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A Closer Look At Oral Antimicrobial Therapy For Pedal Osteomyelitis

With a rising incidence of osteomyelitis, this author reviews the literature and suggests the use of oral antimicrobial regimens for osteomyelitis could facilitate infection remission, and potentially result in lower patient morbidity and lower health care costs.

Current treatment for osteomyelitis consists of prolonged antimicrobial therapy or surgical debridement with or without antimicrobial therapy.1 Treatment decisions are based on the anatomical site of infection, blood supply to the infected bone, the presence of necrotic bone, and patient or clinician preferences.2 For patients who are unwilling to undergo a surgical procedure for treatment of osteomyelitis, antimicrobial therapy can allow for eradication of the infection. When electing to treat osteomyelitis with antimicrobial therapy, many clinicians use the “gold standard” duration of at least six weeks of parenteral antimicrobial therapy.

This standard was popularized by multiple case series written by Waldvogel and colleagues over 40 years ago and the recognition that infected bone requires three to four weeks to revascularize.3 However, there are numerous disadvantages with prolonged parenteral therapy including morbidity related to catheter infections, increased cost associated with catheter insertion and maintenance, and the expense of the parenteral antibiotics.4

In general, oral medications are the preferable route of drug administration but clinicians were not as readily utilizing these therapies in treating osteomyelitis due to the decreased bioavailability. As a result, pharmacological companies began developing oral medications with increased bioavailability to decrease the required oral dose. Decreasing the oral dose allows to decrease one to the risk of toxicity associated with the drug. These pharmaceutical companies are achieving these advances by modifying the physicochemical properties of the given drug’s molecules, developing new drug delivery carrier systems and changing the given drug’s novel functionality.5 With the advancement of oral antimicrobial bioavailability, the question arises if oral antimicrobials for the treatment of osteomyelitis are comparable to parenteral antibiotics.

Many factors prevent prospective, randomized studies to compare therapeutic outcomes of oral versus parenteral antimicrobials for the treatment of osteomyelitis. These factors include heterogeneity of risk factors and disease physiology. Although, Staphylococcus aureus is the most common pathogen isolated in osteomyelitis, many other species of bacteria can cause the disease. Additionally, the ability of infecting pathogens to lie dormant or cause low grade symptoms for multiple years requires long-term follow up that can alter the data researchers collect in these studies. These factors, with others, have prevented well-designed, controlled studies to adequately challenge the “gold standard” of osteomyelitis treatment.

Many smaller studies have shown success in therapeutic outcomes when treating osteomyelitis with oral antimicrobials. For this literature review, I’d like to take a closer look at the common pharmacological terminology and compare the treatment outcomes of parenteral versus oral antimicrobials for the treatment of osteomyelitis.

Understanding The Pharmacokinetics And Pharmacodynamics Of Antimicrobials

Knowledge of drug characteristics assists the clinician in selecting an appropriate antimicrobial for patients with varying comorbidities and infection sites. A significant criterion in selecting antimicrobial therapy is spectrum of activity. The spectrum of activity determines the range of bacterial species susceptible to the antimicrobial.

Susceptibility tests provide in vitro data to determine the spectrum of activity. A lack of susceptibility generally results in clinical failure.6 However, clinical failure can also occur even when susceptibility is achievable per minimal inhibitory concentration (MIC). Minimal inhibitory concentration is defined by the minimal concentration at which the antimicrobial prevents a bacteria colony from becoming turbid after incubation.7 Susceptibility interpretations are determined by the level the antimicrobial achieves in serum, not levels reached in bone. Antimicrobial levels vary between serum and bone. There must be adequate bone penetration of antimicrobials in order to reach effective concentrations at the site of infection for therapeutic success. Having knowledge on the timing, magnitude of drug concentration at the action site and extent of bone penetration is critical in selecting the appropriate antimicrobial therapy.

Pharmacodynamics define the relationship between the timing of drug effects and the drug concentrations in plasma or the targeted area. Bone concentrations should exceed the MIC to allow therapeutic success. The drug’s concentration and duration at the action site determines the drug’s efficacy. Pharmacokinetics is the relationship between the drug dose and the timing of drug concentrations at different sites throughout the body. Drug absorption from the administration site into systemic circulation, distribution of the drug through the systemic circulation into peripheral tissues and elimination through metabolism or renal exertion are affected by the antimicrobial pharmacokinetics. Often, pharmacokinetics are characterized on measurements of drug concentrations in plasma or serum, and not in bone. Drug concentration ratios change over time due to an individual’s different comorbidities that may prevent the drug reaching the site of action. These comorbidities include ischemia, calcified tissues or fat in the cancellous bone. In order to adequately treat bone infections, adequate antimicrobial concentrations are necessary at the site of the bone infection.8

Knowledge of which antimicrobial is able to achieve concentrations greater than the MIC allows for improved therapy outcomes. Antimicrobial bone penetration is usually defined as the concentration ratio between bone and serum, or plasma at a specific point in time. However, due to the varying levels of drug concentrations at varying time periods, calculating the area under the concentration-time curve (AUC) in bone versus AUC in plasma or serum is a more accurate measurement. The antimicrobial concentration levels are measured at certain points in time to determine the average concentration over a time interval. One ascertains antimicrobial bioavailability by measuring the AUC. Bioavailability refers to the amount and rate the antimicrobial is absorbed and available at the drug site of action.9

What The Literature Reveals

In their review of osteomyelitis studies published between 1970 to 2012, Spellberg and Lipsky sought to determine if there were preferred antimicrobial agents; if oral therapies are acceptable in certain cases; the standard for duration of therapy; and if surgical debridement is always a recommendation.10 The authors also obtained pharmacokinetic data on antimicrobials routinely utilized when treating osteomyelitis.

The bone penetration levels for parenteral beta-lactams (penicillins, cephalosporins, carbapenems) reportedly range from ~5 percent to 20 percent.10 It is believed that at these levels, the absolute bone concentration would exceed the MIC of the infecting organism. Oral beta-lactam serum levels are reportedly < 10 percent of the serum levels of parenteral agents.10 This suggests the bone penetration levels would be inadequate to achieve the minimum inhibitory concentration at the site of infection. Beta-lactams achieve higher bone concentration levels in bone with increased vascularity due to infection versus uninfected bone.11-13

Fluoroquinolones, linezolid and trimethoprim reportedly achieve bone concentrations that are 50 percent that of the serum concentrations.10 Clindamycin achieved bone level penetrations ranging from 40 to 70 percent of serum levels. This amount of bone penetration should exceed the MIC levels of the infecting pathogen. Oral metronidazole and rifampin bone penetrations are almost equal to the achieved serum levels.14,15

Nonrandomized trials involving four to six weeks of parenteral beta-lactam therapy in the treatment of osteomyelitis achieved cure rates between 60 to 90 percent.16-18 Beta-lactam class cure rates were decreased when Pseudomonas was an isolated bacterium. Studies of oral fluoroquinolones had overall cure rates ranging between 60 to 80 percent. Researchers also noted decreased cure rates for ciprofloxacin and ofloxacin when Pseudomonas was an isolated pathogen.19-21

In one study looking at multi-drug resistant gram-positive infections including osteomyelitis, Birmingham and coworkers found that linezolid has a 60 percent cure rate.22 Randomized studies have showed that adding rifampin to oxacillin treatment regimens increased cure rates for staphylococcal infections.23

In 2013, Conterno and coworkers published a Cochrane Review to determine the effects of various antimicrobial treatment regimens in treating chronic osteomyelitis in adults.3 Their selection criteria included randomized controlled trails (RCT) or quasi-RCT, published between 1948 to 2012, that addressed effects of antimicrobial treatment after surgical debridement. One primary outcome determined the remission of infection at the end of therapy or at one year post-treatment. Out of the eight trials they found, only five trials compared oral versus parenteral routes for antimicrobial administration. Researchers looked at a total of 150 individuals from these five trials. These trials compared oral quinolones versus a variety of parenteral antibiotics. At the end of antimicrobial treatment, there was not any statistical significance between remission rates at the end of oral (70/80; 88 percent) or parenteral (58/70; 83 percent) treatment.

Additionally, the researchers found no statistical significance with remission rates one year after therapy between oral (49/64; 77 percent) or parenteral (44/54; 81 percent) treatment.3 No trial determined the influence that different species of bacteria had on the rate of remission or the influence that the duration of antibiotic therapy had on the rate of remission. Based on the lack of complete data between these case reports, the authors were “unable to draw robust conclusions” regarding duration of therapy or the administration route of antibiotic therapy. However, data did suggest if the infecting bacteria was sensitive to the antimicrobial researchers used in the trial, the route of administration did not affect the remission rate of osteomyelitis.

Daver and colleagues conducted a retrospective study to evaluate the cure rate of different antimicrobial regimens for patients with Staphylococcus aureus-induced osteomyelitis. Patients had either parenteral antimicrobial therapy or an “early switch” regimen of parenteral to oral antimicrobial therapy. The patient population consisted of 72 patients who were placed into two treatment groups defined by the duration of parenteral therapy and the presence of MRSA or MSSA. Parenteral regimens included anti-staphylococcal beta-lactams or vancomycin. Oral regimens included rifampin combined with quinolones, trimethoprim-sulfamethoxazole (TMP-SMX), or clindamycin.

In this study, Daver and coworkers found similar cure rates in both the prolonged parenteral therapy group and the oral therapy switch group.24 They also found no therapeutic benefit over parenteral to oral switch therapy when treating patients with Staphylococcus aureus osteomyelitis. These findings suggest that treatment of Staphylococcus aureus consisting of parenteral vancomycin or a beta-lactam followed by oral rifampin are acceptable treatment regimens.

In Conclusion

As discussed by Lazzarini and colleagues, a majority of osteomyelitis therapy studies are not randomized and contain a small cohort.1 The majority of these studies were conducted to determine if a new antimicrobial was similar in efficacy to other antimicrobials to establish osteomyelitis treatment regimens. However, the majority of these trials failed to detect statistical significance between the antimicrobials. The research on antimicrobial therapy for the treatment of osteomyelitis increased after the 1970s due to a three-case series published by Waldovgel and colleagues regarding treatment outcomes.3 Potentially, the gold standard of treatment was derived from this research but study limitations could allow for current modifications of this gold standard. Oral antimicrobials were not included in the study due to decreased bioavailabilities in comparison to parenteral therapies. Additionally, it was an uncontrolled, retrospective study with a heterogeneous patient population receiving mainly parenteral penicillin.

In a population-based study conducted by Kremer and coworkers, the incidence of osteomyelitis increased threefold in diabetic patients over the age of 60 between 1969 to 2009.25 With the incidence of osteomyelitis in adult populations rising, finding acceptable antimicrobial treatment regimens for patients can reduce the need for surgical intervention. Although surgical intervention is necessary in certain cases, avoidance of surgery can provide both emotional and financial relief for these patients.

Oral antimicrobial treatment regimens for osteomyelitis have the potential to reduce patient expense and morbidity while still providing remission of infection and patient satisfaction. The readmission rate for complications pertaining to peripherally inserted central catheter (PICC) lines in the outpatient setting was almost 25 percent in a study of over 2,000 patients.26 Although the length of hospitalization for treatment of osteomyelitis is decreasing, the median admission charge can be in excess of $19,000.27 The oral versus intravenous antibiotic treatment for bone and joint infections study (OVIVA) conducted in 30 hospitals across the United Kingdom estimated a 10-fold increased cost associated with a six-week course of outpatient parenteral therapy versus oral therapy.26

Other randomized, high-power studies are ongoing in assessing whether oral antimicrobial therapy is sufficient in treatment of osteomyelitis. Although sufficient data is lacking on the duration of treatment, cure rates of oral regimens are equivalent to parenteral therapies if the isolated bacteria is susceptible to the antimicrobial.10 With the development of oral antimicrobials with bone penetration levels equivalent to parenteral modalities, one must question if parenteral antimicrobial therapy is necessary in all patients with osteomyelitis.

Dr. McCann is a second-year podiatry resident with the Wake Forest Baptist Medical Center in Winston-Salem, N.C.

References
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2.    Walter G, Kammerer M, Kappler C, Hoffmann R. Treatment algorithms for chronic osteomyelitis. Dtsch Ärztehl Int. 2012;109(14):257–264.
3.    Conterno L, Turchi MD. Antibiotics for treating chronic osteomyelitis in adults. Cochrane Database Syst Rev. 2013; 9.
4.    Fowler Jr VF, et al. Risk factors for hematogenous complications of intravascular catheter-associated Staphylococcus aureus experimental osteomyelitis with ciprofloxacin or vancomycin alone or in combination with rifampin. Am J Med. 1987;(82):73-75.
5.    Fasinu P, Pillay V, Ndesendo VM, du Jolt LC, Choonara YE. Diverse approaches for the enhancement of oral drug bioavailability. Biopharm Drug Dispos. 2011;32(4):185-209.
6.    Leekha S, Terrell CL, Edson RS. General principles of antimicrobial therapy. Mayo Clin Proc. 2011;86(2):156-167.
7.    Andrews JM. Determination of minimum inhibitory concentrations. J Antimicrob Chemother. 2001;48(1):5-16.
8.    Landersdorfer CB, Bullitta JB, Kinzig M, Holzgrabe U, Sangel F. Penetration of antibacterials into bone: pharmacokinetic, pharmacodynamic and bioanalytical considerations. Clinc Pharmacokinet. 2009:48(2):89-124.
9.    Chow SC. Bioavailability and bioequivalence in drug development. Wiley Interdiscip Rev Comput Stat. 2014;6(4):304-312.
10.    Spellberg B, Lipsky B. Systemic antibiotic therapy for chronic osteomyelitis in adult. Clin Infect Dis. 2012;54(3):393-407.
11.    Handa N, Kawakami T, Kitaoka K, et al. The clinical efficacy of imipenem/cilastatin sodium in orthopedic infections and drug levels in the bone tissue. Jpn J Antibiot. 1997;50(7):622–627.
12.    Breilh D, Boselli E, Bel JC, Chassard D, Saux MC, Allaouchiche B. Diffusion of cefepime into cancellous and cortical bone tissue. J Chemother. 2003;15(2):134–138.
13.    Wittmann DH, Kuipers TH, Fock R, Holl M, Bauernfeind A. Bone concentrations of imipenem after a dose of imipenem/cilastatin. Infection. 1986; 14(Suppl 2):S130–37.
14.    Hahn F, Barner K, Koeppe P. Concentration of metronidazole in bones. Aktuelle Traumatol. 1988;18(2):84–86.
15.    Roth B. Penetration of parenterally administered rifampicin into bone tissue. Chemotherapy. 1984;30(6):358-65.
16.    Fass RJ. Treatment of osteomyelitis and septic arthritis with cefazolin. Antimicrob Agents Chemother. 1978;13(3):405-11.
17.    MacGregor RR, Gentry LO. Imipenem/cilastatin in the treatment of osteomyelitis. Am J Med. 1985;78(6A):100-3..
18.    Munckhof WJ, Carney J, Neilson G, et al. Continuous infusion of ticarcillin-clavulanate for home treatment of serious infections: clinical efficacy, safety, pharmacokinetics and pharmacodynamics. Int J Antimicrob Agents. 2005;25(6):514–522.
19.    Gilbert DN, Tice AD, Marsh PK, Craven PC, Preheim LC. Oral ciprofloxacin therapy for chronic contiguous osteomyelitis caused by aerobic gram-negative bacilli. Am J Med. 1987;82(4A):254-8.
20.    Ketterl R, Beckarts T, Stubinger B, Claudi B. Use of ofloxacin in open fractures and in the treatment of post-traumatic osteomyelitis. J Antimicrob Chemother. 1988; 22(Suppl C):159–166.
21.    Peterson LR, Lissack LM, Conter K, Fasching CE, Clabots C, Gerding DN. Therapy of lower extremity infections with ciprofloxacin in patients with diabetes mellitus, peripheral vascular disease, or both. Am J Med. 1989;86(6 Pt 2):801–808.
22.    Birmingham MC, Rayner CR, Meagher AK, Flavin SM, Batts DH, Schentag JJ. Linezolid for the treatment of multidrug-resistant, gram-positive infections: experience from a compassionate-use program. Clin Infect Dis. 2003;36(2):159-68.
23.    Van der Auwera P, Klastersky J, Thys JP, Mennier-Carpentier F, Legrand JC. Double-blind, placebo-controlled study of oxacillin combined with rifampin in the treatment of staphylococcal infections. Antimicrob Agents Chemother. 1985; 28(4):467–472.
24.    Daver NG, Shelburne SA, Atmar RL, et al. Oral step-down therapy is comparable to intravenous therapy for Staphlycoccus aureus osteomyelitis. J Infect. 2007; 54(6):539-544.
25.    Kremer HM, Nwojo ME, Rabsom JE, et al. Trends in the epidemiology of osteomyelitis: a population-based study, 1969 to 2009. J Bone Joint Surg Am. 2015;97(10):837-845.
26.    Matthews PC, Conlon CP, Berendt AR, et al. Outpatient parenteral antimicrobial therapy (OPAT): is it safe for selected patients to self-administer at home? J Antimicrob Chemother. 2007; 60(2)356–362.
27.    Henke PK, Blackburn SA, Wainess RW, et al. Osteomyelitis of the foot and toe in adults is a surgical disease: conservative management worsens lower extremity salvage. Ann Surg. 2005; 241(6):885-892.

Additional References
28.    Gentry LO, Rodriguez GG. Oral ciprofloxacin compared with parenteral antibioitcs in the treatment of osteomyelitis. Antimicrob Agents Chemother. 1990;34(1):40-43.
29.    Gentry LO, Rodriguez-Gomez G. Ofloxacin versus parenteral therapy for chronic osteomyelitis. Antimicrob Agents Chemother. 1991;35(3):538-541.
30.    Gomis M, Barberan J, Sanchez B, Khorrami S, Baria J, Garcia-Barbal J. Oral ofloxacin versus parenteral imipenem-cilastatin in the treatment of chronic osteomyelitis. Rev Esp Quimioter. 1999;12(3):244-249.
31.    Greenberg R, Newman MT, Shariaty S, Pectol RW. Ciprofloxacin, lomefloxacin, or levofloxacin as treatment for chronic osteomyelitis. Antimicrob Agents Chemother. 2000; 44(1):164-166.
32.    Mader JT, Shirtliff ME, Bergguist SC, Calhoun J. Antimicrobial treatment of chronic osteomyelitis. Clin Orthop Relat Res. 1999; 360:47-65.

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By Michael McCann, DPM
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