Pharmacological Approaches for Pediatric Patients With Osteomyelitis: Current Issues and Answers

By Amanda Geist, PharmD; Robert Kuhn, PharmD
ORTHOPEDICS 2009; 32:573

Recent studies suggest that the current dosing recommendations of 40 mg/kg to 60 mg/kg per day of vancomycin may not be adequate for the treatment of severe MRSA infections in children.

Previously, methicillin-resistant Staphylococcus aureus (MRSA) was a common pathogen in hospitals and rarely was a concern in the community. However, in recent years, community-acquired MRSA (CA-MRSA) has become increasingly prevalent in children.1,2 There are several therapeutic options for the treatment of CA-MRSA in the outpatient setting. Challenges that practitioners face when choosing an optimal regimen for pediatric patients are often related to patient age and preference. For children, in addition to matching “drugs to bug” combinations, the selection of the most optimal regimen requires consideration of several important factors, such as palatability, drug formulation, and cost.
Epidemiology

Osteomyelitis is an inflammatory process of the bone caused by bacterial or fungal infection. The overall incidence of osteomyelitis in children in the United States is unknown; however, the incidence has been reported as approximately 1 per 5000 children, accounting for approximately 1% of all pediatric hospitalizations.3,4 Half of all cases of osteomyelitis in children occur before 5 years of age.3 Boys are affected more commonly than girls, with a ratio of approximately 2:1.4
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Signs and symptoms of osteomyelitis vary depending on the child’s age and the affected area. For example, an older child may report pain and tenderness at the site of the infected area, but osteomyelitis in an infant who is unable to verbalize pain may manifest as guarding of the involved extremity or irritability.5 Other signs and symptoms include fever and swelling, warmth, and erythema of the infected area.5

The most common sites of involvement typically are long bones such as the tibia and femur, comprising approximately 20% to 30% of cases.6 Other less commonly infected sites include short bones, such as the ribs, clavicle, and scapula.6 The most common pathogens implicated in osteomyelitis are bacterial in nature, and the etiology of osteomyelitis in children is typically hematogenous spread, with infection caused by spread from trauma, surgery, or vascular insufficiency occurring much less frequently.5,6 Several pathogens may be involved in osteomyelitis, and in children it will vary depending on age and type of osteomyelitis involved. For example, the most common pathogens for children of any age are S aureus and Streptococcus pyogenes; while Kingella kingae and Streptococcus pneumoniae are more common in younger children.5,6
Prevalence

Recent studies have shown that osteomyelitis caused by CA-MRSA has increased complications compared with infection caused by methicillin­-sensitive Staphylococcus aureus (MSSA) or other pathogens.7,8 These complications include increased need for surgical intervention, more febrile days, increased length of hospitalization, and increased duration of antibiotics.7,8 A rise in the number of cases of culture-proven CA-MRSA also has a direct impact on clinical case load and transition from the inpatient to outpatient setting.
Treatment Approaches

One of the most common empiric treatment options for MRSA in the inpatient setting is vancomycin. Vancomycin is a bacteriostatic glycopeptide that exerts its effects by binding to the precursors necessary in bacterial cell wall formation to inhibit cell wall synthesis. The spectrum of activity for vancomycin only includes Gram-positive organisms such as S aureus, Streptococci, and Enterococcus. Vancomycin is widely distributed; however, penetration into bone and cerebral spinal fluid is limited. Therefore, higher targeted serum concentrations, between 15 and 20 mcg/mL, are warranted in severe infections and those involving the central nervous system and bone.9,10 Due to its low oral bioavailability, only intravenous therapy can be used for the treatment of infections other than those involving Clostridium difficile.

Current empiric dosing guidelines for vancomycin in the treatment of osteomyelitis in children start at 40 mg/kg per day divided every 6 to 8 hours.10 However, a recent study conducted by Frymoyer et al11 proposed that 40 mg/kg per day may not be adequate for treatment of severe MRSA infections with minimum inhibitory concentrations of 1 mcg/mL. This study suggests initial empiric vancomycin doses of 60 mg/kg per day, depending on age, in children without underlying renal dysfunction.11 In addition, clinical experience at our institution has shown that the currently recommended dosing guidelines of 40 mg/kg to 60 mg/kg per day consistently produce trough concentrations below the goal range of 15 to 20 mcg/mL for treatment of serious infections, osteomyelitis, and abscess.

McCabe et al12 suggest that dosing ranging between 75 mg/kg and 95 mg/kg per day, depending on age (Tables 1, 2) and with close monitoring, is a more appropriate dosing schematic to reach goal serum concentrations in a timely manner.

Table 1: Initial Empiric Vancomycin Dosing Regimen Stratified by Age Proposed by McCabe et al

Table 2: Common Dosage Forms and Cost of Agents Used in the Treatment of MRSA Infections in Children

In an era of increased incidence of MRSA infections associated with increased complications, it is important to achieve rapid therapeutic serum concentrations. Prompt achievement of adequate serum concentrations will allow for more rapid stabilization of the treatment regimen and the potential for a faster transition to outpatient therapy, which can have a direct impact on patient case load.

Monitoring of vancomycin therapy should include reaching either serum trough concentrations alone or trough and peak concentrations 30 minutes prior to and 1 hour after the third or fourth dose of therapy, depending on local institutional practice.

Repeat trough concentrations should be conducted at least weekly for those who require therapy longer than 5 to 7 days. Other monitoring parameters should include daily assessment of blood urea nitrogen, serum creatinine, and urine output while on therapy, especially for patients taking other potentially nephrotoxic agents (eg, aminoglycosides).

The most common side effects seen with the use of intravenous vancomycin in the pediatric population involve infusion reactions. Patients can develop red man syndrome, a histamine-mediated infusion reaction characterized by flushing, rash, and hypotension.

Red man syndrome typically occurs with rapid infusions, those given faster than the conventional practice of over 1 hour. Red man syndrome can be minimized by premedicating with diphenhydramine and slowing the infusion rate to administer the dose over 90 to 120 minutes. It may be necessary to slow the infusion rate to administer higher doses proposed by McCabe et al12 over 1.5 to 2 hours to help prevent the development of red man syndrome.

Daptomycin is another potential treatment option for the inpatient management of CA-MRSA in pediatric patients. Daptomycin is a bactericidal lipopeptide antibiotic that acts by causing depolarization of the bacterial cell membrane to cause cellular death.13 It can be used in the treatment of complicated skin and soft tissue infections and bacteremia, and although it is not approved for use in osteomyelitis, case studies in adult populations have shown clinical cure rates of approximately 63% in the treatment of osteomyelitis.14 However because it is inactivated by lung surfactant, daptomycin should never be used in the treatment of pneumonia.13

Although relatively little information exists regarding the use of daptomycin in the pediatric population, case reports have demonstrated an 86% efficacy rate when used at doses ranging between 4 mg/kg to 6 mg/kg per dose given intravenously once daily for the treatment of bacteremia (Table 2).13 Advantages to its use include a once daily dosing regimen as well as a unique mechanism of action that provides coverage against resistant strains of Staphylococci such as MRSA and vancomycin-resistant Enterococci.

A potential side effect associated with daptomycin use is myopathy.13 Patients receiving daptomycin therapy should be monitored for signs and symptoms of muscle pain and weakness, and patients should have creatinine phosphokinase (CPK) levels drawn at least weekly during treatment.13

Several therapeutic options exist for the treatment of CA-MRSA in the outpatient setting. Challenges that practitioners face when choosing an optimal regimen for pediatric patients are often related to patient age and preference. For example, it is important to select an agent that is palatable, easily and accurately measured, and is available in various pharmaceutical dosage forms or able to be extemporaneously compounded into a liquid preparation for those unable to swallow capsules or tablets.

One therapeutic option is that children could receive intravenous antimicrobials in the outpatient setting. However, numerous constraints are associated with home intravenous therapy such as interference with the patient’s ability to perform activities of daily living. A recent study by Zaoutis et al15 that compared the use of prolonged intravenous therapy to early transition to oral therapy for the treatment of osteomyelitis in children showed that those patients who received prolonged intravenous therapy were more likely to experience treatment-related complications. In addition, this study also showed that those patients who received early transition to oral therapy were no more likely to experience treatment failure than those who received prolonged intravenous therapy.15

One of the most common treatment options for MRSA infections in children is sulfamethoxazole and trimethoprim. Each agent in sulfamethoxazole and trimethoprim (SMX-TMP) inhibits bacterial folic acid synthesis at different steps in the enzymatic process to allow for synergy. Its spectrum of activity includes Staphylococci, Streptococci, Escherichia coli, and Proteus, among others. Pathogens such as S aureus that may be resistant to sulfamethoxazole or trimethoprim alone are usually sensitive when used in combination. The traditional dosing recommendation for SMX-TMP in the treatment of pediatric infections is 6 mg/kg to 12 mg/kg per day in 2 divided doses based on the trimethoprim component.10 However, to achieve increased bone penetration; our institution uses doses ranging between 15 mg/kg to 20 mg/kg per day in divided doses up to a maximum of 960 mg per day of the trimethoprim component (Table 2).10

An advantage of SMX-TMP use in the pediatric population is that it is available in various dosage forms, including a commercially available grape flavored suspension containing 200 mg SMX and 40 mg TMP/5 mL.10 Another advantage to its use is that it is relatively inexpensive and available as a generic product. Although SMX-TMP is also available in an intravenous formulation, several problems are associated with its administration. Adequate reconstitution requires the product be diluted in a large volume of hypotonic fluid (D5W or D10W), which may be too large of a fluid volume for younger infants and children.10

The most common side effects associated with the use of SMX-TMP are gastrointestinal upset such as nausea and vomiting.10 Although potential exists for allergic reaction and skin rash that could progress to Stevens-Johnson syndrome, these reactions are rare.9,10

Clindamycin is another commonly used agent in the management of MRSA infections in children. Clindamycin is a derivative of lincomycin that exerts its action by suppressing bacterial protein synthesis. It is either bacteriostatic or bactericidal, depending on the concentration at the site of action. It has a wide spectrum of activity that is active against most Gram-positive aerobic organisms such as Streptococci and Staphylococci including most methicillin-resistant species. Its spectrum of activity also includes anerobic Gram-negative organisms such as Bacteroides fragilis and Fusobacterium; however, it does not possess any activity against aerobic Gram-negative organisms.

Clindamycin distributes extensively into different tissues, including bone, and will accumulate in abcesses.9 It is rapidly absorbed and has high bioavailability (approximately 90%) when administered orally, making the transition from intravenous to oral therapy easy.9,10 For the treatment of pediatric patients unable to swallow capsules, there is a commercially available oral solution of 75 mg/5 mL in addition to other intravenous and oral formulations available.10 The oral solution has the advantage of not requiring refrigeration and is stable at room temperature for 2 weeks after reconstitution.10 However, the oral solution has poor palatability and parents are often faced with the difficult task of administering a medication several times per day that tastes bad and is difficult to mask.

One mechanism of MRSA resistance to clindamycin is mediated via ribosomal methylase and can have clinically significant treatment implications. Resistance can be constitutive in which there is resistance to macrolides, lincosamides, and streptogramin (MLS), or it may be inducible in which lincosamides and streptogramin appear active. If the isolate is resistant to both erythromycin and clindamycin, then the resistance is constitutive. If the isolate is resistant to erythromycin and sensitive to clindamycin, it may carry inducible to MLS resistance and a disk dilution test (D-test) should be conducted. If the isolate is D-test positive, this indicates inducible MLS resistance, therefore, treatment should not include clindamycin.

The typical dose of clindamycin in the treatment of complicated skin and soft tissue infections and osteomyelitis in children is 10 mg/kg to 30 mg/kg per day in divided doses every 6 to 8 hours with a maximum dose of 1800 mg per day orally or 25 mg/kg to 40 mg/kg per day intravenously divided every 6 to 8 hours (Table 2).10 Intravenous doses as high as 4500 mg per day have been given in life-threatening situations.10

The difference between maximum doses of intravenous and oral therapy is due to the most common side effect of clindamycin, gastrointestinal upset and risk for pseudomembranous colitis. The most frequent manifestation of gastrointestinal upset is diarrhea, with incidence reported as being between 2% to 20%, and is more often associated with increasing doses.10 Other manifestations include abdominal pain and cramping, nausea, and vomiting.10 A mechanism by which parents can help to minimize the incidence of adverse gastrointestinal effects caused by clindamycin is to administer with food. Families can also encourage their children to eat yogurt during therapy to help maintain normal intestinal flora.

A third treatment option for the management of osteomyelitis in children is linezolid, which exerts its action early in the process of bacterial protein synthesis to prevent the formation of the ribosomal complex required for bacterial protein synthesis. Its unique mechanism of action also allows it to possess activity against many organisms that have developed other mechanisms of resistance such as methicillin-resistant Staphylococci, penicillin-resistant Streptococci and vancomycin-resistant Enterococci.

Linezolid distributes easily into tissues and has good penetration into bone, joint, fat, and muscle.16,17 It has excellent oral bioavailability that is close to 100%; allowing for easy intravenous to oral conversion in a 1:1 manner.10 Dosing for complicated skin and soft tissue infections and osteomyelitis in infants and children depending on age is 10 mg/kg per dose every 8 to 12 hours intravenous and orally up to a maximum of 600 to 1200 mg per day (Table 2).10 It also has the added advantage of not requiring dosage adjustment for renal impairment.10

Linezolid is available in various dosage forms including a powder for oral suspension that is stable at room temperature for a prolonged period, up to 21 days.10 This makes it an ideal agent to be used for those children whom may require a longer duration of therapy. One of the more rare side effects associated with linezolid use is peripheral and optic neuropathies. There have been case reports of its occurrence in adolescents treated for longer periods, as most cases reported are in those who are treated for >3 months.18 Another important aspect to consider with the use of linezolid is its cost. Linezolid is expensive and many insurance companies require a prior authorization.19

Inpatient primary empiric therapy is usually initiated with vancomycin, and depending on culture and sensitivity data, it may be transitioned to other oral agents such as sulfamethoxazole-trimethoprim, clindamycin, and linezolid. For children, in addition to matching drugs to bug combinations, the selection of the most optimal regimen requires consideration of several important factors such as palatability, drug formulation, and cost.
The Bottom Line

* Community-acquired MRSA has become increasingly prevalent in children.
* Recent studies suggest that the current dosing recommendations of 40 mg/kg to 60 mg/kg per day of vancomycin may not be adequate for the treatment of severe MRSA infections in children.
* Practitioners are faced with multiple challenges when selecting the optimal treatment regimen for MRSA infections in children, including selection of not only the proper drug to bug combination, but also several important factors such as palatability, drug formulation, and cost.

References

1. Paintsil E. Pediatric community-acquired methicillin-resistant Staphylococcus aureus infection and colonization: trends and management. Curr Opin Ped. 2007; 19(1):75-82.
2. Chen AE, Goldstein M, Carroll K, et al. Evolving epidemiology of pediatric Staphylococcus aureus cutaneous infection in a Baltimore hospital. Ped Emer Care. 2006; 22(10):717-723.
3. Vazquez, M. Osteomyelitis in children. Curr Opin Pediatr. 2002; 14(1):112-115.
4. Sonnen GM, Henry NK. Pediatric bone and joint infections. Pediatr Clin N Amer. 1996; 43(4):933-947.
5. Gutierrez K. Bone and joint infections in children. Pediatr Clin N Amer. 2005; 95(2);779-794.
6. Gutierrez K. Bone and joint infections. In: Long SS, Pickering LK, Prober CG, eds. Principles and Practice of Pediatric Infectious Diseases. New York, NY: Churchill Livingstone; 2008:474-482.
7. Saavedra-Lozano J, Mejias A, Ahmad N, Peromingo E, Arudura MI, Guillen S, et. al. Changing trends in acute osteomyelitis in children: impact of methicillin-resistant Staphylococcus aureus infections. J Pediatr Orthop. 2008; 28(5):569-575.
8. Hawkshead JJ, Patel NB, Steele RW, Heinrich SD. Comparative severity of pediatric osteomyelitis attributable to methicillin-resistant versus methicillin sensitive Staphylococcus aureus. J Pediatr Orthop. 2009; 29(1):85-90.
9. Hardman JG, Limbird LE. Goodman and Gillman’s The Pharmacological Basis of Therapeutics. New York, NY: McGraw Hill; 2001.
10. Taketomo CK, Hodding JH, Kraus DM. Pediatric Dosage Handbook. Hudson, OH: Lexi-Comp Inc; 2008.
11. Frymoyer A, Hersh AL, Benet LZ, Guglielmo JB. Current recommended dosing of vancomycin for children With invasive methicillin-resistant Staphylococcus aureus infections is inadequate. Pediatr Infect Dis J. 2009; 28(5):398-402.
12. McCabe T, Iocono J, Davis GA, Nelson C, Kuhn R. Evaluating the empiric dose of vancoycin in pediatric patients. Paper presented at: International PPAG/ACCP Meeting; April 24-28, 2009; Orlando, Florida.
13. Ardura M, Mejias A, Katz K, et al. Daptomycin therapy for invasive gram-positive bacterial infections in children. Pediatr Infect Dis J. 2007; 26(12):1129-1132.
14. Lamp KC, Friedrich LV, Mendez-Vigo L, Russo R. Clinical experience with daptomycin for the treatment of patients with osteomyelitis. Amer J Med. 2007; 120(10A):S13-S20.
15. Zaoutis T, Localio AR, Leckerman K, et al. Prolonged intravenous therapy versus early transition to oral antimicrobial therapy for acute osteomyelitis in children. Pediatrics. 2009; 123:636-642.
16. Lovering AM, Zhang J, Bannister GC, et al. Penetration of linezolid into bone, fat, muscle and haematoma of patients undergoing routine hip replacement. Antimicrob Agents Chemother. 2002; 50(1):73-77.
17. Rana B, Butcher I, Grigoris P, Murnaghan C, Seaton RA, Tobin CM. Linezolid penetration into osteo-articular tissues. Antimicrob Agents Chemother. 2002; 50(5):747-750.
18. Linam WM, Wesselkamper K, Gerber MA. Peripheral neuropathy in an adolescent treated with linezolid. Pediatr Infect Dis J. 2009; 28(2):149-151.
19. Cardinal Health. Pharmaceutical distribution. Available at: www.cardinal.com. Accessed May 12, 2009.

Authors

Drs Geist and Kuhn are from the University of Kentucky HealthCare, Lexington, Kentucky.

Drs Geist and Kuhn have no relevant financial relationships to disclose.

Correspondence should be addressed to: Amanda D. Geist, PharmD, 800 Rose St, H110, Department of Pharmacy, Lexington, KY 40536.

DOI: 10.3928/01477447-20090624-16