Specific Organisms and Therapeutic Regimens

General recommendations and organism-specific therapeutic regimens for osteomyelitis (as shown in the radiograph below) are provided. However, treatment of bone infections can quickly become complicated, and significant morbidity and loss of function can result from failure to treat infections appropriately. It is recommended that consultation with an infectious diseases and orthopedic specialist be obtained to assist in management.

Osteomyelitis of T10.

Principles of treatment

Antibiotic therapy for hematogenous osteomyelitis should be pathogen-directed, based on the results of cultures from bone biopsy and/or blood cultures.

For osteomyelitis from contiguous spread of infection, wound culture is poorly correlated with bone biopsy culture for all organisms except methicillin-resistant Staphylococcus aureus (MRSA); unless MRSA is grown, surgical bone biopsy is recommended to define the correct pathogen.

Orthopedic surgical debridement and drainage is a mainstay of therapy and is necessary to remove sequestrum and prevent chronic osteomyelitis and disease recurrence.

For MRSA, a minimum of 8 weeks of antibiotic therapy is recommended. While parenteral therapy or antibiotics with high oral bioavailability is preferred, oral therapy at the end of the course can be used depending on the severity of the disease.

For MRSA, new data suggest that organisms with a vancomycin minimum inhibitory concentration (MIC) of 2 µg/mL or greater have a greater rate of treatment failure with vancomycin therapy. In this situation, an alternative agent such as daptomycin should be used.

For non-MRSA disease, 4-6 weeks of intravenous therapy or therapy with drugs with high oral bioavailability is preferred. However, a longer course may be indicated in any type of more complicated disease.

Chronic osteomyelitis with multiple recurrences of disease in the same location with the same organism, usually S aureus, may require extensive debridement followed by a prolonged intravenous antibiotic course up to 8 weeks for cure; however, failing this, lifelong suppression may be needed.

Treatment of osteomyelitis in conjunction with an infected orthopedic device is complicated and often requires a surgical resection of the device or a very prolonged course if the device is retained (and sometimes lifelong antibiotic suppression if further surgical manipulation can result in significant morbidity and loss of function). Appropriate consultation with an infectious diseases specialist and an orthopedic surgeon both with experience in dealing with infected prostheses is highly recommended.

Vertebral osteomyelitis infections involving infected neurosurgical or orthopedic hardware often require a course of intravenous therapy from 2-8 weeks followed by 1-2 years of long-term oral suppression in order to allow the vertebral bones to heal enough so that they will be stable enough for another washout or hardware resection if disease recurs.

Owing to the high rates of development of resistance to treatment, rifampin should never be used alone to treat S aureus.

Similarly, owing to the risk of development of resistance when there is a high burden of disease, trimethoprim-sulfamethoxazole should not be used as initial therapy alone for S aureus, even when the isolate is sensitive to trimethoprim-sulfamethoxazole; it should only be used after any necessary debridement of disease occurs and at least a 1- to 2-week course of treatment with another antibiotic.

Aminoglycosides generally have poor bone penetration and should only be used if all other antibiotic options are unavailable; however, they can theoretically be used synergistically to improve the bactericidal activity of beta-lactam antibiotics, vancomycin, and daptomycin in streptococcal and enterococcal infections, though clinical data are lacking.

As with any prolonged course of antibiotic treatment, monitoring for adverse effects is appropriate, and drug level monitoring of vancomycin and, in particular, aminoglycosides is necessary to avoid toxicity and maintain efficacy.

Long-term toxicities should be taken into account before any prolonged antibiotic course. Of particular concern are the following:

• Ototoxicity and renal failure with vancomycin and aminoglycosides
• Bone marrow suppression and acute interstitial nephritis with oxacillin and nafcillin
• Lactic acidosis, optic neuritis, and peripheral neuropathy with linezolid
• Tendinitis and tendon rupture with fluoroquinolones
• Confusion and acute interstitial nephritis in the elderly particularly with ciprofloxacin

Methicillin-sensitive S aureus ^{[1, 2, 3, 4, 5, 6]}

Preferred:

• Nafcillin 2 g IV q4h
• Oxacillin 2 g IV q4h
• Ceftriaxone 2 g IV q24h
• Cefazolin 2 g IV q8h or 1.5 g IV q6h

Patients with penicillin allergy:

• Clindamycin 600 mg IV q6h or 900 mg IV q8h
• Vancomycin 15 mg/kg IV q12h with or without rifampin 600 mg PO daily or 300-450 mg q12h (dose should be adjusted to maintain a trough level of 15-20 µg/mL)

Oral therapy (to be used after an appropriate course of intravenous therapy only and if sensitivity testing suggests these agents will be effective):

• Doxycycline 100 mg PO q12h
• Clindamycin 450 mg PO q6h
• Dicloxacillin 500 mg PO q6h or
• Trimethoprim-sulfamethoxazole (160 mg/800 mg) 2 DS tablets PO q8-12h
• Cephalexin 500 mg PO q6h

MRSA ^{[1, 5, 7, 8]}

Preferred:

• Vancomycin 15 mg/kg IV q12h if MIC < 2 mcg/mL (adjust dose to maintain a trough level of 15-20 µg/mL)
• Daptomycin (preferred, if vancomycin MIC >1 µg/mL) 6-8 mg/kg IV q24h
• Linezolid 600 mg IV/PO q12h

Alternative based on results of sensitivity testing and intolerance of agents above:

• Trimethoprim-sulfamethoxazole 4 mg/kg IV q12h (dose based on trimethoprim component) plus rifampin 600 mg PO q24h or 300-450 mg PO q12h
• Clindamycin 900 mg IV q8h

Oral therapy based on results of sensitivity testing:

• Doxycycline 100 mg PO q12h
• Clindamycin 450 mg PO q6h or 600 mg PO q8h
• Trimethoprim-sulfamethoxazole (160 mg/800 mg) 2 DS tablets PO q8-12h
• Levofloxacin 500-750 mg PO daily plus rifampin 600-900 mg PO qd (only if the isolate is sensitive to both antibiotics)

Coagulase-negative staphylococci ^[5]

Preferred:

• Vancomycin 15 mg/kg IV q12h (dose adjusted to maintain a trough level of 15-20 µg/mL)
• Linezolid 600 mg IV/PO q12h

Oral therapy based on results of sensitivity testing:

• Doxycycline 100 mg PO q12h
• Trimethoprim-sulfamethoxazole (160 mg/800 mg) 2 DS tablets PO q8-12h
• Levofloxacin 500-750 mg PO qd plus rifampin 600-900 mg PO qd (only if the isolate is sensitive to both antibiotics)

Penicillin-sensitive streptococci ^{[1, 5, 8]}

Preferred:

• Ceftriaxone 2 g IV q24h
• Cefazolin 2 g IV q8h
• Penicillin G 20 million units (MU) continuous IV infusion over 24 h or 2-3 MU q4h

Patients with penicillin allergy:

• Clindamycin 900 mg IV q8h or
• Vancomycin 15 mg/kg IV q12h (adjust dose to maintain a trough level of 15-20 µg/mL)

Oral therapy:

• Amoxicillin 875 mg PO q12h or 500 mg PO q8h
• Clindamycin 300-450 mg PO q6h

Intermediately sensitive streptococci (penicillin MIC ≥0.5) ^{[1, 5, 8]}

• Ampicillin 2 g IV q4h
• Aqueous crystalline penicillin G 20 MU continuous IV infusion over 24 h or 4 MU IV q4h
• Vancomycin 15 mg/kg IV q12h
• Daptomycin 6-8 mg/kg IV q24h
• Linezolid 600 mg IV/PO q12h
• Adding gentamicin at 1 mg/kg IV q8h for 2 weeks to maintain a peak MIC of 3-4 µg/mL and trough < 1 µg/mL to the first 3 regimens theoretically can synergistically increase bactericidal killing

Oral therapy:

• Amoxicillin-clavulanate extended-release (ER) 1000 mg/62.5 mg 2 tablets PO q12h or
• Moxifloxacin 400 mg PO q24h
• Levofloxacin 500-750 mg PO q24h

Enterococci ^{[1, 5, 8]}

• Ampicillin 2 g IV q4h (if organism is sensitive to ampicillin)
• Vancomycin 15 mg/kg IV q12h (if organism is sensitive to vancomycin, adjusting dosage to maintain a trough MIC of 15-20 µg/mL)
• Daptomycin 6-8 mg/kg IV q24h
• Linezolid 600 mg IV/PO q12h
• If the organism is sensitive to gentamicin, adding gentamicin at 1 mg/kg IV q8h for 2 wk to maintain a peak MIC of 3-4 µg/mL and trough < 1 µg/mL to the first 3 regimens theoretically can synergistically increase bactericidal killing

Oral therapy:

• Amoxicillin/clavulanate ER 1000 mg/62.5 mg 2 tablets PO q12h or
• Moxifloxacin 400 mg PO q24h
• Levofloxacin 750 mg PO q24h

Gram-negative bacilli (other than Pseudomonas) ^{[1, 5, 8]}

• Ceftriaxone 2 g IV q24h (if organism is sensitive to ceftriaxone)
• Ciprofloxacin 400 mg IV q8-12h (if organism is sensitive to ciprofloxacin)
• Levofloxacin 500-750 mg IV q24h (if organism is sensitive to levofloxacin)
• Ampicillin-sulbactam 3 g IV q6h (if organism is sensitive to ampicillin-sulbactam)
• Piperacillin-tazobactam 3.375 g IV q6h (if organism is sensitive to piperacillin-tazobactam)
• Ertapenem 1 g IV q24h (if organism is sensitive to ertapenem)

Oral therapy:

• Ciprofloxacin 500-750 mg PO q12h (if organism is sensitive to ciprofloxacin)
• Levofloxacin 500-750 mg PO q24h (if organism is sensitive to levofloxacin)

Pseudomonas aeruginosa ^{[1, 5, 8]}

• Cefepime 2 g IV q8h (if organism is sensitive to cefepime)
• Ceftazidime 2 g IV q8h (if organism is sensitive to ceftazidime)
• Piperacillin-tazobactam 4.5 g IV q6h (if organism is sensitive to piperacillin-tazobactam)
• Ciprofloxacin 400 mg IV q8h (if organism is sensitive to ciprofloxacin)
• Levofloxacin 750 mg IV q24h (if organism is sensitive to levofloxacin)
• Imipenem-cilastatin 1 g IV q8h (if organism is sensitive to imipenem)
• Meropenem 1 g IV q8h (if organism is sensitive to meropenem)

Oral therapy:

• Ciprofloxacin 750 mg PO q12h (if organism is sensitive to ciprofloxacin)
• Levofloxacin 750 mg PO q24h (if organism is sensitive to levofloxacin)

Anaerobes ^{[1, 5, 8]}

• Ampicillin-sulbactam 3 g IV q6h
• Ticarcillin-clavulanate 3.1 g IV q4h
• Piperacillin-tazobactam 3.375 q6h or
• Amoxicillin-clavulanate 875 mg/125 mg PO bid
• Metronidazole 500 mg IV/PO q8h
• Clindamycin 600 mg IV or 450 mg PO q6h (not effective against Bacteroides fragilis)
• Moxifloxacin 400 mg IV/PO q24h

Newer agents for gram-positive organisms ^{[9, 10, 11, 12, 13]}

The following agents could theoretically be used to treat osteomyelitis caused by MRSA and other gram-positive organisms, though at present, there are no good data on their use. There are more anecdotal reports of ceftaroline and telavancin being used with reportedly good results, but reporting bias could be taking place.

• Ceftaroline 600 mg IV q12h is the standard dosage (the optimal dosage for osteomyelitis is uncertain)
• Telavancin 10 mg/kg IV q24h is the standard dosage but optimal dose uncertain for osteomyelitis (the optimal dosage for osteomyelitis is uncertain)
• Dalbavancin 1 gram IV once, followed a week later by 500 mg IV weekly is the standard dosage (the optimal dosage for osteomyelitis is uncertain)
• Oritavancin could theoretically be used if necessary, though it is only approved for skin and soft-tissue infections with a dose of 1200 mg administered once; it has a half-life of 10 days, and a long-term dosing schedule has yet to be determined; experience in osteomyelitis is quite limited
• Tedizolid 200 mg IV or orally daily is the standard dosage (the optimal dosage for osteomyelitis is uncertain)

In view of their very long half-lives, dalbavancin and oritavancin could be very useful in treating osteomyelitis for a long course, but there currently are no good data to support their use, and therefore these drugs should be used only as a last resort. There are no known data regarding the use of tedizolid for osteomyelitis, though the oral dosing and good bioavailability make this an attractive option that is similar to linezolid but has the same poor side-effect profile.

Newer agents for highly resistant gram-negative organisms

Theoretically, the following antibiotics could be used to treat osteomyelitis when caused by a highly resistant gram-negative organism that is resistant to all other antibiotics; however, they should be used only as a last resort, given that there are absolutely no data regarding efficacy in the treatment of osteomyelitis or the increased likelihood of adverse effects with long-term administration.

• Ceftazidime-avibactam 2.5 g IV q8h is the standard dosage (the optimal dosage for osteomyelitis is uncertain)
• Ceftolozane-tazobactam (the optimal dosage for osteomyelitis is uncertain)