Pharmacokinetic Considerations in the Treatment of Methicillin-resistant Staphylococcus aureus Osteomyelitis
By Meredith B. Toma, PharmD; Kelly M. Smith, PharmD; Craig A. Martin, PharmD; Robert P. Rapp, PharmD
ORTHOPEDICS 2006; 29:497
June 2006
Many treatment options are available for the treatment of methicillin-resistant S aureus osteomyelitis and several factors should be considered when deciding on the best therapy.
In the United States, >2 million Americans become infected with a hospital-acquired organism each year.1 Over 70% of these infections are caused by a bacteria resistant to at least one agent typically used in treatment. Unfortunately, approximately 90,000 of these patients will die. The emergence of multidrug-resistant organisms complicates the treatment of osteomyelitis, an already difficult-to-treat infection.
Staphylococcus aureus is one of the most common bacteria isolated in osteomyelitis cases, and treatment can be difficult because of resistant strains that have emerged.2 Data from 2003 indicate that resistance rates for methicillin-resistant S aureus are approaching 60% in United States intensive care units, a 12% increase from 1998-2002 results.3
table 1Physicians will continue to struggle with methicillin-resistant S aureus osteomyelitis treatment as resistance rates continue to climb. Without proper and prompt treatment of this infection, patients can suffer progressive bone destruction and, ultimately, death. Therefore, it is important to review appropriate treatment options, paying special attention to current standards of care, newer agents, and older agents that may have a novel place in treatment.
The current standard of care for osteomyelitis involves prolonged treatment with antibiotics, usually four to six weeks, in addition to surgical debridement in some instances. Because patients require antibiotic therapy for extended periods of time, it is important to note that a host of factors can alter the effectiveness of antibiotic regimens. These factors include, but are not limited to, type of infection, local resistance patterns, and patient-specific characteristics.4 This article reviews antibiotic treatment options for osteomyelitis caused by methicillin-resistant S aureus including: vancomycin, minocycline, doxycycline, clindamycin, sulfamethoxazole-trimethoprim, linezolid, tigecycline, and daptomycin.
Though some antibiotics are monitored by measuring serum drug concentrations, bone concentrations are of utmost importance when treating methicillin-resistant S aureus osteomyelitis. However, comparison of serum and bone drug concentrations is somewhat problematic. The two parameters are measured in different units with serum concentrations measured in mcg/mL and bone concentrations reported as mcg/g.4 In addition, there is no standardized method for determining bone concentrations of antibiotics. For these reasons, animal models of osteomyelitis often are used to predict bone concentrations of medications. This article discusses pharmacokinetic characteristics, animal models, clinical studies, and observations for each antimicrobial agent.
Vancomycin
Vancomycin demonstrates activity against gram-positive microorganisms, including methicillin-resistant S aureus. It acts by binding to the D-alanyl-D-alanine portion of a cell wall precursor, thus inhibiting cell wall synthesis.5 Vancomycin is available in both oral and intravenous (IV) formulations but only IV vancomycin can be used in the treatment of methicillin-resistant S aureus osteomyelitis. Oral vancomycin is not significantly absorbed from the gastrointestinal tract, and therapeutic serum concentrations needed to treat methicillin-resistant S aureus osteomyelitis are not achieved.
Wilson and Mader6 reported on a rabbit model examining the bone penetration of vancomycin after administration of a single dose (30 mg/kg) in S aureus osteomyelitis. Concentrations were obtained from serum, non-infected, and infected bone (from right and left tibia, respectively). Concentrations in the serum (36.4±4.6 mcg/mL) were higher than in either type of bone. Infected bone samples, however, demonstrated greater penetration of vancomycin than non-infected samples (5.3±0.8 mcg/g versus 3.0±0.2 mcg/g).
A follow-up study in humans examined the concentrations of vancomycin in infected and non-infected bone.7 Non-infected bone samples were obtained from patients who received a vancomycin dose of 15 mg/kg prior to total hip replacement. Infected bone samples were collected from patients with sternal or tibial osteomyelitis receiving vancomycin doses based on serum concentrations (peaks 20-40 mcg/mL; troughs=12 mcg/mL). Again, patients with infected bone showed higher concentrations of vancomycin. Concentrations in both cancellous and cortical bone were higher in patients with infected bone, when compared to patients with uninfected bone (3.6 mcg/g versus 2.3±4.0 mcg/g and 5.94±3.48 mcg/g versus 1.14±0.84 mcg/g, respectively).
It is important to note that higher vancomycin trough concentrations of 15-20 mcg/mL are the current standard of practice when treating osteomyelitis, as opposed to the trough levels <12 mcg/mL used in Graziani et al’s7 study. Thus, one would expect to see higher concentrations in infected bone compared to study results. Some proposed mechanisms for increased infected bone concentrations include: better blood flow, serum trapping of the medication, or increased penetration of the chosen antibiotic.6 Regardless of the mechanism, vancomycin concentrations in bone range from 15%-35% of those seen in the serum, well above the minimum inhibitory concentration of 1 mcg/ml for susceptible S aureus strains.7 Today, vancomycin is commonly used for methicillin-resistant S aureus osteomyelitis and practitioners are comfortable with this agent. Vancomycin serum concentrations can be obtained to ensure that patients are receiving adequate treatment doses without adverse effects.
Tetracyclines
Tetracycline antibiotics, specifically minocycline and doxycycline, are active against methicillin-resistant S aureus in a bacteriostatic fashion. These agents enter bacterial cells in two ways, either by passive diffusion or an energy-dependent transport system.5,8 Once inside the cell, tetracyclines inhibit cell wall synthesis by binding to the 30S ribosomal unit that halts protein synthesis. Both agents are lipophilic, facilitating their passage into tissues.9
In a case series of 24 patients with methicillin-resistant S aureus infections treated with minocycline or doxycycline, clinical success occurred in 83% of patients.10 This study included four patients with osteomyelitis who were treated with minocycline alone (n=1), minocycline plus rifampin (n=2), or minocycline plus sulfamethoxazole-trimethoprim (n=1). The cure rate of 50% in patients with osteomyelitis was lower than that seen in the entire study population. The reasons for treatment failure were not specified, but the authors postulate it may be attributed to development of resistance to rifampin by the methicillin-resistant S aureus isolate. The overall resistance of methicillin-resistant S aureus to tetracycline antibiotics is approximately 16% in the United States (Table 1).11 This may indicate that doxycycline and minocycline may be suitable for outpatient therapy of methicillin-resistant S aureus osteomyelitis. Perhaps these two agents can be used in patients who have finished four to six weeks of IV antibiotics, but continued suppressive oral antibiotic therapy is necessary.
table 2
Clindamycin
Clindamycin is another older antimicrobial agent that may have a newfound place in the treatment of methicillin-resistant S aureus osteomyelitis. The lincosamide antibiotic exerts its effect on bacteria by acting on the ribosome to prevent protein synthesis, but interacts at different locations compared to previously mentioned antimicrobials (Table 2).12 It is theorized that the efficacy of clindamycin in gram-positive osteomyelitis can be attributed to its bone penetration, despite its classification as a bacteriostatic agent.13
A rabbit model of osteomyelitis demonstrated that clindamycin achieves significant concentration in bone.14 Rabbits were infected with S aureus osteomyelitis and divided into three treatment groups: no antibiotic therapy, 30 mg/kg clindamycin 3 times per day for 28 days, or 30 mg/kg clindamycin 3 times daily for 14 days. Serum and bone concentrations were examined one, two, and four hours after injection. Serum levels were found to be 11.7±3.2 mcg/mL, 6.6±0.8 mcg/mL, and 2.1±0.1 mcg/mL, respectively. Bone concentrations indicate that clindamycin achieved concentrations 29, 28, and 10 times greater than the organism minimum inhibitory concentration (MIC) (4.6±1.1 mcg/g, 4.3±0.7 mcg/g, and 1.6±0.3 mcg/g, respectively). These concentrations resulted in bone sterilization rates of 84%, with a greater percentage of rabbits treated for 28 days showing negative cultures at the end of treatment compared to those treated for only 14 days (84% versus 22%). Caution should be used when interpreting the above study results. Concentrations achieved in bone depend on the serum concentration obtained and differs between patients. Thus, bone concentrations achieved may not mimic those seen by Norden et al.14
A case series of 29 pediatric patients confirmed the efficacy of clindamycin in both acute and chronic cases of osteomyelitis.15 Patients initially received clindamycin 100 mg/kg/day IV for four weeks and then clindamycin 30 mg/kg/day orally for four additional weeks. Doses later were decreased to 50 mg/kg/day IV for three weeks and 25 mg/kg/day orally for four to six weeks because serum concentrations easily exceeded the susceptibility breakpoint for S aureus. Maximal serum concentrations were 32 mcg/mL one hour after clindamycin infusion. Bone concentrations determined six hours after administration of a 25 mg/kg dose were 42%-46% of those achieved in the serum, far above the breakpoints. A smaller clindamycin dose of 12.5 mg/kg showed a bone concentration equal to 30% of the serum concentration.
Clindamycin bone penetration also has been examined in adults undergoing knee or hip replacement.16 Clindamycin 600 mg IV every 8 hours was initiated between 12 and 20 hours prior to incision. During the procedure, cancellous bone was removed from the femoral neck or head. Two of three patients treated with clindamycin showed measurable concentrations in bone (9.26 mcg/g and 7.33 mcg/g). Concurrent serum concentrations were 12.5 mcg/mL and 10.0 mcg/mL, respectively.
Evidence from the literature has suggested two situations appropriate for the use of clindamycin in methicillin-resistant S aureus osteomyelitis. First, extended courses of oral clindamycin may be used in patients who display osteomyelitis refractory to other agents.17 Second, community-acquired methicillin-resistant S aureus infections often retain susceptibility to clindamycin.18
Sulfamethoxazole-Trimethoprim
The use of sulfamethoxazole-trimethoprim (SMX-TMP), a combination agent with observed activity against methicillin-resistant S aureus, has been well documented in both hospital-acquired and community-acquired infections, and overall resistance rates of methicillin-resistant S aureus appear to be low (26%) (Table 2). A case series of six patients with methicillin-resistant S aureus osteomyelitis demonstrated its efficacy.19 Five of these patients previously had received antibiotics, including vancomycin, for osteomyelitis without resolution. Sulfamethoxazole-trimethoprim was initiated at a dose of 800 mg/160 mg (one double strength tablet) every six hours; osteomyelitis resolved in five of the six patients. Four patients received sulfamethoxazole-trimethoprim for 8-12 weeks, one patient responded but had neutropenia successfully treated with folinic acid, and one patient remained on therapy for at least 56 weeks.
Perhaps the greatest role of sulfamethoxazole-trimethoprim lies in the continuation of antibiotic therapy after initial IV antibiotics have been used. Often sulfamethoxazole-trimethoprim will be given in combination with rifampin in the outpatient setting.20 Also, the use of sulfamethoxazole-trimethoprim has been suggested in the suppression of osteomyelitis. As with clindamycin, sulfamethoxazole-trimethoprim is an acceptable option for use in community-acquired methicillin-resistant S aureus infections.21
Newer Antimicrobials
Linezolid, a synthetic oxazolidinone, has emerged as a new treatment for methicillin-resistant S aureus infections. It most often is used in patients intolerant of vancomycin therapy or those experiencing treatment failure while receiving vancomycin.22 It is available in both IV and oral formulations and requires no dosage adjustment in liver or renal failure (caution should be used in severe hepatic failure).
A compassionate use program in human subjects conducted between 1997 and 2000 showed clinical success in 90% of linezolid treated patients with osteomyelitis (caused by methicillin-resistant S aureus or vancomycin-resistant enterococci), with an average duration of therapy of 40 days.23 In this same study, treatment success for methicillin-resistant S aureus infections was 86.6%. Perhaps the greatest benefit of linezolid is the available oral formulation with almost 100% bioavailability.5 However, linezolid therapy comes with a significant financial burden to patients. In addition, linezolid causes reversible myelosuppression, and patients undergoing prolonged treatment should have complete blood cell counts monitored regularly.24 For these reasons, other treatment options should be considered in patients when frequent monitoring is not possible.
Another new option in the fight against methicillin-resistant S aureus infection is tigecycline, a glycylcycline antibiotic structurally related to minocycline that exhibits bacteriostatic action. This agent has a large volume of distribution, suggestive of rapid distribution into tissues.25,26 Radio-labeled tigecycline given to rats showed greatest concentrations in the liver, spleen, and bone at the end of a 30-minute infusion. Levels were estimated to be eight times higher than in serum, and the half-life in bone was predicted to be approximately 200 hours.27 One benefit that tigecycline may have over its precursors is protection from established mechanisms of resistance common to the tetracycline class.9 Though tetracyclines and glycylcyclines bind to the same location of the bacterial ribosome, tigecycline has a stronger binding affinity. This may offer protection against the ribosomal resistance mechanism that can either prevent binding of the drug at the ribosome or promote dissociation from the site of action.
Daptomycin is a bactericidal cyclic lipopeptide that binds to bacterial cell membranes and causes depolarization.28This, in turn, alters protein synthesis in the bacteria. Daptomycin was compared to vancomycin in a rabbit model of methicillin-resistant S aureus osteomyelitis.29 Rabbits were given either daptomycin 4 mg/kg IV every 12 hours or vancomycin 40 mg/kg IV every 6 hours. Concentrations of both agents were significantly higher in infected bone when compared to non-infected bone. Methicillin-resistant S aureus eradication rates in this study were 41% for rabbits receiving daptomycin and 39% for vancomycin-treated rabbits. Mader and Adams29 noted the similar efficacy between the two agents and also noted that higher treatment success rates should be expected with either agent in humans, as humans with methicillin-resistant S aureus osteomyelitis will likely undergo debridement in addition to antibiotic therapy. Although daptomycin treatment of methicillin-resistant S aureus sounds promising, there have been recent reports of methicillin-resistant S aureus strains with reduced or no susceptibility to daptomycin.30-32 Therefore, clinicians should use this agent cautiously.
Conclusion
There are many treatment options available for the treatment of methicillin-resistant S aureus osteomyelitis and several factors should be considered when deciding on the best therapy. These include the type of osteomyelitis (acute versus chronic), previous antibiotic therapy, duration of therapy, and cost. Many of the above agents can be used once a patient has completed initial therapy with IV antibiotics but continued antimicrobials are desired. The use of oral agents in the long-term may help to enhance patient adherence and have potential benefits in eradication of the infecting organism. Previously, physicians may have felt limited to the use of vancomycin for methicillin-resistant S aureus osteomyelitis. This article identifies emerging antimicrobial agents for methicillin-resistant S aureus osteomyelitis and illustrates that older medications still have a place in therapy, allowing clinicians to expand treatment options outside of vancomycin.
The Bottom Line
* Finding the best treatment options for methicillin-resistant S aureus osteomyelitis continues to be difficult.
* Several established antibiotic options demonstrate good bone penetration.
* Other antibiotics, with limited clinical data in methicillin-resistant S aureus osteomyelitis, have demonstrated clinical success.
* Newer agents show promise in treatment of methicillin-resistant S aureus infections and may lack issues associated with resistance of classical agents.
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Authors
Drs Toma, Smith, Martin, and Rapp are from the University of Kentucky Chandler Medical Center, Lexington, Ky.
Reprint requests: Kelly M. Smith, PharmD, 800 Rose St, Rm C-113, Lexington, KY 40536.
Courtesy OthoSupersite