The potential role of newer gram-positive antibiotics in the setting of osteomyelitis of adults

Authors


Correspondence: Travis W. Linneman, Clinical Pharmacy Specialist – Internal Medicine, St. Louis VA Medical Center – John Cochran Division, Assistant Professor of Pharmacy Practice, St. Louis College of Pharmacy, 915 N. Grand Avenue, St. Louis, MO 63106, USA. Tel.: 314-652-4100, 5-3627; fax: 314.289.7007; e-mail: Travis.Linneman@VA.gov

Summary

What is known and Objective

To summarize available literature regarding the potential role of linezolid, daptomycin, telavancin, tigecycline and ceftaroline for the treatment of osteomyelitis caused by resistant gram-positive organisms.

Methods

Literature was obtained through PubMed searches from January 1980 to October 2011 using the terms osteomyelitis, bone, linezolid, daptomycin, telavancin, tigecycline and ceftaroline. Results were limited to those published in English. All articles identified from the PubMed searches were evaluated. Any published data related to bone penetration (animal or human) or clinical outcomes in adult osteomyelitis of these agents were included in the review.

Results and Discussion

Animal models report bone concentrations of 2·3 mcg/dL (vertebral) for linezolid, 0·45 mcg/mL (tibiae) for daptomycin, 0·78 mcg/mL (tibiae) for tigecycline and 0·27 mcg/mL (tibiae) for telavancin; no data are available for ceftaroline. Human studies demonstrate bone concentrations of 4·6, 17·0 and 3·9 mcg/mL (sternal, metatarsal and cancellous bone respectively) for linezolid, 4·7 mcg/mL (metatarsal) for daptomycin and 0·078 mcg/mL (unspecified) for tigecycline; no data are available for telavancin and ceftaroline. Retrospective cohort data, and prospective/retrospective case series support the use of linezolid in this setting; however, side-effects may limit use. Retrospective and prospective cohort data support daptomycin use. A retrospective case series is available supporting the use of telavancin. No data are available supporting clinical effectiveness for ceftaroline or tigecycline in the setting of osteomyelitis.

What is New and Conclusion

Limited data are available evaluating the safety and efficacy of these agents in osteomyelitis in adults. Daptomycin and telavancin may be potential alternatives or second-line agents to vancomycin in selected patients. Linezolid, because of an increase in clinically important ADRs with prolonged use, should be reserved as a second- or third-line agent. Due to a lack of clinical data and poor bone penetration, along with concerns regarding outcomes in severe infections, tigecycline's potential is limited. Little data exist regarding ceftaroline use in osteomyelitis.

What is Known and Objective

Osteomyelitis in adults is a complicated and challenging disease to treat. It is associated with a high cost of care, requires extended treatment regimens, and can often result in profound morbidity including amputation, and when severe could lead to mortality.[1] Osteomyelitis can be classified based on mechanism of inoculation (direct, haematogenous, contiguous), duration of infection (acute vs. chronic) or stages based on extent of bone structures involved.[2, 3] Multi-modal therapy may be indicated with surgery/debridement along with antibiotic therapy targeting suspected organisms. Gram-positive organisms remain the predominant causative pathogens in osteomyelitis of adults.[4, 5]

The emergence, and in some cases high prevalence, of resistance in these pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococcus (VRE) and vancomycin-intermediate S. aureus (VISA) present new challenges in antibiotic therapy for some cases of osteomyelitis.[1, 3]

Ideal agents for treatment of resistant gram-positive pathogens in osteomyelitis would have activity against these pathogens, would achieve adequate bone concentrations to meet pharmacokinetic/pharmacodynamic targets for bacterial cell death and eradication of infection; have a safety, tolerability and monitoring profile to allow it to be used for 4–6 weeks; and preferably have documented success in treating this condition in humans. Other considerations would include ease of dosing, available formulations (intravenous vs. oral) and need for continuing monitoring and/or dosing adjustments.

Vancomycin has long been utilized for osteomyelitis confirmed or suspected to be secondary to resistant gram-positive organisms. Its long history of use, available clinical data and relatively easy-to-use pharmacokinetic dosing nomograms and models are some of vancomycin's advantages.[1, 3, 6, 7] Garazzino et al. demonstrated cancellous bone concentrations and AUC/MIC ratios similar to plasma.[8] However, vancomycin use also has complications and challenges, including an elevated risk of acute renal failure with higher trough concentrations.[1, 6] Even with appropriate dose and duration of vancomycin therapy, osteomyelitis recurrence rates of 30–50% have been reported after 12 months.[9] The emergence of VRE and VISA strains, along with suboptimal effectiveness rates and challenges in dosing and tolerability of vancomycin, necessitate evaluation of alternative agents for use in osteomyelitis secondary to resistant gram-positive organisms.

Recently, several new antibiotics, including linezolid, daptomycin, telavancin, tigecyline and ceftaroline, with activity against resistant gram-positive bacteria, have been approved by the Food and Drug Administration (FDA). Table 1 contains a summary of the mechanism of action/class, bacteriostatic or bacteriocidal classification, approved spectrum of gram-positive activity, and common serious adverse events for these agents and vancomycin. Specific pharmacodynamic goals, bone penetration data, dosing adjustment requirements and types of clinical evidence supporting specific agent use in osteomyelitis can be found in Table 2.

Table 1. Pharmacology, FDA approved antimicrobial spectra and significant adverse reactions
Agent (class)Mechanism of actionBactericidal or bacteriostaticApproved gram-positive spectrumPotential significant adverse reactions
  1. a

    MSSA, methicillin-susceptible Staphylococcus aureus.

  2. b

    MRSA, methicillin-resistant Staphylococcus aureus.

  3. c

    VSE, vancomycin-susceptible Enterococcus.

  4. d

    VRE, vancomycin-resistant Enterococcus.

  5. e

    CK, creatine phosphokinase.

  6. f

    PBP, penicillin-binding protein.

Vancomycin[7] (Glycopeptide)Inhibits bacterial cell wall synthesis by blocking glycopeptide polymerization through binding to D-alanyl D-alanine portion of the cell wall precursorBactericidalMSSAa, MRSAb, VSEc, streptococciNephrotoxicity, ototoxicity, thrombocytopenia
Linezolid[10] (oxazolidinone)Inhibits protein synthesis by binding to a site on the 23S ribosomal RNA of the 50S subunit and preventing the formation of a functional 70S initiation complex

Bacteriostatic: staphylococci and enterococci

Bactericidal: streptococci

MSSAa, MRSAb, VSEc, VREd, streptococciThrombocytopenia, anaemia, optic neuropathy, peripheral neuropathy
Daptomycin[28, 38] (cyclic lipopeptide)Binds to components of the cell membrane causing rapid depolarizationBactericidalMSSAa, MRSAb, VSEc, streptococciCKe elevation, eosinophilic pneumonia
Tigecycline[40] (glycylcycline)Binds to the 30S ribosomal subunit, thereby inhibiting protein synthesisBacteriostaticMSSAa, MRSAb, VSEc, streptococciNausea, vomiting, hepatic failure, pancreatitis
Telavancin[49, 50, 56, 64] (lipoglycopeptide)Inhibits bacterial cell wall synthesis by blocking glycopeptide polymerization through binding to D-alanyl D-alanine portion of the cell wall precursor; also disrupts membrane potential and changes cell permeability resulting in cell lysisBactericidalMSSAa, MRSAb, VSEc, streptococciNephrotoxicity, QTc prolongation, taste disturbances, nausea, vomiting
Ceftaroline[59, 61] (cephalosporin)Inhibits cell wall synthesis by binding to PBPfs 1–3BactericidalMSSAa, MRSAb, streptococciNausea, vomiting, diarrhoea, crystalluria, elevated transaminases
Table 2. Pharmacodynamic goals, bone penetration and dosing considerations
AgentPharmacodynamic goalBone penetration data Renal adjustment necessary? (Y or N)Hepatic adjustment necessary? (Y or N)Available clinical Evidence supporting use
Animal dataHuman data
  1. a

    > MIC, time of free drug above minimum inhibitory concentration.

  2. b

    24 h AUC/MIC, 24 h area-under-the-curve to minimum inhibitory concentration ratio.

  3. c

    Strep, streptococci.

  4. d

    Staph, staphylococci.

  5. e

    EC, enterococci.

 
Linezolid> MICa ≥ 40%[65]2·3 mcg/mL (vertebral bone) [13]4·6 mcg/mL (sternal bone)[14]17·0 mcg/mL (metatarsal bone)[15]3·9 mcg/mL (cancellous bone) [16]NNRetrospective cohort[11, 19, 22, 23, 27]Prospective cohort[21, 25, 26]Retrospective Case series[24]
Daptomycin

24 h AUC/MIC[28, 29, 66, 67]b:

Strepc: 13·5–93 mcg*h/ml

Staphd: 294–375 mcg*h/ml

ECe: 8·2–67 mcg*h/ml

0·45 mcg/mL (tibiae)[34] 4·7 mcg/mL (metatarsal bone) [31]YNRetrospective cohort[67]Prospective cohort[38]
Tigecycline

24 h AUC/MIC[43, 68]b:

6·96–17·9 mcg*h/ml

0·78 mcg/mL (tibiae) [47]0·078 mcg/mL (unspecified) [48]NY
Telavancin

24 h AUC/MIC[69]b:

≥ 50 mcg*h/ml

0·27 mcg/g (tibiae) [57]YNRetrospective case series[58]
Ceftaroline> MIC[70]a ≥ 92%YN

Methods

To assess the potential role of these antibiotics in the setting of osteomyelitis secondary to resistant gram-positive bacteria, we reviewed current published evidence of these agents from a search of PubMed (1980 – October 2011). Search terms included the specific agents along with ‘bone’ or ‘osteomyelitis,’ and publications evaluated were limited to those published in English. Identified literature was also evaluated for references pertinent to this review. We include information regarding agents’ bone penetration, bone infection eradication and outcomes data, and tolerability profiles from both animal and human studies.

Results and Discussion

Linezolid

Linezolid is broadly active against gram-positive pathogens, including MRSA and VRE, and is currently approved by the FDA for the treatment of nosocomial and community-acquired pneumonia, and complicated skin and skin structure infections (cSSSI).[10] An oral formulation of linezolid is available with 100% bioavailability and subsequent peak serum concentrations achieved 1–2 h after administration.[10]

Although linezolid is generally well tolerated, serious adverse events increase in prevalence with prolonged use. Therapy beyond 28 days is not recommended per the package insert. The most common serious adverse events seen with extended linezolid therapy include thrombocytopenia, anaemia, optic neuritis and peripheral neuropathy.[10] Although haematological abnormalities are reversible, 75% of patients with peripheral neuropathy report persistent symptoms for more than 2 years.[11] In addition, linezolid is a weak monoamine oxidase inhibitor (MAOI) and should not be given with selective serotonin reuptake inhibitors (SSRIs), other MAOIs, or serotonergic medications due to the potential risk of developing serotonin syndrome.[12]

Linezolid bone penetration has been studied in human and animal models. Komatsu et al. found vertebral bone concentration in rabbits to be 10% of plasma concentrations after a single infusion. These results suggest that the MIC was not high enough to be active against most gram-positive organisms.[13] In contrast, Metallidis et al. found linezolid concentration in human sternal bone to be 44% and 32% of plasma concentrations after a single dose of linezolid at 2 and 5 h respectively.[14] Traunmüller et al. observed higher concentrations in metatarsal bone in humans. The free drug area under the curve (AUC) in metatarsal bone to plasma ratio was 1·09 once linezolid reached steady state. The authors stated these results suggested linezolid concentrations would be sufficient to treat diabetic foot infections and osteomyelitis.[15] Kutscha-Lissberg et al. studied linezolid bone and serum concentrations in 13 patients with MRSA or methicillin-resistant Staphylococcus epidermidis (MRSE) bone infection and determined mean cancellous bone concentration to be 3·9 mcg/mL.[16] In addition, other studies investigating linezolid's penetration into human hip and patella found concentrations higher than MIC's for susceptible gram-positive organisms.[17, 18]

Many case-series report the use of linezolid in the treatment of osteomyelitis and joint infections. Most commonly, these reports outline results of linezolid as salvage therapy for patients who have failed previous antibiotics or refuse intravenous (IV) therapy. Overall, linezolid has demonstrated high success rates in these reports, with a combined cure rate of 83·4% (286/343).[11, 19-27] These results suggest that linezolid may be an effective option for osteomyelitis salvage therapy, or for patients refusing or unable to receive IV therapy. Despite the mixed evidence regarding bone penetration, available clinical evidence appears to suggest linezolid has a potential, but restricted, role in the treatment of osteomyelitis caused by gram-positive organisms. The risk of adverse effects such as anaemia, thrombocytopenia and peripheral neuropathy increase with long-term therapy and may limit linezolid's potential use in osteomyelitis treatment.

Daptomycin

Daptomycin is active against gram-positive pathogens, including MRSA and VRE, and is currently approved by the FDA for treatment of cSSSIs and S. aureus bloodstream infections, including those due to right-sided endocarditis.[28] Nearly, 80% of a total dose may be recovered in the urine with no metabolism by cytochrome P450 or other hepatic enzymes and it exhibits linear pharmacokinetics at doses up to 12 mg/kg.[28, 29]

Daptomycin appears to be relatively well tolerated, with elevation of creatine phosphokinase (CPK) and, in some cases, myopathies being the most commonly encountered adverse effects. Early studies conducted by Cubist Pharmaceuticals in beagle puppies indicated that frequency of administration (administering the drug multiple times per day), rather than higher individual doses, was most associated with CPK elevation.[30] Analysis of a small subgroup of patients from a larger study evaluating daptomycin's efficacy in patients with S. aureus bacteraemia determined, similar to the beagle studies, daptomycin minimum serum concentrations (Cmin) were the most significant predictor of CPK elevation.[31, 32] A review of a post-marketing, manufacturer maintained, retrospective database of daptomycin use [the Cubicin Outcomes Registry and Experience (CORE) database] in 2008, including 6 patients being treated for osteomyelitis, revealed that of patients who had received at least one and up to 90 days (median 6 days) of therapy with daptomycin dosing ≥ 8mg/kg only 6% (7 of 108) had an elevation in CPK, and there were no reports of myopathies.[33]

In an early animal model, daptomycin (4 mg/kg q12h) was compared with vancomycin (40 mg/kg q6h) for the treatment of MRSA osteomyelitis in 53 rabbits. After a single subcutaneous injection, significantly higher concentrations of daptomycin and vancomycin were observed in infected bone than in uninfected bone, with daptomycin being undetectable in uninfected bone. Average vancomycin concentrations in infected bone reached levels slightly less than 30 mcg/mL, whereas daptomycin concentrations were less than 1 mcg/mL (P not reported). At the time of sacrifice, 41% of the tibiae in the daptomycin treated group and 39% in the vancomycin group were negative for MRSA (P = NS). This animal model demonstrated that bacterial clearance rates were not significantly different from treatment with vancomycin, even though less daptomycin penetrated the bone. A major limitation of this evaluation is that the dosing used does not reflect current recommendations or clinical practice, and would appear to favour vancomycin.[34]

A more recent study conducted in 10 patients with diabetic foot infections was designed to measure daptomycin concentrations in healthy subcutaneous tissue, inflamed tissue and infected bone. After surgical intervention, patients were treated with daptomycin dosed at 6 mg/kg daily. At steady state (4–5 days after daptomycin initiation), the average serum maximum concentration (Cmax) was 72·9 mcg/mL, free serum concentration was 6·3 mcg/mL and concentration in metatarsal bone was 4·7 mcg/mL. These authors demonstrated that daptomycin, at approved doses, rapidly equilibrated between plasma and bone. In addition, the concentrations exceeded the MIC90s for all relevant gram-positive pathogens.[31] Further bone penetration and pharmcodynamic/pharmacokinetic target achievement data may soon be available from a study listed on the United States National Institutes of Health registry (NCT01306825) currently recruiting to evaluate the clinical bone penetration (intra-osseous) of daptomycin in the setting of osteomyelitis.

Clinical evidence with daptomycin in the treatment of osteomyelitis is sparse. Lalani et al. reported results from a subgroup of patients from the daptomycin in S. aureus bacteraemia study who had a baseline diagnosis of osteoarticular infection. These patients were treated with 6 mg/kg of daptomycin (n = 21), or the comparator agent (vancomycin or an anti-staphylococcal penicillin, n = 11) for at least 4 weeks. Six weeks after the end of therapy, a successful outcome was documented in 67% (14/21) of patients treated with daptomycin and 55% (6/11) of those in the comparator group (95% CI: −23·5–47·8%).[32, 35] A recently published report described 2 cases of MRSA infection in the spine, each treated initially with vancomycin but ultimately switched to daptomycin (the first because of low troughs and the second because of declining renal function) and oral rifampin; patient 1 was treated with 8 mg/kg daily and patient 2 with 6 mg/kg daily of daptomycin. After 6 weeks of therapy, both had documented infection clearance 6–7 months post-treatment; neither experienced any adverse reactions related to daptomycin while receiving treatment.[36]

Most published data describing daptomycin's use in osteomyelitis come from the CORE database.[37] In a 2004 review of the database, 67 patients were diagnosed with osteomyelitis and had clinical outcome data available. The mean daptomycin starting dose was 5·3 mg/kg and patients were treated for a median of 35 days (range 3–546 days). Clinical cure was documented in 55% (37/67), 39% (26/67) improved on therapy and 6% (4/67) failed therapy. Thirty of the 67 patients (45%) were infected with MRSA and 90% (27/30) achieved clinical cure. Dosing appeared to be related to outcomes, as patients receiving ≥ 4 mg/kg (n = 17) were significantly more likely to be clinically cured than those receiving < 4 mg/kg (n = 50) (88 vs. 65%; P = 0·013).[38] Data from the European CORE (Eu-CORE) database, showed clinical success was achieved in 79·7% (53/67) of patients receiving daptomycin for osteomyelitis. Sixty-nine per cent of patients received 6 mg/kg daily, but no information regarding clinical success by dosing strategy was available.[39]

Even though in early animal models daptomycin appeared to penetrate bone to a lesser extent than vancomycin, available clinical evidence does not support vancomycin superiority when compared with daptomycin. Given that daptomycin is a concentration-dependent bactericidal agent, and taking into account the evidence regarding dosing gleaned from review of the CORE database, dosing for osteomyelitis must be carefully considered and should likely exceed 6 mg/kg. Available clinical evidence and the safety profile of daptomycin suggest it has a place in the optimal management of gram-positive osteomyelitis.

Tigecycline

Tigecycline demonstrates in vitro activity against many gram-positive pathogens, including MRSA, Enterococcus (VSE and VRE), and, unlike linezolid, daptomycin or vancomycin, has activity against some gram-negatives and anaerobes. Tigecycline is currently FDA approved for the treatment of cSSSIs, complicated intraabdominal infections and community-acquired bacterial pneumonia.[40, 41]

Tigecycline has a large volume of distribution (7–10 L/kg) and is extensively distributed into tissues, resulting in low plasma concentrations. It is primarily metabolized in the liver by glucuronidation, and less than 30% of the drug is excreted unchanged in the urine and faeces.[41, 42] Clinically significant organ toxicity has not been observed with tigecycline use during clinical trials.[43] The most common side-effects are nausea (43·2%), vomiting (26·7%) and diarrhoea (12·7%). Nausea and vomiting are dose-limited and are not diminished by decreasing the rate of the infusion. Older adults (age > 75) and men have reported less nausea than women. Other known adverse events include elevated transaminases, total bilirubin, amylase, prolonged prothrombin time, vertigo, pancreatitis and abdominal pain.[40, 41, 44-46]

Data regarding the bone penetration and clinical outcomes of tigecycline when used in the treatment of osteomyelitis are limited. In a rabbit model of S. aureus osteomyelitis, Yin et al. demonstrated higher bone penetration into infected bones (0·78 ± 0·01 mcg/mL) than non-infected bones (0·49 ± 0·01 mcg/mL). In these rabbits, tigecycline plus oral rifampicin showed 100% infection clearance, tigecycline alone demonstrated 90% infection clearance, vancomycin plus oral rifampicin was associated with 90% infection clearance and vancomycin alone cleared 81·8% of infections.[47] After evaluating human bone concentrations, Rodvold et al. concluded the results were lower than anticipated (average site-to-serum ratio 0·41) and that these results were inconsistent with previous animal studies (average site-to-serum ratio ranging from 4·1 to 45·6).[48]

Given the lack of clinical data and mixed nature of bone penetration data, current evidence does not support a role for tigecycline for the treatment of osteomyelitis caused by gram-positive pathogens. In addition, an FDA warning was released in 2010 regarding increased risk of mortality associated with tigecycline use in serious infections. Yahav et al. concluded that the increase in mortality could likely be explained by decreased clinical and microbiological efficacy combined with higher rates of superinfections.[46] It remains unclear how these effects might relate to the treatment of osteomyelitis; however, the authors suggested that clinicians should avoid tigecycline monotherapy in the treatment of severe infections and reserve it as a therapy of last-resort. Because of these findings, more studies are needed to evaluate the use of tigecycline as monotherapy in osteomyelitis before more definitive conclusions can be made about its place in therapy.

Telavancin

Telavancin has a spectrum of activity similar to that of vancomycin, but is characterized by an MIC that is generally 2–8 times lower than vancomycin's for most organisms tested.[49, 50] It is active against gram-positive organisms such as S. aureus, including MRSA, most strains of VISA, VSE, non-VanA-type VRE and streptococci. Currently, it is approved by the FDA for treatment of cSSSI.[51-55]

Telavancin has a relatively low volume of distribution (130–145 mL/kg), but still achieves effective tissue, cellular and lung concentrations. Seventy to 80% of a dose of telavancin is excreted renally, with 60–70% recovered unchanged in the urine.[56] The most commonly reported adverse events with telavancin included taste disturbances, nausea, vomiting and foamy urine. More serious events include nephrotoxicity, which may occur with greater frequency than with vancomycin and more often in patients with baseline renal insufficiency, infusion-related reactions and prolongation of the corrected QT (QTc) interval.50,56. Concomitant use with other QTc prolonging medications is strongly cautioned. Of additional concern, in patients with cSSSI, telavancin has been noted to have poor outcomes more often in patient with decreased renal function.[56]

Little published evidence exists regarding telavancin's ability to penetrate bone, but in a rabbit model of MRSA osteomyelitis, telavancin achieved concentrations only slightly greater than 0·25 mcg/g in infected bone. Although bone levels appeared low, infection clearance was documented in 80% of animals. Telavancin appeared to produce low mean bone to serum ratios in infected and uninfected bones (0·9% and 0·8% respectively), but was still able to attain high enough concentrations to be effective in infections of the bone.[57]

Telavancin has yet to be studied in clinical trials for the treatment of gram-positive osteomyelitis in humans. However, a recently published report describes four cases of MRSA osteomyelitis (3 cases of vertebral, 1 case of hip; vancomycin MIC 1–2).[58] In each case, the patient failed vancomycin therapy, but was ultimately successfully treated with telavancin and surgical intervention. Two of the cases of vertebral osteomyelitis and the case of hip infection were initially treated with vancomycin, daptomycin, linezolid or some combination for 2–5 weeks before lack of improvement and/or clinical worsening resulted in a change to telavancin. Each patient was treated with 10 mg/kg of telavancin daily for 6–10 weeks and achieved improvement and/or resolution of signs and symptoms; no recurrence was documented 4–7 months after completion of therapy. The third case of vertebral osteomyelitis had been previously treated with three separate courses of vancomycin prior to discovery of a vertebral abscess and osteomyelitis. The patient improved clinically after 4 weeks of telavancin, but therapy had to be discontinued after a sustained elevation in serum creatinine and eosinophiluria.[58]

Telavancin has been shown to effectively clear infection in a rabbit model of MRSA osteomyelitis, with results comparable to that of vancomycin and linezolid.[57] A recent case-series reports telavancin being effectively utilized in four patients with MRSA osteomyelitis following failure of standard therapy.[58] Current limitations include a lack of clinical trial and experiential data on telavancin's use in this setting and potential for significant renal injury. Telavancin appears to have the potential to provide valuable benefits in this setting, but further data will be required before this indication can be routinely supported.

Ceftaroline

Ceftaroline, a novel broad-spectrum cephalosporin, is similar to other antimicrobials of the cephalosporin class, binding to penicillin-binding proteins (PBPs) and thereby inhibiting bacterial cell wall synthesis. However, ceftaroline also displays an especially high affinity for PBP2a, which is associated with methicillin-resistance. This unique binding site expands ceftaroline's coverage to include MRSA, while also providing activity against MSSA, VISA, vancomycin-resistant S. aureus (VRSA) and coagulase-negative staphylococcal species (CNS).[59-61] Ceftaroline is currently approved for the treatment of cSSSI and community-acquired bacterial pneumonia.[59]

Ceftaroline is generally well tolerated, with the most common adverse events being gastrointestinal (nausea, vomiting, diarrhoea, constipation), headache, insomnia, pruritus and rash. Abnormalities in laboratory parameters were infrequent and included crystals in urine (9·0%), elevated CPK (7·5%), alanine aminotransferase (6·0%) and aspartate aminotransferase (6·0%).[61, 62]

Given its recent introduction into the market, little is known about ceftaroline's role in the treatment of osteomyelitis. Jacqueline et al. compared ceftaroline, vancomycin and linezolid in a rabbit model of MRSA osteomyelitis. The knees and femurs of the rabbits were injected with one of two strains of MRSA, one glycopeptide susceptible and one glycopeptide intermediate. Each animal was randomized to be a control, receive ceftaroline 10 mg/kg q12h (equivalent to the human dose of 600 mg q12h), linezolid 10 mg/kg q12h (equivalent to the human dose of 600 mg q12h) or vancomycin (equivalent to the human dose of 30 mg/kg daily). After 4 days of therapy in the glycopeptide-susceptible group, ceftaroline induced significantly lower bacterial titres in joint fluid, bone marrow and bone when compared with vancomycin, and significantly lower titres in joint fluid when compared with linezolid. In the rabbits infected with the glycopeptide-intermediate strain, ceftaroline demonstrated significantly lower bacterial titres in all samples when compared with vancomycin, but was not statistically superior to linezolid in any samples. Ceftaroline demonstrated good bone penetration and was more effective than vancomycin, after a short course of therapy, at decreasing bacterial concentrations within bone tissue.[63]

Little evidence is available to help determine the potential role of ceftaroline in the treatment of osteomyelitis. While no clinical evidence exists at this time to support its use in the treatment of osteomyelitis, its spectrum of activity, relative safety and the fact that it comes from a class of agents long used to treat osteomyelitis make it an intriguing option for further study. The early animal data seem promising, and it appears ceftaroline could have a role in the treatment of MRSA or VISA osteomyelitis.

What is New and Conclusions

There is a relative paucity of data to support the use of newer gram-positive agents in the setting of osteomyelitis. Bone penetration data are available for most of these agents (Fig. 1), but the data do not always correlate well with clinical outcomes. Despite the challenges in its use and the emergence of strains with resistant or intermediate susceptibility profiles, vancomycin likely remains first-line therapy for this condition.

Figure 1.

Percentage of Cmax serum drug concentration recovered in bone aUninfected human bone bInfected human bone cMetatarsal bone dTibia cortical bone eInfected rabbit bone *Tigecycline concentrations were measured 4 times during the 24-h period after the infusion, and, at 24 h post-infusion, tigecycline's bone concentration was actually actually 95% above the concurrent plasma concentration; however, the plasma concentration at that time was only 0·057 mcg/mL.

Available data support the use of daptomycin and telavancin as potential alternatives or second-line agents to vancomycin in selected patients. Although published human data are unavailable, the history of cephalosporin use in the setting of osteomyelitis and the available data demonstrating activity against clinically important resistant gram-positive organisms support the investigation of ceftaroline as a potential agent for osteomyelitis.

A lack of clinical data, variable bone penetration data, along with recent concerns regarding safety and outcomes in severe infections, relegates tigecycline to salvage or last-resort situations. Despite evidence demonstrating its effectiveness, because of its adverse event profile, especially with prolonged use, linezolid should be reserved as a last-resort medication for use in specific situations in which alternative therapies cannot be utilized. All of the newer therapies will require close monitoring of the patient for safety and effectiveness.

Conflict of Interest

Dr. Moenster is a member of the Pfizer, Inc. Speakers Bureau for Tygacil® and the Forest Pharmaceuticals Speakers Bureau for Teflaro® – he reports that these affiliations in no way biased or affected the development of this review. None of the other authors report any conflict of interest.

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