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Sections Osteomyelitis Organism-Specific Therapy
Specific Organisms and Therapeutic Regimens
References

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 specialist and 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 are mainstays of therapy and are necessary to remove sequestrum and prevent chronic osteomyelitis and disease recurrence.

For MRSA, a minimum of 6 weeks of antibiotic therapy is recommended. Parenteral therapy or administration of antibiotics with high oral bioavailability is preferred.

For MRSA, data suggest that organisms with a vancomycin minimum inhibitory concentration (MIC) of 2 µg/mL or greater have a higher 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 (IV) 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 (up to 8 weeks) IV antibiotic course for cure; however, failing this, lifelong suppression may be needed.

Treatment of osteomyelitis in conjunction with an infected orthopedic device is complicated and often necessitates surgical resection of the device or a very prolonged course of medication 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.

Guidelines from the Infectious Diseases Society of America (IDSA) have provided guidance for management of osteomyelitis with prosthetic joints but not for other kinds of orthopedic hardware infections (though extrapolations can be made from the IDSA guidance).^[1]

The IDSA guidelines advocated the removal of all hardware if at all possible, with reimplantation of the prosthetic joint after a 6-week course of targeted antimicrobial therapy.^[1]During this period, the patient requires an internal cement spacer, an external fixator, or traction to maintain future limb function and joint integrity. For some individuals, this would result in unacceptable morbidity and loss of limb function. In such cases, the orthopedic surgeon may perform a one-stage explantation of the joint and immediate reimplantation of a joint or may perform a simple surgical washout and debridement of infected tissue without any exchange of hardware.

In cases where hardware is retained involving the knee, a 6-month course of targeted antimicrobial therapy is recommended, whereas in cases involving all other joints, a 3-month course is recommended. Between 2 and 6 weeks of the course should be with IV or IV-equivalent antimicrobial therapy. More recent data have suggested that oral therapy is equivalent to IV therapy (see Intravenous vs Oral Antimicrobial Agents, below), but this has yet to be incorporated into guidelines.^[1]

In cases involving rifampin-sensitive S aureus, the IDSA guidelines advocated adding rifampin at 450 mg PO q12hr if the patient can tolerate the medication and does not have significant liver disease.^[1]

Vertebral osteomyelitis infections involving infected neurosurgical or orthopedic hardware often require a 2- to 8-week course of IV therapy followed by 1-2 years of long-term oral suppression in order to allow the vertebral bones to heal enough 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 has been carried out.

Aminoglycosides generally have poor bone penetration and should oly be used only 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:

Vancomycin and aminoglycosides can result in ototoxicity, vestibulotoxicity, and nephroxicity; because of the very narrow therapeutic window, drug-level monitoring is mandatory when these antibiotics are used
The methicillin-based antibiotics oxacillin and nafcillin are associated with much greater risks of bone-marrow suppression and acute interstitial nephritis than any other beta-lactam antibiotics
Linezolid use is confounded by multiple drug-drug interactions, lactic acidosis, optic neuritis, and peripheral neuropathy with linezolid; because of potentially severe adverse effects, prolonged use of linezolid should be a last resort, despite its appealing oral bioavailability
Fluoroquinolones have been associated, as a class, with tendinitis, tendon rupture, aortic dissection, and QT-interval prolonagation
Ciprolfoxacin in particular has been associated with confusion and acute interstitial nephritis, especially in the elderly
Doxycycline is far safer than its precursor antibiotic, tetracycline, but compound acidity can result in pill esophagitis, and patients must be warned to take the medication with a full glass of water and to remain upright for 30-60 minutes after administration; an annoying side effect of sun sensitivity can be avoided with sun avoidance or the assiduous use of sun screen
Trimethoprim-sulfamethoxazole can be associated with nephrotoxicity, hyperkalemia, rash, and sometimes severe skin reaction; there is a significant interaction with warfarin, and it can also result in hemolysis with severe glucose-6-phosphate dehydrogenase (G6PD) deficiency
Daptomycin is quite safe, but at higher doses with prolonged use, it can result in myopathy and creatine phosphokinase elevation; it is also associated, very rarely, with drug-induced eosinophilic pneumonia

Methicillin-sensitive S aureus ^{[2, 3, 4, 5, 6, 1, 7]}

Preferred intravenous therapy:

Cefazolin 2 g IV q8hr or 1.5 g IV q6hr (generally the preferred regimen because of narrowed spectrum and safety profile)
Nafcillin 2 g IV q4hr
Oxacillin 2 g IV q4hr

Previous versions of this article mentioned ceftriaxone as a preferred therapy for treatment of methicillin-sensitive S aureus (MSSA) infections. Although ceftriaxone does have MSSA activity, some studies suggest it is associated with higher rates of treatment failure than are agents such as antistaphylococcal penicillins or cefazolin. Additionally, in view of its broader gram-negative coverage, ceftriaxone would be considered not favorable from an antimicrobial stewardship perspective.

Alternative intravenous options for patients with penicillin allergy:

Clindamycin 600 mg IV q6hr or 900 mg IV q8hr (to be used only if sensitivity testing shows susceptibility)
Vancomycin 15 mg/kg IV q12hr with or without rifampin 600 mg PO daily or 300-450 mg q12hr (adjust dosage to maintain a trough level of 15-20 µg/mL)

Preferred oral therapy

Cefadroxil 1 g PO q12hr
Cephalexin 500 mg PO q6hr
Dicloxacillin 500 mg PO q6hr

Alternative oral options for patients with penicillin allergy:

Clindamycin 450 mg PO q6hr (use only if sensitivity testing shows susceptibility)
Doxycycline 100 mg PO q12hr (use only if sensitivity testing shows susceptibility)
Linezolid 600 mg PO q12hr (use with caution; as noted, prolonged use is associated with severe adverse effects)
Trimethoprim-sulfamethoxazole (160 mg/800 mg) 1-2 DS tablets PO q8-12hr depending on body weight (to be used only if sensitivity testing shows susceptibility)

MRSA and coagulase-negative staphylococci ^{[2, 6, 8, 9]}

Preferred intravenous options guided by results of sensitivity testing:

Daptomycin (preferred, if vancomycin MIC >1 µg/mL) 6-8 mg/kg IV q24hr (usually the first-line alternative to vancomycin)
Linezolid 600 mg IV q12hr (use with caution; as noted, prolonged use is associated with severe adverse effects)
Vancomycin 15 mg/kg IV q12hr if MIC < 2 μg/mL (adjust dosage to maintain a trough level of 15-20 µg/mL; usually the preferred option because of cost and experience)

Alternative intravenous options guided by results of sensitivity testing and intolerance of agents above:

Ceftaroline 600 mg IV q12hr (although this antibiotic is not in current guidelines, more recent experience has resulted in its being a frequent alternative to vancomycin and daptomycin)
Clindamycin 900 mg IV q8hr
Trimethoprim-sulfamethoxazole 4 mg/kg IV q12hr (dose based on trimethoprim component) plus rifampin 600 mg PO q24hr or 300-450 mg PO q12hr

Oral therapy guided by results of sensitivity testing:

Doxycycline 100 mg PO q12hr
Clindamycin 450 mg PO q6hr or 600 mg PO q8hr
Trimethoprim-sulfamethoxazole (160 mg/800 mg) 1-2 DS tablets PO q8-12hr
Levofloxacin 500-750 mg PO daily plus rifampin 600-900 mg PO qd (only if the isolate is sensitive to both antibiotics)
Linezolid 600 mg PO q12hr (use with caution; as noted, prolonged use is associated with severe adverse effects)

Penicillin-sensitive streptococci ^{[2, 6, 9]}

Preferred intravenous options:

Cefazolin 2 g IV q8hr
Ceftriaxone 2 g IV q24hr
Penicillin G 20 million units (MU) continuous IV infusion over 24 hr or 2-3 MU q4hr

Alternative intravenous options for patients with penicillin allergy:

Clindamycin 900 mg IV q8hr or
Vancomycin 15 mg/kg IV q12hr (adjust dosage to maintain a trough level of 10-15 µg/mL)

Preferred oral therapy:

Amoxicillin 875 mg PO q12hr or 500 mg PO q8hr
Cefadroxil 1 g PO q12 hr
Cephalexin 500 mg PO q6hr

Alternative oral options for patients with penicillin allergy:

Clindamycin 300-450 mg PO q6hr

Intermediately sensitive streptococci (penicillin MIC ≥0.5) ^{[2, 6, 9]}

Preferred intravenous options:

Ampicillin 2 g IV q4hr
Aqueous crystalline penicillin G 20 MU continuous IV infusion over 24 hr or 4 MU IV q4hr
Daptomycin 6-8 mg/kg IV q24hr
Linezolid 600 mg IV/PO q12hr (use with caution; as noted, prolonged use is associated with severe adverse effects)
Vancomycin 15 mg/kg IV q12hr (adjust dosage to maintain a trough level of 10-15 µg/mL)

Oral therapy:

Amoxicillin-clavulanate extended-release (ER) 1000 mg/62.5 mg 2 tablets PO q12hr
Levofloxacin 500-750 mg PO q24hr
Moxifloxacin 400 mg PO q24hr

Enterococci ^{[2, 6, 9]}

Preferred intravenous options guided by susceptibility testing:

Ampicillin 2 g IV q4hr (if organism is sensitive to ampicillin)
Daptomycin 6-8 mg/kg IV q24hr
Linezolid 600 mg IV q12hr (use with caution; as noted, prolonged use is associated with severe adverse effects)
Vancomycin 15 mg/kg IV q12hr (if organism is sensitive to vancomycin, adjust dosage to maintain a trough of 15-20 µg/mL)

Oral therapy guided by susceptibility testing:

Amoxicillin 500 mg PO q8hr
Amoxicillin-clavulanate ER 1000 mg/62.5 mg 2 tablets PO q12hr
Linezolid 600 mg PO q12hr (use with caution; as noted, prolonged use is associated with severe adverse effects)

Gram-negative bacilli (other than Pseudomonas) ^{[2, 6, 9]}

Preferred intravenous options guided by susceptibility testing:

Ampicillin-sulbactam 3 g IV q6hr
Ceftriaxone 2 g IV q24hr
Ciprofloxacin 400 mg IV q8-12hr
Ertapenem 1 g IV q24hr
Imipenem 500 mg IV q6hr
Levofloxacin 500-750 mg IV q24hr
Meropenem 1 g IV q8hr
Piperacillin-tazobactam 3.375 g IV q6hr

Oral therapy guided by susceptibility testing:

Amoxicillin-clavulanate 500 mg/125 mg PO q8hr
Amoxicillin-clavulanate 875 mg/125 mg PO q12hr
Ciprofloxacin 500-750 mg PO q12hr (if organism is sensitive to ciprofloxacin)
Levofloxacin 500-750 mg PO q24hr (if organism is sensitive to levofloxacin)
Trimethoprim-sulfamethoxazole (160 mg/800 mg) 1-2 DS tablets PO q8-12hr

Previous versions of this article listed oral cefdinir as an option for the treatment of osteomyelitis, however, because of its low oral bioavailability, cefdinir would not be considered ideal for the treatment of osteomeylitis.

Pseudomonas aeruginosa ^{[2, 6, 9]}

Preferred intravenous options guided by susceptibility testing:

Cefepime 2 g IV q8hr
Ceftazidime 2 g IV q8hr
Ciprofloxacin 400 mg IV q8hr
Imipenem-cilastatin 1 g IV q8hr
Levofloxacin 750 mg IV q24hr
Meropenem 1 g IV q8hr
Piperacillin-tazobactam 4.5 g IV q6hr

Oral therapy guided by susceptibility testing:

Ciprofloxacin 750 mg PO q12hr
Levofloxacin 750 mg PO q24hr

Anaerobes ^{[2, 6, 9]}

Amoxicillin-clavulanate 875 mg/125 mg PO BID
Ampicillin-sulbactam 3 g IV q6hr
Clindamycin 600 mg IV or 450 mg PO q6hr (not effective against Bacteroides fragilis)
Ertapenem 1 g IV q24hr
Metronidazole 500 mg IV/PO q8hr
Moxifloxacin 400 mg IV/PO q24hr
Piperacillin-tazobactam 3.375 q6hr
Ticarcillin-clavulanate 3.1 g IV q4hr

Newer agents for gram-positive organisms ^{[10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21]}

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 q12hr is the standard dosage (optimal dosage for osteomyelitis is uncertain); it can be used to treat MRSA and coagulase-negative staphylococcal infection
Dalbavancin 1 g IV once, followed 1 week later by 500 mg IV weekly, is the standard dosage (optimal dosage for osteomyelitis is uncertain)
Delafloxacin 300 mg IV q12h or 450 mg PO q12h (optimal dosage for osteomyelitis is uncertain)
Omadacycline 300 mg orally daily is a newer tetracycline-class antibiotic with activity against MRSA and VRE
Oritavancin could theoretically be used if necessary, though it is only approved for skin and soft-tissue infections in 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 (optimal dosage for osteomyelitis is uncertain)
Telavancin 10 mg/kg IV q24hr is the standard dosage (optimal dosage for osteomyelitis is uncertain)

The most promising agent is ceftaroline; it is a cephalosporin derivative, and successful use of cephalosporins in osteomyelitis is well documented. In view of their very long half-lives, dalbavancin and oritavancin could be useful in treating osteomyelitis for a long course. At present, however, only limited data are available to support their use, and therefore, these drugs should be used only as a last resort. No data are available regarding the use of tedizolid, omadacycline, or delafloxacin for osteomyelitis, though the oral dosing and good bioavailability make these agents attractive options. Tedizolid has the same concerns as linezolid in terms of its 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 only very limited data regarding their efficacy in the treatment of osteomyelitis or the likelihood of adverse effects with long-term administration.^{[22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32]}

Cefiderocol 2 g IV q8hr is the standard dosage (optimal dosage for osteomyelitis is uncertain)
Ceftazidime-avibactam 2.5 g IV q8hr is the standard dosage (optimal dosage for osteomyelitis is uncertain)
Ceftolozane-tazobactam 1.5 g IV q8hr is the standard dosage (optimal dosage for osteomyelitis is uncertain)
Eravacycline 1 mg/kg IV q12hr is the standard dosage (optimal dosage for osteomyelitis is uncertain)
Imipenem-relebactam 1.25 gm IV q6h (optimal dosage for osteomyelitis is uncertain)
Meropenem-vaborbactam 4 g IV q8hr is the standard dosage (optimal dosage for osteomyelitis is uncertain)

Intravenous vs oral antimicrobial agents

In January 2019, the OVIVA (Oral Versus IntraVenous Antibiotics for bone and joint infection) study was published.^[33]In this multicenter one-to-one randomized open-label noninferiority trial comparing IV with oral therapy in 1054 patients, oral antibiotic therapy was found to be noninferior to IV antibiotic therapy when used during the first 6 weeks for complex orthopedic infections. As of December 2020, the use of oral antibiotic therapy had not been included in the IDSA guidelines. However, designations of options for treatment have been changed to remove the preference for IV therapies.

Since the OVIVA trial was published, there has been a growing body of evidence to show that in the right patient, oral therapy is at least as effective as IV therapy for the treatment of bone infections. Treatment with oral antibiotics may not be appropriate for all patients. Some experts have proposed the following criteria for deciding whether a patient is a suitable candidate for transition to oral therapy^[34]:

The patient is clinically and hemodynamically stable
Surgical or procedural source control has been achieved, if possible, with no persistent bacteremia
The patient is likely to be able to tolerate and absorb oral medications
A published regimen is available with clinical outcomes data for targeted pathogens
There are no psychosocial or logistical reasons to prefer IV therapy

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