A novel treatment option for MRSA pneumonia: ceftaroline fosamil-yielding new hope in the fight against a persistent infection

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) hospital-acquired pneumonia (HAP) and healthcare-associated pneumonia (HCAP) patients treated with current antibiotic therapies have exhibited poor outcomes, increased hospital length of stay, and higher costs of care. The optimal management of these infections is undetermined; thus, it is critical to look at ways to improve outcomes in these patients. There is insufficient data on clinical efficacy in patients with MRSA HAP or HCAP infection treated with ceftaroline-fosamil. In a recent pilot study, nearly 90% of patients treated with ceftaroline-fosamil survived, despite the difficulties associated with administrating bactericidal antimicrobial therapy for this increasingly resistant pathogen. These data suggest a possible benefit in the use of ceftaroline-fosamil for MRSA pneumonia. Presently, we have identified cases over a two-year period treated with ceftaroline-fosamil, and will conduct a comparative analysis to controls (those treated with vancomycin and/or cefepime, and linezolid) to determine optimal therapeutic agents; these findings will have important implications for control of further spread of infection, recurrence, readmission, and mortality attributable to MRSA HAP and HCAP.

Keywords::

• antimicrobials
• ceftaroline fosamil
• MRSA
• pneumonia
• vancomycin

Methicillin-resistant Staphylococcus aureus (MRSA) remains a major cause of nosocomial pneumonia and has high rates of incidence and prevalence, and is a leading cause (20–40%) of hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia [1–3]. The prevalence of S. aureus causing community acquired pneumonia along with risks for acquisition is uncertain. The emergence of new strains, rise in antibiotic resistance and frequently documented outbreaks of severe pneumonia among healthy persons have complicated the management of MRSA pneumonia [1,4,5]. Additionally, MRSA pneumonia patients treated with current antibiotic therapies have exhibited poor outcomes, increased hospital length of stay and readmissions, and pose a burden on the health system with high costs for care [6]. Respiratory complications, ICU admissions and death are all consequences of untreated MRSA pneumonia infection. The mortality for treated MRSA pneumonia is high, with mortality rates of up to 32.3% from earlier studies [7].

In a study from February 2012, there were no clinical efficacy data in MRSA pneumonia-infected patients treated with ceftaroline [5]. Ceftaroline fosamil (CPT-F) is a recently FDA-approved broad-spectrum cephalosporin β-lactam antibiotic with activity against MRSA and has been further investigated by our team at a tertiary care center in Detroit, MI, USA, yielding favorable results. CPT-F is approved by the US FDA for the treatment of MRSA-related acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia.

Current antibiotic regimens

The most commonly used agents in the treatment paradigm of MRSA pneumonia include vancomycin and linezolid. Vancomycin is modest itself in its benefits due to increasing reports of failures when minimum inhibitory concentration (MICs) to vancomycin are higher than >2.0 mg/l or infection is due to heteroresistant strains. Additionally, vancomycin dosing is difficult in achieving the recommended target AUC/MIC, and a subsequent successful clinical outcome due to adverse effects and toxicity- primarily renal toxicity. Nephrotoxicity in vancomycin patients treated more than doubled from 9.4 to 19.6% when recommended trough levels of 15–20 ug/ml were reached, causing decreases in renal clearance from a 2008 study [8]. In a meta-analysis of eight randomized control trials of linezolid versus vancomycin for MRSA pneumonia, Walkey et al. found that linezolid was not superior to glycopeptide antibiotics for

• Clinical success (linezolid vs glycopeptide [p = 0.28])

• Microbiological success (p = 0.12)

• 28-day mortality (p = 0.47)

Additionally, the risk for adverse events was not different between the two antibiotic classes (p = 0.48) [9]. Conversely, in a recent prospective clinical trial, Wunderink et al. documented clinical superiority of linezolid over vancomycin in the treatment of MRSA pneumonia infection, where vancomycin was dose-optimized and 58% of linezolid-treated patients achieved clinical success versus 47% of vancomycin-treated patients (p =.042), and nephrotoxicity occurred more frequently with vancomycin (18.2% vs linezolid, 8.4%) [10]. Both studies presented significant findings but had limitations as well, thus superiority of linezolid over vancomycin in the treatment of MRSA pneumonia remains debatable.

Efficacy of CPT-F as an alternative

To assess the epidemiology and effectiveness based on clinical outcomes in patients treated with CPT-F, a single-center retrospective cohort study was conducted in which our infectious diseases team at Henry Ford Hospital identified 40 consecutive cases of MRSA pneumonia treated with CPT-F from July 2011 to August 2013. The primary outcome of interest was 28-day all-cause mortality; secondary outcomes included 14-day clinical response identified as success (cure or improvement of symptoms) or failure, early response to treatment within first 72 h from admission, hospital LOS and treatment failure defined as persistence and/or deterioration of signs and symptoms of pneumonia infection. Twenty-seven cases were HCAP and thirteen cases were HAP. Mean age (± SD) was 58.8 ± 16.1 years, 50% female, 46% Caucasian and mean APACHE II score of 15 ± 6.8. Vancomycin MIC90 = 1.5 µg/ml by E-test, and mean hospital LOS was 27.7 days. Twenty percent of cases (n = 8) were hospitalized for ≥5 days before antibiotic therapy for MRSA pneumonia was started. Forty-six percent of HAP cases were hospitalized for two or more days within prior 90 days before antibiotics for HAP were started – current hospitalization excluded. Additionally, one case was clinically diagnosed with bronchiectasis, but completed CPT-F therapy successfully. Sixty percent (n = 24) of cases were ICU patients, and 25% had diabetes. Fifty-three percent of patients were routinely discharged home. Seven cases (17.5%) demonstrated an early clinical response to treatment with CPT-F within first 72 h from admission on the basis of absence of the following symptoms: fever (≥38^®C), leukocytosis, O₂ requirement, cough and chest pain. If two of the three symptoms (fever (≥38°C), leukocytosis and/or O₂ requirement) did not persist within the first 72 h, the patient was considered to have exhibited an early response to treatment. Overall 28-day mortality was observed in 10% (n = 4). Of the 22 patients who had an outcome for hospital discharge before day 14 available, clinical success/cure was seen in 91% (n = 20) of cases, one patient was considered a failure and one expired. Of the four patients that died, three had debilitating comorbid conditions and an overall APACHE II score greater than 18. Additionally, half of the 40 cases (n = 20) were considered switch patients as they were initially started on standard antibiotic therapy (i.e., vancomycin alone or in combination with cefepime, or linezolid) but failed initial therapy and were switched to CPT-F; consequently, all switched patients cleared infection and observed success by the end of the treatment. Lastly, only one patient reported an allergy to CPT-F and it was discontinued; for this reason that patient was excluded from the total cohort of cases.

Suggestive criteria of when to start CPT-F

When should clinicians relate to standard and opt to start a patient on CPT-F? The decision is of course based on clinical judgment. However, ceftaroline can be considered when patients have failed therapy with vancomycin, are intolerant of vancomycin or are at high risk of toxicity with the agent, which are similar factors seen in our pilot study of the 20 patients who were switched to CPT-F. Persistent fever (≥38°C) or spiking temperatures, leukocytosis, difficulty with attaining proper vancomycin trough levels, concern for nephrotoxicity and an uncleared MRSA culture after 72 h of administered vancomycin or linezolid treatment warrant initiating a ceftaroline-directed regimen.

Future perspective

With a large percentage of patients failing standard therapy, or intolerant of therapy and requiring alternative treatment, MRSA pneumonia presents serious therapeutic challenges. In our experience, CPT-F has shown to be well tolerated by patients and no major complications have been reported. The strikingly low mortality rate of 10% versus commonly reported 28-day mortality rates ranging as high as 30–50% suggest a possible benefit with the use of CPT-F. Many factors including providing safe and the most effective therapy fall under the umbrella of proper and appropriate MRSA pneumonia treatment. The unanswered question remains regarding treatment optimization with CPT-F. With mortality rates of up to 38%, new strategies for improving on outcomes are needed. One unexplored direction is to determine the success of CPT-F in synergistic therapies with other β-lactams. Another approach is to start with agents other than vancomycin early on in a patient's treatment course in comparison to salvage therapy. Presently, ceftaroline has not been approved by FDA for MRSA pneumonia; however, additional comparative data from clinical trials and epidemiological studies will have a wider implication on the treatment of the ever-evolving MRSA pathogen. It is critical for us to find alternative agents in order to improve patient outcomes, and further research is needed to test the efficacy of CPT-F on a larger patient population as the prospect of achieving success with CPT-F is exciting and may offer clinicians another viable option in the management of MRSA pneumonia.

Disclaimer

The preliminary results of this study were presented as S. Arshad, P. Hartman, D. Moreno, M. Perri, M. Zervos, 2013. Evaluation of Epidemiology, Prevalence, and Outcomes in MRSA, HAP & HCAP Pneumonia patients treated with Ceftaroline Fosamil (CPT-F).

Abstract number 1104 at the 2013 ICAAC Annual Conference, Denver, Colorado, USA; poster presentation.

Financial & competing interests disclosure

S Arshad receives research funding from Forest Research Institute, Pfizer and Merck. MJ Zervos receives research funding from Merck, Cubist and Pfizer. P Hartman has no funding or conflicts of interest to disclose. The data for the pilot study cited were supported by Forest Research Institute. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.