Point-Counterpoint: Are Oral Antibiotics Better Than IV Antibiotics For Osteomyelitis?

Oral.

These authors argue oral antibiotic therapy can be a reasonable first-line treatment for osteomyelitis, citing its efficacy and lower risk of adverse effects.

By Andrew J. Meyr, DPM, and Jennifer A. Skolnik, DPM

When considering this debate over oral versus intravenous (IV) antibiotics, one might first propose that this argument suffers from a flawed initial premise by making the assumption that any antibiotics, via any route, are able to treat diabetic foot osteomyelitis effectively.

The problem within this broad assumption is most likely the result of an inherent weakness of our diagnostic definition for osteomyelitis. The primary problem with the definition is that it does not differentiate between infection in the setting of viable bone with an intact vascular supply and infection in the setting of necrotic bone with surrounding soft tissue necrosis. Although antibiotics might effectively treat infection in viable bone, it is unlikely, to say the least, that antibiotics are able to bring necrotic bone back to life.

The viability of the infected bone is an important consideration in this argument because certainly, most instances of diabetic foot osteomyelitis are the result of infection by contiguous extension. In other words, both the bone and the soft tissue around the bone are at risk for necrosis. Before implementing any interventional treatment plan, we would encourage physicians to evaluate if the “osteomyelitic” bone is viable or non-viable, and further evaluate if there is an intact vascular supply or not.

In the presence of non-viable bone and/or bone without an intact vascular supply, then surgical resection is likely the best treatment option as opposed to antibiotics. In contrast, in situations in which the affected bone and surrounding soft tissue are primarily viable, then the route of antibiotic administration is an important consideration.

With this concession in mind, we would certainly argue that there is no clear evidence indicating a requirement for IV antibiotics in the treatment of osteomyelitis. In fact, the available evidence points fairly clearly toward at least the non-inferiority of an oral route of administration.

We admit, however, that parenteral therapy has generally been considered the historical preferred therapy. In their frequently cited 1997 article in the New England Journal of Medicine, Lew and Waldvogel clearly state that “Early antibiotic treatment, before extensive destruction of bone or necrosis, produces the best results and must be administered parenterally for at least four—and usually six—weeks to achieve an acceptable rate of cure.”¹ Note the utilized language including “best results,” “must be administered” and “acceptable rate.” Despite this strong language, it is interesting to note this statement and the associated paragraph were not accompanied by a single reference to support these bold proclamations. It was a recommendation based on clinical experience and not empiric data.   

A Closer Look At The Efficacy Of Newer Oral Agents                             

We would argue that the advent of newer oral agents with improved bioavailability and good bone penetration has shifted the paradigm. In fact, through a comprehensive 2012 review of nearly 200 articles, Spellberg and Lipsky demonstrated that there have actually been a greater number of articles published studying oral antibiotics for chronic osteomyelitis in comparison to parenteral antibiotics, and that those articles broadly show similar efficacy when comparing the two methods of administration.² Further, researchers have found the use of oral antibiotics has many advantages over IV therapy including decreased drug and administrative costs, decreased length of hospital stay, fewer side effects, increased patient satisfaction, and decreased complications related to intravenous catheter usage.^3,4

The contemporary antibiotic stewardship movement has shifted its focus to limiting unnecessary antibiotic administration, including the use of intravenous antibiotics when oral antibiotics may suffice. Oral antibiotics with a bioavailability of at least 90 percent absorption are generally considered equivalent to intravenous antibiotics from a pharmacokinetic standpoint.⁴ Examples of this include clindamycin, fluoroquinolones, trimethoprim/sulfamethoxazole, linezolid (Zyvox, Pfizer) and metronidazole.³

Additionally, studies have provided evidence that fluoroquinolones, trimethoprim/sulfamethoxazole, linezolid and other oral agents can readily achieve levels in bone that exceed the minimum inhibitory concentration (MIC) at about 50 percent of serum.² Clindamycin, another common oral agent with excellent bone penetration, has a 90 percent absorption rate after oral administration, indicating no additional advantage to intravenous therapy.⁵ Linezolid also possesses oral bioavailability at nearly 100 percent and low levels of resistance although it can be expensive, and side effects may be problematic with increasing length of treatment.⁵ Doxycycline is a final example that has nearly 100 percent bioavailability.⁵

Beyond theoretical pharmacokinetics, the clinical data shows the efficacy of oral agents. Oral fluoroquinolone therapy, for example, has a cure rate in the literature of between 60 to 80 percent.² Spellberg and Lipsky reviewed multiple randomized studies in which researchers compared patients with chronic osteomyelitis on oral fluoroquinolones to intravenous therapy, and the cure rates were similar.²

Other studies have found similar results of efficacy with different agents. One study compared trimethoprim/sulfamethoxazole to cloxacillin for chronic osteomyelitis caused by methicillin-resistant Staphylococcus aureus (MRSA), and found comparable cure and relapse rates between the two drugs.² In a study by Waagsbø and colleagues, patients transitioned from intravenous to oral antibiotics after three days of administration.⁶ With this early switch to oral therapy, the authors saw no significant difference in the rehospitalization rate, reinitiation rate of IV antibiotics or the mortality rate.

A separate study noted an 80 percent success for oral therapy for osteomyelitis, indicating no recurrence of infection for patients being treated for a mean 40 +/- 30 weeks.⁷ In this study, patients were most commonly prescribed trimethoprim/sulfamethoxazole, ciprofloxacin, amoxicillin-clavulanic acid and metronidazole, all of which are considered to have acceptable bioavailability and bone penetration levels.

What You Should Know About Adverse Effects With IV Antibiotics

Note that patients on prolonged courses of antibiotics to treat osteomyelitis in the foot are at an increased risk for developing adverse reactions. Multiple studies comparing intravenous and oral therapy have found no significant difference in terms of relapse of osteomyelitis at greater than one year of follow-up but the likelihood of moderate or severe side effects was significantly greater in those taking parenteral therapy than oral therapy (15.5 versus 4.8 percent).² Vancomycin, one of the most common drugs clinicians use in the treatment of diabetic foot infections, is known to have potentially devastating side effects, including nephrotoxicity.⁸

Other intravenous drugs such as daptomycin (Cubicin, Merck) are known to cause muscle toxicity and thus, one must monitor patients with weekly serum creatine phosphokinase levels.⁸ In a study evaluating patients receiving at least four weeks parenteral antibiotic therapy in an outpatient setting, most commonly for bone and joint infections, there was an 11 percent incidence of adverse effect for patients on daptomycin and ertapenem (Invanz, Merck).⁹ Other studies have demonstrated similar adverse drug reaction rates in patients on outpatient parenteral therapy. Lee and colleagues demonstrated an antibiotic switch rate of 12.5 percent, 84 percent of which was due to side effects.¹⁰  

Additionally, parenteral therapy requires the use of either central or peripheral catheters to deliver the medication, which carries additional risk. In a study looking at peripherally inserted central catheters (PICCs) for multiple indications, 52 percent of which were for long-term antibiotic administration, Chopra and colleagues found subsequent bloodstream infection to be a common complication.¹¹ This was also associated with an increased length of hospitalization.

In a separate study looking at complications from the use of central venous catheters for children with acute hematogenous osteomyelitis, 41 percent had at least one complication including catheter-associated bacteremia in 11 percent, malfunction of the catheter in 23 percent and 5 percent of patients developing local skin infection at the catheter site.¹² The authors found of all the patients who transitioned to oral antibiotics within two weeks, none required readmission or visited the emergency department after discharge. Studies have also demonstrated that PICCs carry a risk of deep venous thrombosis, greater than that of central venous catheters.¹³

In Conclusion

One can consider oral antibiotic therapy as a reasonable first-line therapy for patients with osteomyelitis as it likely has similar efficacy with less associated cost and a decreased side effect profile in comparison to IV antibiotics.

Dr. Meyr is a Clinical Associate Professor at the Temple University School of Podiatric Medicine in Philadelphia.

Dr. Skolnik is a second-year resident in the Temple University Hospital Podiatric Surgical Residency Program.

References

1.    Lew DP, Waldvogel FA. Osteomyelitis. N Engl J Med. 1997;336(14):999-1007.
2.    Spellberg B, Lipsky BA. Systemic antibiotic therapy for chronic osteomyelitis in adults. Clin Infect Dis. 2011; 54(3):393-407.
3.    White CN, Rolston KV. Osteomyelitis: Drug bioavailability and bone penetration are key. J Am Acad Phys Asst. 2012; 25(7):21-27.
4.    Cunha CB. Antibiotic stewardship program perspective: oral antibiotic therapy for common infectious diseases. Med Clin North Am. 2018; 102(5):947–54.
5.    Thompson S, Townsend R. Pharmacological agents for soft tissue and bone infected with MRSA: which agent and for how long? Injury. 2011; 42(Suppl 5):S7-S10.
6.    Waagsbø B, Sundøy A, Quist Paulsen E. Reduction of unnecessary iv antibiotic days using general criteria for antibiotic switch. Scand J Infect Dis. 2008; 40(6-7):468-473.
7.    Embil JM, Rose G, Trepman E, et al. Oral antimicrobial therapy for diabetic foot osteomyelitis. Foot Ankle Int. 2006; 27(10):771-779.
8.    Kosinski MA, Lipsky BA. Current medical management of diabetic foot infections. Expert Rev Anti Infect Ther. 2010; 8(11):1293-1305.
9.    Suleyman G, Kenney R, Zervos MJ, Weinmann A. Safety and efficacy of outpatient parenteral antibiotic therapy in an academic infectious disease clinic. J Clin Pharm Ther. 2017; 42(1):39-43.
10.    Lee B, Tam I, Weigel IV B, et al. Comparative outcomes of βbeta-lactam antibiotics in outpatient parenteral antibiotic therapy: treatment success, readmissions and antibiotic switches. J Antimicrob Chemother. 2015; 70(8):2389-2396.
11.    Chopra V, Ratz D, Kuhn L, Lopus T, Chenoweth C, Krein S. PICC-associated bloodstream infections: prevalence, patterns, and predictors. Am J Med. 2014; 127(4):319-328.
12.    Ruebner R, Keren R, Coffin S, Chu J, Horn D, Zaoutis TE. Complications of central venous catheters used for the treatment of acute hematogenous osteomyelitis. Pediatrics. 2006; 117(4):1210-1215.
13.    Chopra V, Anand S, Hickner A, et al. Risk of venous thromboembolism associated with peripherally inserted central catheters: a systematic review and meta-analysis. Lancet. 2013; 382(9889):311-325.

Editor’s note: For further reading, see “Top 10 Antibiotics For Managing Diabetic Foot Infections” in the August 2017 issue of Podiatry Today, “Point-Counterpoint: Osteomyelitis: Can It Be Treated With Antibiotic Therapy Alone?” in the January 2015 issue, or the DPM Blog “A New Review Of Antibiotic Therapy For Osteomyelitis” at www.podiatrytoday.com/blogged/new-review-antibiotic-therapy-osteomyelitis .

For other related articles, visit the archives at www.podiatrytoday.com

Intravenous.

This author says IV antibiotics are better at fighting infection and providing optimal levels of antibiotic concentration for patients with various stages of osteomyelitis.

By Jeffrey Karr, DPM

When treating acute or chronic osteomyelitis and given the choice between oral and intravenous (IV) antibiotic treatment, IV antibiotics are clearly a better choice. The advantages of IV antibiotics are higher rates of infection eradication, prevention of long-term sequelae or recurrent bone infection, and obtaining adequate levels of antibiotic bone concentration. Comorbidities such as cardiac disease or lower extremity peripheral arterial disease (PAD) will interfere with obtaining adequate bone antibiotic levels, which would make IV antibiotics a better choice. Oral antibiotics have several considerations that can limit their use in the treatment of acute or chronic osteomyelitis.

Staging the bone infection by the Cierny-Mader clinical classification system will further clarify which course of action is most appropriate.¹ The Cierny-Mader clinical classification system is based on anatomic, clinical and radiologic features. The system classifies the area of osteomyelitis by duration (acute or chronic), pathogenesis (trauma, contiguous spread, hematogenous, surgical), site, extent and patient health type. This system characterizes osteomyelitis as being in one of four anatomic stages.

In Cierny-Mader stage 1 (medullary) osteomyelitis, the bone infection is confined to the medullary cavity of the bone.¹ Cierny-Mader stage 2 (superficial) osteomyelitis involves only the cortical bone and most often originates from a direct inoculation or a contiguous focus infection. Cierny-Mader stage 3 (localized) osteomyelitis usually involves both cortical and medullary bone. In stage 3, the bone remains stable and the infectious process does not involve the entire bone’s diameter. Cierny-Mader stage 4 (diffuse) osteomyelitis involves the entire thickness of the bone with loss of stability.

This system further characterizes the host health as either A, B or C.¹ The A hosts are patients without systemic or local compromising factors. The B hosts are affected by one or more compromising factors. The C hosts are patients who are so severely compromised that the radical treatment necessary would have an unacceptable risk-benefit ratio.

Weighing IV Versus Oral Agents

There are several considerations before using oral antibiotics in the treatment of osteomyelitis. Clindamycin is well known to have excellent tissue penetration, particularly in bone, and is a viable oral antibiotic option. However, there are other considerations with oral clindamycin. Clindamycin-induced diarrhea is the most common adverse effect and occurs in up to 20 percent of patients.² Clostridium difficile with clindamycin use may cause abdominal pain, pseudomembranous colitis, esophagitis, nausea, vomiting and diarrhea.²  

Clindamycin’s side effects may occur more frequently in comparison with other oral antibiotic agents.² Children often do not tolerate oral clindamycin suspension. Tetracycline has side effect considerations as well. Tetracycline is a pregnancy category D medication and is not recommended for children because of the potential for tooth enamel discoloration and decreased bone growth.^3,4

When using trimethoprim/sulfamethoxazole (TMP-SMX), be cautious about administration of the drug in treating geriatric patients, particularly those taking concurrent inhibitors of the renin-angiotensin system. Both of these medicines increase blood levels of potassium, which may cause and/or increase breathing difficulties, chest pain, slow or irregular heartbeat, confusion, or muscle weakness. Clinicians should also exercise caution when using TMP-SMX in patients who have chronic renal insufficiency because of an increased risk of hyperkalemia. Researchers do not recommend TMP-SMX in pregnant women in their third trimester or in infants younger than two months of age.^3,4 One should also exercise caution when using TMP-SMX for patients with diabetes as TMP-SMX can have the side effect of hypoglycemia.
When high-dose oral beta-lactam antibiotics (cloxacillin and cephalexin) use begins, there can be limited antibiotic bioavailability and poor antibiotic gastrointestinal tolerance.

Oral quinolones such as ciprofloxacin and levofloxacin (Levaquin, Janssen) have their drawbacks as well. In vivo studies have shown that high doses of quinolones have caused articular damage in young animals. Side effects of oral quinolones include tendon rupture, pain, “pins and needles” sensations as well as depression, anxiety and thoughts of suicide.⁵ About half of the patients who had serious side effects from quinolones said the side effects began after the first or second dose. Long-term oral quinolone therapy can suppress the symptoms and signs of chronic, refractory osteomyelitis.⁵ Even though oral quinolones in osteomyelitis treatment are effective, researchers have yet to show the efficacy of oral quinolones over conventional therapy for infections due to P. aeruginosa, Serratia species and S. aureus.⁶   

How IV Antibiotics Work For Different Stages Of Osteomyelitis

Intravenous antibiotics are the mainstay of treating acute pediatric osteomyelitis. In the management of acute pediatric Cierny-Mader stage 1 osteomyelitis, one can safely administer IV antibiotics, when monitored, in high doses so the patient reaches adequate antimicrobial concentrations within the infected bone and joint.¹ The specific duration of IV antibiotic therapy necessary in the management of pediatric stage 1 osteomyelitis is usually four to six weeks.⁷ One can expect cure rates exceeding 80 percent for patients with acute pediatric stage 1 osteomyelitis who have surgery and receive IV antibiotics for four to six weeks. Adult stage 1 osteomyelitis is uncommon and is usually due to an infected implant, such as an intramedullary rod.

Intravenous antibiotics offer several advantages in treating adult stage 1 osteomyelitis. If the patient has an implant that is removable, one can provide a four-week course of IV antibiotics from the date of implant removal. If the implant is not removable, usually because of bone instability, place the patient on suppressive oral therapy until the bone is stable. Once the bone is stable, remove the implant and give a four-week course of IV antibiotics from the date of implant removal.   

Intravenous antibiotics are a superior choice to oral antibiotic treatment for Cierny-Mader stages 2, 3 and 4 chronic osteomyelitis. One may treat stage 2 osteomyelitis with two to four weeks of IV antibiotics following superficial bone debridement and soft tissue coverage. For patients with stages 3 and 4 osteomyelitis, which are often chronic stages, one would prescribe four to six weeks of IV antibiotics following bone debridement.

For chronic osteomyelitis in stages 2, 3 and 4, there are several factors that will compel for stronger consideration in utilizing IV antibiotics. One consideration is the difficulty of eradicating biofilm. Chronic osteomyelitis harbors sessile bacteria as well as adherent bacterial biofilm reservoirs that make the bone infection very difficult to eliminate. Biofilm has an increased resistance to antibiotics, requiring higher bone antibiotic levels to eradicate the bacterial biofilm colonies. Intravenous antibiotic treatment will allow optimal bone antibiotic levels over oral antibiotics in diseased bone. Bone antibiotic levels, typically 10 to 20 percent that of antibiotic serum levels, are even less likely to remain above the minimum inhibitory concentration (MIC) with most oral antibiotics. Infected bone also has a diminished blood supply. This diminished blood supply further complicates obtaining adequate antibiotic bone concentrations.

Additional Insights On The Utility Of IV Antibiotics

When weighing the use of IV antibiotics in the treatment of chronic osteomyelitis, other considerations include PAD and cardiac disease. Peripheral arterial disease and chronic heart failure influence bone perfusion and bone antibiotic levels. Lower extremity PAD will impede antibiotic delivery and antibiotic bone concentration. Intravenous antibiotics allow higher serum antibiotic concentration and thus higher bone antibiotic concentration. Normal healthy bone is moderately vascularized, receiving only about 10 percent of cardiac output. Patients with chronic heart failure will have further decreased bone perfusion, requiring higher serum antibiotic levels, as one would see with IV antibiotics, to obtain sufficient bacterial minimal inhibitory concentration within the infected bone.

Intravenous antibiotics have several distinct advantages in treating certain bacteria. For methicillin-susceptible Staphylococcus aureus (MSSA) osteomyelitis, penicillin drugs such as oxacillin, nafcillin and flucloxacillin given intravenously have traditionally been considered the drugs of choice.⁸ Spellberg and Lipsky describe b-lactam antibiotics (penicillins, cephalosporins and carbapenems) penetrating bone at levels ranging from about 5 to 20 percent of those in serum.⁹ Since the serum levels of these parentally delivered b-lactam antibiotics are so high, Spellberg and Lipsky felt absolute bone levels likely exceeded target MICs of etiologic bacteria in most cases.

In contrast, because serum levels of oral b-lactam agents are less than 10 percent of those of parenteral agents, oral dosing is unlikely to achieve adequate bone levels.⁹ When it comes to parenteral administration of oral b-lactam agents, bone penetration is higher in infected than in uninfected bone^.9 The first-generation cephalosporin cefazolin given every eight hours can be a preferred IV antibiotic for MSSA osteomyelitis and may have a better safety profile with lower rates of neutropenia.¹⁰ Most streptococcal osteomyelitis involves b-hemolytic streptococci, especially Streptococcus agalactiae (group B) and Streptococcus pyogenes (group A). These organisms remain highly susceptible to intravenous penicillin at doses of 12 to 24 million units/day. While this drug dosing is the most optimal choice, doing of other intravenous penicillins, cephalosporins and carbapenems can also be effective.^4,11 When treating vancomycin-resistant Enterococci (VRE), intravenous ampicillin is the drug of choice.

Patient adherence is always a concern, especially with bone infection in the diabetic foot population. Home IV antibiotics administered by a home health care agency help ensure monitoring of medication and treatment adherence to increase the likelihood of a positive outcome. Home health care IV antibiotic administration also allows easy access to IV antibiotic treatment. This access also has reduced costs in comparison to inpatient or facility long-term IV antibiotic treatment, providing an alternative to oral antibiotics when such monitoring would not be as available. Once-daily administered drugs, such as ceftriaxone, are preferable, especially for outpatient therapy.¹² The cost of IV antibiotics at home for six weeks can range from $3,500 to $10,000, which is much more cost-effective than a course of inpatient antibiotic treatment for the same time period or more costly surgical procedures such as an amputation.¹³

In Conclusion

Intravenous antibiotics are preferable in treating osteomyelitis. Intravenous antibiotic therapy is the standard in treating acute pediatric Cierny-Mader stage 1 osteomyelitis and is beneficial in treating adult Cierny-Mader stage 1 osteomyelitis. Intravenous antibiotics are a superior choice to oral antibiotic therapy in treating chronic Cierny-Mader stages 2, 3 and 4 osteomyelitis when considering local factors such as biofilm, MIC antibiotic levels and avascular bone antibiotic penetration.

A further advantage of IV antibiotics in treating chronic osteomyelitis stages 2, 3 and 4 is the ability to overcome systemic pathology that can negatively effect osteomyelitis treatment, thus improving treatment outcomes.

Dr. Karr is the founder and Medical Director of the Osteomyelitis Center of Central Florida– Treatment of the Lower Leg. He is the Medical Director of the Central Florida Limb Salvage Alliance.

References
1.    Cierny GC, III, Mader JT, Penninck JJ. A clinical staging system for adult osteomyelitis. Clin Orthop Relat Res. 2003;414:7–24
2.    Raveh D, Rabinowitz B, Breuer GS, et al. Risk factors for Clostridium difficile toxin-positive nosocomial diarrhoea. Int J Antimicrob Agents. 2006; 28(3):231–7.
3.    Ezra E, Cohen N, Segev E, et al. Primary subacute epiphyseal osteomyelitis: Role of conservative treatment. J Pediatr Orthop. 2002;22(3):333–337.
4.    Nelson JD. A critical review of the role of oral antibiotics in the man- agement of hematogenous osteomyelitis. In: Remington RS, Swartz MN (eds.). Clinical Topics in Infectious Disease, Volume 4. McGraw-Hill, New York, 1996, pp. 64-74.
5.    Entry LO. Oral antimicrobial therapy for osteomyelitis. Ann Intern Med. 1991;114:986-7.
6.    Lew DP, Waldvogel FA. Quinolones and osteomyelitis: state-of-the-art. Drugs. 1995;49(Suppl 2):100-11.
7.    Lazzarini L, Lipsky BA, Mader JT. Antibiotic treatment of osteomyelitis: what have we learned from 30 years of clinical trials? Int J Infect Dis. 2005;9(3):127–138.
8.    Lew DP, Waldvogel FA. Osteomyelitis. Lancet. 2004;364: 369–379.
9.    Spellberg B, Lipsky BA. Systemic antibiotic therapy for chronic osteomyelitis in adults. Clin Infect Dis. 2012; 54(3):393–407.
10.    Tice AD, Hoaglund PA, Shoultz DA. Risk factors and 9 treatment outcomes in osteomyelitis. J Antimicrob Chemother. 2003;51(5):1261–1268
11.    Mader JT, Norden C, Nelson JD, Calandra GB. Evaluation of new antiinfective drugs for the treatment of osteomyelitis in adults. Clin Infect Dis. 1992;15(Suppl 1):S155–S161.
12.    Lazzarini L, Lipsky BA, Mader JT. Antibiotic treatment of osteomyelitis: what have we learned form 30 years of clinical trials? Int J Infect Diseases. 2005; 9(3):127–38.
13.    Gilbert DN, Dworkin RJ, Raber SR, Leggett JE. Outpatient parenteral antimicrobial-drug therapy. N Engl J Med. 1997;337(12):829-38.