCT) n=59

Surgical debridement + Ciprofloxacin 750 mg PO BID (n=31)

VS Nafcillin-aminoglycoside IV (n=28)

6 weeks 4- 6 weeks

Clinical success: 24 of 31 (77%) Adverse events: 1 of 31 (3%) Clinical success: 22 of 28 (79%) Adverse events: 4 of 28 (14%)

Clinical Success: Causative organisms were absent from the cultures taken at the end of therapy or infection site sufficiently improved as determined by investigator Organisms included: S. aureus, E. faecalis, P.aeruginosa, P. mirabilis, K. pneumoniae, S. marcescens, E. cloacae, E aerogenes, E. coli, Morganella morganii, P, stuartii, Acinetobacter calcoaceticus, Pseudomonas fluorescens

Gentry (1991) Parallel RCT n=33

Ofloxacin 400 mg PO BID (n=19)

VS.

Cefazolin 1g IV q8hr OR ceftazidime 2g IV q12hr (n=14)

6 weeks 4 weeks

Clinical success: 14 of 19 (74%) Adverse events: 7 of 19 (37%) Clinical success: 12 of 14 (86%) Adverse events: 4 of 14 (29%)

Mader (1990) RCT n=26

Ciprofloxacin 750 mg PO BID (n=14)

VS. Nafcillin 2 g IV q6hrs OR clindamycin 900 mg IV q8hrs OR gentamicin 80 mg IV q8hrs (n=12)

4 weeks 4 weeks

Clinical success:11 of 14 (78%) Clinical success: 10 of 12 (83%)

Duration of follow up Approximately 30 months

Limitations • Follow-up was determined by phone or letter follow up

• Small sample size

Author’s Conclusions • PO FQ non-inferior to IV antibiotics for treatment of post-traumatic and chronic OM

• PO options provide additional cost and convenience benefits Abbreviations: FQ: Fluoroquinolones, RCT: Randomized controlled trial

Table 10. Clinical response to oral fluoroquinolones 34

Greenberg (2000)

Objective To evaluate the safety and efficacy of ciprofloxacin, high-dose lomefloxacin, or levofloxacin for the treatment of chronic OM caused by susceptible organisms

Design Prospective, non-blinded RCT

Studied population Inclusion

• >17 years old

• Patients who had cultured specimens that were obtained from time of surgical debridement or an aspirate from infected bone

Exclusion

• Pregnancy or breastfeeding

• Severe disease requiring concomitant antimicrobial therapy

• FQ hypersensitivity

• Resistance to the isolated pathogen

• CrCl <30 ml/min

Interventions • Ciprofloxacin 750 mg PO q12 hours (n=5)

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• Levofloxacin 500 mg PO q24 hours (n=15)

• Lomefloxacin 800 mg PO q12 hours (n=7)

Primary outcome • Clinical cure (defined as healed wound without drainage or swelling)

Results • Organisms: Staphylococcus aureus, Enterobacteriaceae, anaerobes, staphylococci, streptococci, and Pseudomonas aeruginosa

• Average duration of follow up was 11.8 months for those who completed course

• Average duration of therapy was 60.6 days Clinical cure rate:

• Ciprofloxacin 2 of 5 (40%)

• Levofloxacin 9 of 15 (60%)

• Lomefloxacin 5 of 7 (71%)

Critique Strengths

• All patients had debridement of infected bone

• Treatment lasted until wound closure

Limitations

• Treatment duration not consistent among patients

• Small sample size

• No statistical comparison between three agents

Author’s conclusion • Oral fluoroquinolone therapy provides an easy regimen in comparison to IV antibiotics for S. aureus osteomyelitis and can be used in patients with susceptible isolates

Conclusion • Oral FQ are safe and efficacious if prolonged therapy is needed, if used in combination with surgical debridement

• FQs provide broad coverage of common pathogens of concern for osteomyelitis Abbreviations: RCT: randomized controlled trial; FQ: fluoroquinolone; CrCl: creatinine clearance Table 11. Comparing PO antibiotics to IV + PO sequential therapy33

Euba (2009)

Objective To evaluate the possible non-inferiority of oral therapy compared to sequential oral and intravenous therapy for the treatment of chronic osteomyelitis

Design RCT

Studied population Inclusion criteria: Patients who had surgery for chronic nonaxial OM due to S. aureus

Exclusion criteria:

• Prosthetic joint infection

• Polymicrobial infections

• Infections with cloxacillin, cotrimoxazole, or rifampin-resistant isolates

Interventions Group A (n=22)

• Cloxacillin 2g IV q4hrs for 6 weeks then Cloxacillin 500mg PO q6hrs for 2 weeks

Group B (n=28)

• Cotrimoxazole 7-8mg/kg PO q12hrs +

• Rifampin 600mg PO q24hrs (combination for total of 8 weeks)

Primary outcome • Clinical cure rate: remission of symptoms and absence of failure during (10-year) follow-up

Secondary outcome • Treatment tolerability

• Length of hospital stay

Results

Group A (n=22) Group B (n=28)

Relapse rate: 2 of 21 (10%) 3 of 27 (11%)

Duration of hospital stay

51 days 31 days

P value = 0.002

Side effects 3 of 22 (13.6%) 5 of 28 (17.9%)

Reported side effects: phlebitis, skin rash, bronchospasm, and vomiting

Critique Strengths

• Long-term follow up design

• Early oral therapy used in Group B

• Patients had surgical debridement

Limitations

• Small sample size

• Excluded PJI

• Comparator antibiotics not from same class

Author’s conclusions • Oral rifampin-cotrimoxazole can be helpful in treating S.aureus that are resistant to FQ

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• 8-week PO rifampin-cotrimoxazole regimen may be as efficacious as 6 weeks of IV cloxacillin treatment followed by 2 weeks of oral cloxacillin

Conclusions • Oral rifampin-cotrimoxazole therapy is a comparable alternative to IV therapy in the treatment of chronic staphylococcal OM with surgical debridement and also provides additional treatment option in fluoroquinolone-resistant MRSA osteomyelitis

Abbreviations: FQ: fluoroquinolone Table 12. Oral vs intravenous antibiotics for bone and joint infection (OVIVA)

Li (2019) Objective To determine if administration of oral therapy is noninferior to intravenous therapy for the

treatment of orthopedic infections

Design Multicenter, open-label, parallel group, non-inferiority RCT

Inclusion/exclusion criteria

Inclusion

• Patients > 18 years old

• Provided written informed consent

• Would have qualified for 6 weeks of IV therapy for an acute/chronic bone or joint infection:

o Native OM o Native joint infection

requiring excision arthroplasty

o PJI o Orthopedic fixation device

infection o Vertebral OM with or

without associated diskitis or soft-tissue infection

Exclusion

• Staphylococcus aureus bacteremia on presentation or within previous month

• Bacterial endocarditis

• Other concomitant infection

• Mild OM

• Infection in which there was no appropriate antibiotic choices that would allow for randomization

• Prior enrollment in the trial

• Septic shock or systemic symptoms requiring IV antibiotics

• Patient deemed unlikely to comply with trial requirements

• Clinical, histological, microbiological evidence of mycobacterial, fungal, parasitic, or viral infection

• Receiving investigational drugs from another clinical trial

Intervention Randomly assigned treatment strategy (IV or PO therapy) was started as soon as possible (not >7 days) after surgical intervention

Outcome measures/endpoints

Primary endpoint: definite treatment failure within 1 year after randomization (defined as presence of >1 clinical criterion, microbiologic criterion, or histologic criterion) Secondary endpoint:

• Probable or possible treatment failure

• Early discontinuation of the randomly assigned treatment strategy

• IV catheter complications

• Clostridium difficile associated diarrhea

• Serious AE

• Resource use

• Health status

• The Oxford hip and knee scores

• Adherence to treatment

Population Recruited 1054 participants between June 2010 and October 2015

• IV group: 527 patients assigned

• PO group: 527 patients assigned Baseline characteristics:

• Overall well-matched; only significant difference was gender (P=0.02)

• Predominant characteristics are as follows: o Surgical procedure: no implant or device present, 30.6% o Deep-tissue histologic results: infected, 51.5% o Microbiologic diagnostic sampling: >2 samples positive for same organism, 65.9%

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o Organisms (in order of prevalence): Staphylococcus aureus (of 186 cases of Staphylococcus aureus, MRSA was reported in 19 cases (10.2%)), Coagulase-negative staphylococcus, gram negative organisms, Streptococcus species

Site of infection IV antibiotic (n=527)

PO antibiotic (n=527)

Total (n=1054)

Spinal infection, n (%) 37 (7.0%) 35 (6.6%) 72 (6.8%)

Upper limb, n (%) 43 (8.2%) 59 (11.2%) 102 (9.67%)

Lower limb, n (%) 436 (82.7%) 419 (79.5%) 855 (81.1%)

Other, n (%) 12 (2.3%) 14 (2.7%) 26 (2.5%)

Baseline Surgical Procedure IV antibiotic (n=527)

PO antibiotic (n=527)

Total (n=1054)

No implant/device present; debridement performed, n (%)

153 (29) 169 (32.1) 322 (30.6)

Debridement/implant retention, n (%) 124 (23.5) 123 (23.3) 247 (23.4)

Removal orthopedic device, n (%) 89 (16.9) 78 (14.8) 167 (15.8)

Prosthetic joint implant removed, n (%) 68 (12.9) 67 (12.7) 135 (12.8)

Prosthetic joint exchange (one-stage), n (%) 47 (8.9) 43 (8.2) 90 (8.5)

Surgery for diskitis, spinal OM, NO epidural abscess debridement, n (%)

13 (2.5) 13 (2.5) 26 (2.5)

Surgery for diskitis, spinal OM, epidural abscess debridement, n (%)

8 (1.5) 5 (0.9) 13 (1.2)

Results

Primary outcomes: Intention-to-treat

IV PO P value

Definitive treatment failure, n (%) 74/506 (14.6) 67/509 (13.2) 0.91 (0.63,1.32)

Difference in risk of definitive treatment failure

-1.4 pts (meets non-inferiority margin 7.5)

Secondary Outcomes

Probable/possible treatment failure, n (%)

6/50 (1.2) 10/509 (2.0)

Early discontinuation of treatment, n (%) 99/523 (18.9) 67/523 (12.8) P=0.006

Median total duration of therapy 78 days 71 days

Duration antibiotic therapy was continued beyond 6 weeks

805/1049 (76.7)

IV catheter complications, n (%) 49/523 (9.4) 5/523 (1.0) p<0.001

C. difficile, n (%) 9/523 (1.7) 5/523 (1.0) P=0.3

Median length of hospital stay (LOS) 14 11 P<0.001

Oxford Hip Score P=0.18

Oxford Knee Score P=0.01 and P=0.04

Morisky Scores, n (%) 75/80 (93.8) 283/323 (87.6)

No evidence of heterogeneity of the center (P=0.51)

IV agents used >1 week during initial 6-week period PO agents used >1 week during initial 6-week period

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Author’s conclusions

Appropriately selected oral antibiotic therapy was noninferior to intravenous therapy when used during the first 6 weeks for the management of bone and joint infections

Critique

Strengths

• Subgroup analyses which were consistent with the primary outcome showed no outcome advantage of either IV or PO therapy

• Total treatment duration did not differ between groups

• Included broad selection of infecting organism, surgical procedures, and anatomical sites

• Antibiotics were selected by different infection specialists which resembles practice in the real-world setting

Limitations

• Antibiotic dosing not provided

• Antibiotics were selected by different infection specialists and were assumed to be appropriate but could differ based on clinical judgement

• Open-label

• Patients who received IV therapy had more frequent health-care assessments

• Breakdown of antibiotics used by indication and pathogen not provided

• Rifampin more commonly used in PO antibiotic group

• Adverse effects subjectively determined by ID specialists

• No subgroup analysis performed on different types of bone and joint infections

Take Home Points:

• Oral therapy demonstrated to be non-inferior in comparison to IV therapy when patients were assessed for definitive treatment failure at 1 year after randomization

• PO group had shorter hospital stays and fewer complications compared to IV group

• Patients on PO antibiotics were less likely to discontinue therapy and had overall better patient-reported outcomes

• There still is uncertainty on the appropriate duration of treatment for bone and joint infections Abbreviations: RCT: randomized controlled trial; OM: osteomyelitis; PJI: prosthetic joint infection

VIIII. Overall Conclusions (Figure 4)

a. Route of administration b. Antibiotic selection

i. Most robust data with FQ ii. FQ have numerous black boxed warnings, including:

1. Tendon rupture 2. Peripheral neuropathy 3. CNS effects 4. QT prolongation 5. Psychiatric disturbances 6. Hypo/hyperglycemia

c. Future directions

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Figure 4. Overall conclusions

X. Recommendations (Figure 5)

a. When to initiate oral therapy b. How to choose an oral agent

Figure 5. When to initiate oral therapy

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Route of administration

•Oral antibiotics are a safe and effective alternative therapy to IV therapy

•Oral antibiotics preferred for:

• Convenience

•Cost considerations

•Safety

•IV preferred for:

• Oral intolerance

• Severe infections involving systemic symptoms

•Resistance to PO therapy

Antibiotic selection

•FQ well studied in BJI but have numerous black box warnings

•Other highly bioavailable oral options with clinical data for BJI include: tetracyclines, macrolides, clindamycin

• Limited data for oral beta-lactams and tetracyclines

•Rifampin as adjunctive therapy for:

•MRSA implant associated infection

•S. aureus infections

Future directions

•Missing gaps in current literature

• More data needed for oral tetracyclines and β-lactams

•Limited data on benefit of rifampin as adjunctive therapy for non-PJI and non-S. aureus infectoins

•Is oral therapy effective without surgical debridement?

•Specific duration of therapy associated with better outcomes

1) Patient can tolerate PO abx; no absorption issues

2)Temperature <38C for 24-48 hours

3) No signs of sepsis

4) PO option available based on susceptibilities

1) Cultures and Susceptibilities

2) Side effect profile

3) Dosing convenience

4) Bone penetration

5) (Appendix B)

1) May initiate oral therapy as soon as clinically stable if a safe and effective oral agent is available

Clinical improvement

Antibiotic selection

When to start PO agent

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APPENDICES Appendix A. Classifications of osteomyelitis

Waldvogel Cierny-Mader Chronicity

1) Hematogenous – spread through the blood

2) Contiguous – spread from a local source (no generalized vascular disease/ generalized vascular disease)

3) Chronic – presence of necrotic bone

Staging:

• Stage 1: Medullary

• Stage 2: Superficial

• Stage 3: Localized

• Stage 4: Diffuse Host:

• A host: normal host

• B host: o Systemic compromise (Bs) o Local compromise (Bl) o Systemic and local compromise (Bls)

• C host: treatment is worse than disease

• Acute: signs and symptoms for < 2 weeks

• Chronic: signs and symptoms > 2 weeks

Appendix B. Selection of oral antibiotics

Agent Bone and joint penetration

Strong clinical data Safety concerns Doses per day

Fluoroquinolones 50% Yes BBW: Tendon rupture, peripheral neuropathy, CNS effects Pregnancy Children QTC>500 milliseconds

QD /BID

SMX/TMP 50% Yes Sulfa allergy Renal/hepatic impairment SJS GP6D deficiency

BID

Linezolid 50% Yes >2weeks: bone marrow suppression Serotonin syndrome

BID

Tetracycline Not listed Pregnancy children <8 years old QD/BID

Metronidazole 80-100% Pregnancy, alcohol use BID/TID

Cephalexin 0.5-2% Hypersensitivity QID

Clindamycin 40-70% Good pediatric data C. difficile infections QID Abbreviations: BBW: black box warning Appendix C. Recommended dosing from IDSA Guidelines

Organism Primary agents/dosing Alternative regimens/dosing NVO

Staphylococci (oxacillin susceptible)

Nafcillin/oxacillin 1.5-2g IV q4-6hrs or continuous infusion Cefazolin 1-2g IV q8hrs Ceftriaxone 2g IV q24hrs

Vancomycin 15–20mg/kg IV q12hrs Daptomycin 6–8mg/kg IV q24hrs Linezolid 600mg PO/IV q12hrs Levofloxacin 500–750mg PO q24hrs + Rifampin PO 600mg daily Clindamycin 600–900mg IV q8hrs

Staphylococci (oxacillin resistant)

Vancomycin 15-20mg/kg IV q12hrs (consider loading dose)

Daptomycin 6–8mg/kg IV q24hrs Linezolid 600mg PO/IV q12hrs Levofloxacin 500–750mg PO q24hrs + rifampin PO 600 mg daily

Enterococcus species (penicillin susceptible)

Penicillin G 20-24 million units IV q24hrs continuously or in 6 divided doses Ampicillin 12g IV q24hrs continuously or in 6 divided doses

Vancomycin 15–20mg/kg IV q12hrs Daptomycin 6mg/kg IV q24hrs Linezolid 600mg PO/IV q12hrs

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Enterococcus species (penicillin resistant)

Vancomycin 15-20mg/kg IV q12hrs (consider loading dose)

Daptomycin 6mg/kg IV q24hrs Linezolid 600mg PO/IV q12hrs

Pseudomonas aeruginosa Cefepime 2 g IV q8-12hrs Meropenem 1g IV q8hrs Doripenem 500mg IV q8hrs

Ciprofloxacin 750mg PO q12hrs (or 400mg IV q8hrs) Aztreonam 2g IV q8hrs (severe penicillin allergy or quinolone-resistant strains) Ceftazidime 2g IV q8hrs

Enterobacteriaceae Cefepime 2g IV q8-12hrs Ertapenem 1g IV q24hrs

Ciprofloxacin 500–750mg PO q12hrs (or 400mg IV q12hrs)

DFO No preferred (first-line) antibiotic regimen defined

MILD Staphylococus aureus (MSSA), Streptococcus spp.

Dicloxacillin QID Clindamycin Cephalexin QID Levofloxacin QD Amoxicillin-clavulanate

Staphylococcus aureus (MRSA)

Doxycycline Trimethoprim/sulfamethoxazole

MODERATE MSSA; Streptococcus spp; Enterobacteriaceae; obligate anaerobes

Levofloxacin QD Cefoxitin Ceftriaxone QD Ampicillin-sulbactam Moxifloxacin QD Ertapenem1g IV QD Tigecycline

MRSA

Linezolid 600mg PO/IV q12hrs Daptomycin 6mg/kg IV q24hrs Vancomycin 15–20mg/kg IV q12 hrs

Pseudomonas aeruginosa

Piperacillin-tazobactam TID-QID

PJI

Staphylococci (oxacillin susceptible)

Nafcillin 1.5-2g IV q4-6hrs Cefazolin 1-2g IV q8hrs Ceftriaxone 1-2g IV q24hrs

Vancomycin 15mg/kg IV q12hrs Daptomycin 6mg/kg IV q24hrs Linezolid 600mg PO/IV q12hrs

Staphylococci (oxacillin resistant)

Vancomycin 15-20mg/kg IV q12hrs + rifampin 300-450mg PO BID

Daptomycin 6mg/kg IVq24hrs + rifampin 300-450mg PO BID Linezolid 600mg PO/IV q12hrs + rifampin 300-450mg PO BID

Enterococcus spp. Penicillin-susceptible

Penicillin G 20-24 million units IV q24hrs continuously or 6 divided doses Ampicillin 12g IV q24hrs continuously or 6 divided doses

Vancomycin 15mg/kg IV q12hrs Daptomycin 6mg/kg IV q24hrs Linezolid 600mg PO/IV q12hrs

Enterococcus spp. Penicillin-resistant

Vancomycin 15mg/kg IV q12hrs Linezolid 600mg PO/IV q12hrs Daptomycin 6mg/kg IV q24hrs

Pseudomonas aeruginosa Cefepime 2g IV q12hrs Meropenem 1g IV q8hrs

Ciprofloxacin 750mg PO BID/ or 400mg IV q12hrs Ceftazidime 2g IV q8hrs

Enterobacter spp. Cefepime 2g IV q12hrs Ertapenem 1g IV q24hrs

Ciprofloxacin 750mg PO BID/ or 400mg IV q12hrs

Enterobacteriaceae IV β-lactam based on susceptibilities Ciprofloxacin 750mg PO BID

β-hemolytic streptococci Penicillin G 20-24 million units IV q24hrs continuously or in 6 divided doses Ceftriaxone 2g IVq24hrs

Vancomycin 15mg/kg IV q12hrs

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Appendix D. Comparison of agents used in OPAT

Antibiotic Oral BA % Doses per day Infusion time Most common ADR Comments

Aztreonam NA 2-4 3–5 min push or 20–60 min infusion

Rare cross-allergenicity with other beta-lactams

Cefazolin NA 3-4 or CI 3–5 min push or 30–60 min infusion

HSN Dialysis-only dosing possible

Cefepime NA 2-3 or CI 5 min push or 30 min infusion

HSN Neurotoxicity

Dialysis-only dosing possible

Ceftazidime NA 3 3-5-minute push/ 15-30-minute infusion

HSN Dialysis-only dosing possible

Ceftriaxone NA 1-2 1-4 min push /30 min infusion

HSN

Daptomycin NA 1 2-minute push/ 30-minute infusion

Myopathy; rhabdomyolysis

Baseline and weekly CK

Ertapenem NA 1 30 HSN

Meropenem NA 3-4 30 HSN

Nafcillin NA 4-6 or CI 30-60 HSN Phlebitis risk

Oxacillin NA 4-6 or CI 10-30 HSN; hepatotoxicity Phlebitis risk

Penicillin G 25-73 4-6 or CI 15-30 HSN

Piperacillin-tazobactam

NA 3-4 or CI 30-240 HSN (including anaphylaxis)

Oral penicillin VK is not substitute for IV PCN

Vancomycin NA 1-2 or CI 60-120 Nephrotoxicity; infusion related reactions

Dialysis-only dosing possible; vancomycin trough or AUC/MIC weekly and with dose changes

Abbreviations: BA: Bioavailability; CI: Continuous Infusion; SJS: Stevens Johnson Syndrome; HSN: Hypersensitivity; PN: Peripheral neuropathy