Combination Therapy With Vancomycin and Ceftaroline for Refractory Methicillin-resistant Staphylococcus aureus Bacteremia: A Case Series

Abstract

Purpose

Although vancomycin has been the mainstay of therapy for methicillin-resistant Staphylococcus aureus (MRSA) infections, its effectiveness has been challenged. Combination therapy may be used for patients with persistent MRSA bacteremia refractory to initial therapy. Studies have reported in vitro synergy between vancomycin and ceftaroline; however, clinical experience with this therapy is limited. Here, we report our experience with 5 cases of vancomycin-refractory MRSA bacteremia treated with the combination of vancomycin and ceftaroline.

Methods

Between January 2014 and August 2016, 5 patients were identified who received vancomycin and ceftaroline combination therapy due to persistent bacteremia or deterioration of their clinical status on vancomycin alone (despite a vancomycin MIC within the susceptible range).

Findings

Five patients presented with MRSA bacteremia secondary to endocarditis (n = 2), epidural abscess (n = 2), or left iliopsoas abscess (n = 1). Four of the 5 patients experienced microbiologic cure, and 1 patient transitioned to palliative care.

Implications

This case series serves to describe additional clinical experience with vancomycin and ceftaroline combination therapy. This combination may be considered when vancomycin monotherapy does not lead to microbiological and/or clinical improvement in patients with metastatic MRSA bacteremia. Additional studies are warranted to further define its role in salvage therapy for persistent MRSA bacteremia.

Introduction

Methicillin-resistant Staphylococcus aureus (MRSA) infections pose a substantial clinical and economic burden on the health care system. Although vancomycin has been the mainstay of therapy for decades, its effectiveness has been challenged.1, 2, 3, 4 For MRSA infections, treatment failure with vancomycin was reported for isolates within the susceptible range (MIC ≤2 µg/mL).5, 6, 7 Alternatives to vancomycin such as linezolid, daptomycin, and ceftaroline have indicated noninferiority to vancomycin for the treatment of MRSA infections, but none have established superiority.8, 9 In addition, MRSA isolates with increased vancomycin MICs were correlated with reduced daptomycin susceptibility, and exposure to vancomycin can select for higher daptomycin MICs.10, 11, 12 For cases of persistent MRSA bacteremia or vancomycin-intermediate S aureus (VISA) infections combination antibiotic therapy may be an option. In vitro studies have reported synergy between vancomycin and ceftaroline that may be greater than other β-lactam antibiotics.13, 14

Ceftaroline is an attractive option for combination therapy because it possesses anti-MRSA activity, may enhance neutrophil killing, and may reduce bacterial virulence, even in subinhibitory ceftaroline concentrations.14, 15, 16, 17 Notably, evidence suggests that vancomycin and ceftaroline possess greater bactericidal activity than ceftaroline alone, the combination of either vancomycin and oxacillin, or daptomycin and ceftaroline.13, 17 To date, only one case report describing vancomycin and ceftaroline combination therapy for MRSA bacteremia has been published.¹⁷ Here, we report our experience with 5 cases of vancomycin-refractory MRSA bacteremia treated with the combination of vancomycin and ceftaroline. (Figure 1)

A 66-year-old woman presented with 4 days of lower back pain and bilateral lower extremity radiculopathy. She required emergent surgical decompression after a magnetic resonance image (MRI) revealed cauda equina syndrome with an L3 sacral epidural abscess. Blood tests revealed leukocytosis (22.7 × 10⁹ cells/L). Four blood cultures and the epidural abscess fluid culture grew MRSA. Vancomycin 1000 mg (15 mg/kg) every 12 hours was initiated (trough concentration range, 13–15 µg/mL). Repeat blood cultures drawn daily until hospital day 9 continued to be positive for MRSA (MIC ≤ 0.5 µg/mL days 1–5, 1 µg/mL days 6–9). (Table 1)

On day 10, ceftaroline 600 mg IV every 8 hours (E-test MIC = 0.38 µg/mL) was added, and a repeat blood culture drawn in less than 24 hours was negative for growth. Vancomycin was stopped on hospital day 22 because of worsening renal function, and the patient was discharged the same day. The patient had received the combination vancomycin and ceftaroline for 13 days, and ceftaroline monotherapy was continued for 14 days after discharge. At 2-week follow-up to the infectious disease clinic, the patient had completed therapy and was free of bacteremia.

A 42-year-old man with a past medical history of IV drug use presented with chest pain, back pain, and shortness of breath for 3 days. X-ray and chest computed tomographic (CT) scan found multiple bilateral patchy opacities suspicious for septic emboli to the lungs. Transthoracic echocardiogram revealed a mobile tricuspid mass >3 cm in length. Therapy was started with vancomycin 1000 mg (17 mg/kg) every 12 hours and nafcillin 2 g every 4 hours. Blood cultures were positive for gram-positive cocci in clusters in 4 bottles. Vancomycin troughs ranged from 15 to 18 µg/mL.

CT scan of the abdomen and pelvis revealed abscesses within the right iliacus muscle and left iliopsoas muscle, which was unable to be drained. MRI of the spine revealed C6-C7 osteomyelitis. On day 4 of therapy, repeat blood cultures remained positive, and cultures from day 1 grew MRSA (vancomycin MIC = 1 µg/mL, ceftaroline E-test MIC = 0.38 µg/mL). Nafcillin was discontinued, and ceftaroline 400 mg every 12 hours (renally adjusted for creatinine clearance of 38 mL/min) was initiated. Repeat blood cultures drawn on hospital day 5 were negative for growth. After 14 days of combination therapy, the patient was transitioned to vancomycin monotherapy for 3 weeks until development of an acute kidney injury. The patient was converted to ceftaroline monotherapy to complete an additional 4 weeks of therapy and was discharged home from inpatient rehabilitation on hospital day 98.

A 46-year-old man with a past medical history of AIDS (CD4 count of 2 cells/mm³) presented with left-sided pain radiating from his pelvis down to the left foot which was inhibiting ambulation. The patient was afebrile, and blood tests revealed leukocytosis (18.8 × 10⁹ cells/L). CT scan of the abdomen and pelvis found asymmetric enlargement and stranding surrounding the left psoas, left iliacus, left rectus femoris, and left sartorius muscles with regions of faint hyperdensity within the left psoas muscle. Vancomycin, metronidazole, and cefepime were initiated. Because of development of acute kidney injury, vancomycin was dosed by level (redose threshold < 20 µg/mL). Two sets of blood cultures resulted in MRSA (vancomycin MIC ≤ 0.5 µg/mL). The psoas abscess was not amenable to drainage.

On hospital day 3, repeat blood cultures were positive for MRSA. The patient developed septic shock with multiorgan failure, including lungs, liver, and kidneys (he required hemodialysis). Cefepime was discontinued, and ceftaroline 200 mg IV every 12 hours (ceftaroline E-test MIC = 0.5 µg/mL) was initiated. Blood cultures drawn 24 hours later were negative for growth. After 5 days of combination therapy, repeat blood cultures remained negative, and the patient transitioned to ceftaroline monotherapy. On hospital day 15, the patient was discharged to complete an additional 4 weeks of ceftaroline therapy. Recurrence of MRSA bacteremia was not identified on multiple visits to the infectious disease clinic.

An 82-year-old woman with a past medical history of hypertension, atrial fibrillation, and end-stage renal disease (on hemodialysis) presented to our institution after a blood culture taken at a dialysis center grew MRSA (vancomycin MIC ≤ 0.5 µg/mL). The arteriovenous graft was determined not to be infected and was not removed. MRI revealed discitis/osteomyelitis of the C6 vertebra and a ventral epidural abscess at C6-C7, which was not amenable for drainage. Gallium scan revealed increased uptake at the right sacroiliac joint, right shoulder in the periarticular region, and the manubrium. Vancomycin was started at 750 mg (15 mg/kg) post-hemodialysis (post-HD) with pre-hemodialysis (pre-HD) vancomycin troughs from 19 to 41.2 µg/mL. Repeat blood cultures drawn on hospital day 7 were still positive and revealed a second MRSA morphotype (vancomycin MIC = 1 µg/mL).

Ceftaroline 200 mg every 12 hours was initiated on hospital day 8. Repeat blood cultures drawn 3 days later were negative. Combination therapy was continued for 17 days until hospital discharge (hospital day 25). On discharge, therapy was changed to daptomycin 6 mg/kg every 48 hours for an additional 4 weeks because of the nursing home not being able to provide ceftaroline. At the patient’s 12-week follow-up appointment at the infectious disease clinic, no recurrence of bacteremia was reported.

A 50 year-old undomiciled man with a history of IV drug use, alcohol abuse, and hepatitis C presented with a 2-week history of worsening bilateral upper and lower extremity weakness. Blood cultures drawn in the emergency department were positive for MRSA (vancomycin MIC = 1 µg/mL). The patient was started on vancomycin 1000 mg (15 mg/kg) every 12 hours (troughs ranged between 18 and 20 µg/mL). MRI performed on admission found a 2.5-cm parenchymal hematoma in the occipital lobe and subarachnoid hemorrhage in the bilateral occipital lobe.

On hospital day 3, the patient’s condition altered, and he experienced asterixis with repeat blood cultures still positive for MRSA. Ceftaroline 600 mg IV every 12 hours was added. A TEE found a vegetation measuring 0.8 cm by 1.4 cm in the mitral valve with severe mitral regurgitation. Repeat MRI found massive enlargement of previously seen hematomas, multiple new hematomas with hydrocephalus, and downward transtentorial herniation. Hematomas were suspected to be secondary to multiple mycotic aneurysms. The course was complicated by multiorgan failure and development of disseminated intravascular coagulation. On hospital day 4, the ceftaroline dose was increased to 600 mg IV every 8 hours, but blood cultures remained positive until hospital day 7. The patient was palliatively extubated on hospital day 10.