Abstract
Persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia can be difficult to treat, with growing adult literature supporting the combination of ceftaroline and daptomycin for these patients. Here, we report a pediatric patient with persistent MRSA bacteremia with associated cellulitis, fasciitis, myositis, and a deep venous thrombosis causing septic pulmonary emboli. After being unable to clear the bacteremia on vancomycin and then daptomycin monotherapy, the bacteremia cleared quickly with rapid clinical improvement after the addition of ceftaroline to daptomycin. In support of this case, we also review the adult literature supporting treatment with this combination of antibiotics.
Keywords: antibacterial agents, bacteremia, ceftaroline, child, daptomycin, methicillin-resistant Staphylococcus aureus, staphylococcal infections
Introduction
Refractory or persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia can be a very challenging clinical situation. A growing number of case reports in addition to in vitro data have suggested a role for the addition of ceftaroline to daptomycin for refractory cases of staphylococcal bacteremia (particularly MRSA) in the treatment of adult patients.1–4 There is limited evidence on the use of ceftaroline in pediatrics for the treatment of bacteremia, and there are no known pediatric cases published on the use of coadministered daptomycin and ceftaroline. Here, we present the case of a pediatric patient with refractory MRSA bacteremia that benefitted from this combination therapy, as well as a review of the available adult literature.
Case
A 12-year-old female presented with bilateral hip pain progressing during 1 week that worsened with movement. She was febrile to 38.0°C while seeing her pediatrician and was sent to the emergency department. Her past medical history included attention deficit hyperactivity and reactive attachment disorders, with no history of being immunocompromised or of recent antibiotic exposure. She had no previous surgeries. Her medications included fluoxetine, lisdexamfetamine, and guanfacine. She had no medication allergies. Her family history was largely unknown because she was adopted. On exam, she was afebrile on presentation, with tachycardia to 131 beats per minute and with vital signs otherwise within normal limits. Her weight was 31.3 kg. She had tenderness upon palpation of her bilateral thighs and hips, with associated pain with all passive and active movements of both hips. She had no warmth or erythema of any joints and no tenderness elsewhere. She had no skin lesions. She did have mild right lower quadrant abdominal tenderness.
Initial laboratory studies were significant for a white blood cell count of 14.4 × 103/μL (×109/L; with 75% neutrophils, 13% lymphocytes, 10% monocytes, 1% eosinophils, and 1% immature granulocytes), serum creatinine of 0.46 mg/dL, albumin of 2.2 g/dL, erythrocyte sedimentation rate of 57 mm/hr, and C-reactive protein (CRP) 22.9 mg/dL. X-rays of the pelvis, bilateral hips, and femurs demonstrated soft tissue edema around the right femur, with no effusions on bilateral hip ultrasound. An abdominal ultrasound revealed a proximal right common femoral vein thrombosis, confirmed on lower extremity duplex imaging. She received fluid resuscitation and was admitted. Therapeutic subcutaneous enoxaparin (Lovenox, Sanofi-Aventis US LLC, Bridgewater, NJ) at 1 mg/kg per dose every 12 hours was started for the deep vein thrombosis. The dose was adjusted based on anti-Xa concentrations, with the patient ultimately requiring 1.5 mg/kg per dose every 12 hours.
She developed a fever to 39.4°C on hospital day 2, with initial blood culture growing MRSA (see Table 1 for sensitivities). Intravenous vancomycin (Vancocin, Hospira, A Pfizer Company, Lake Forest, IL) was initiated via a syringe pump at 20.8 mg/kg per dose every 8 hours. With an initial and appropriately timed vancomycin trough of 12.4 mg/L prior to the fourth dose, the dosage was changed to 22.4 mg/kg per dose every 8 hours. Magnetic resonance imaging of the pelvis and proximal lower extremities showed diffuse and symmetric cellulitis, fasciitis, and myositis without a drainable abscess or osteomyelitis. A computed tomography pulmonary angiogram revealed a filling defect in a right lower lobe pulmonary artery with necrotizing pneumonitis and an associated moderate pleural effusion. Septic emboli were also present in the upper lobes. Three serial transthoracic echocardiograms showed no vegetations.
Table 1.
Staphylococcus aureus Blood Culture Susceptibilities
| Antibiotic | MIC, mg/L* |
|---|---|
| Ceftaroline | 0.75 |
| Clindamycin | 0.19 |
| Daptomycin | 1.0 |
| Oxacillin | 96 |
| Trimethoprim/sulfamethoxazole | 0.094 |
| Vancomycin | 2 |
MIC, minimal inhibitory concentration
*The MICs remained consistent on all blood cultures.
Daily blood cultures remained positive for 9 consecutive days (Table 2), and the patient continued with daily fevers until day 12. For treatment of the MRSA sepsis, she was continued on vancomycin for 3 days and then switched to intravenous daptomycin (10 mg/kg/day via syringe pump; Cubicin, Merck Sharp & Dohme Corp, Whitehouse Station, NJ) monotherapy on day 5, given the vancomycin minimal inhibitory concentration of 2 mg/L and delay in achieving a therapeutic concentration of 15 to 20 mg/L. With continued fevers and persistent bacteremia, intravenous ceftaroline (12 mg/kg per dose every 8 hours via syringe pump; Teflaro, Forest Pharmaceuticals Inc, St Louis, MO) was added to daptomycin on day 9. The blood culture drawn on day 11 was the first negative culture during admission. Although the blood culture on day 12 was positive, all subsequent cultures from day 13 onward remained sterile. With the clearance of bacteremia, the patient defervesced and CRP trended towards normalization.
Table 2.
Trend of Pertinent Laboratory Studies and Antibiotics
| Hospital Day | WBC, ×109/L (% neutrophils) | Platelets, ×109/L | CRP, mg/dL | ESR, mm/hr | Blood Culture + MRSA | Antibiotic |
|---|---|---|---|---|---|---|
| 1 | 14.4 (75) | 260 | 22.9 | 57 | — | — |
| 2 | — | — | — | — | 1/1 | VAN |
| 3 | 19.3 (80) | 218 | — | — | 1/1 | VAN |
| 4 | 18.4 (79) | 225 | 23.2 | — | 1/1 | VAN |
| 5 | — | — | — | 78 | 1/1 | VAN→DAP |
| 6 | 20.2 (81) | 357 | — | — | 1/1 | DAP |
| 7 | 17.3 (79) | 433 | 20.2 | — | 1/1 | DAP |
| 8 | 15.5 (75) | 518 | — | — | 1/1 | DAP |
| 9 | 17.0 (79) | 775 | — | — | 1/1 | DAP + CPT |
| 10 | 18.3 (73) | 999 | — | — | 1/1 | DAP + CPT |
| 11 | 17.5 (77) | 1168 | — | — | 0/1 | DAP + CPT |
| 12 | — | — | 12.1 | 57 | 1/1 | DAP + CPT |
| 13* | 11.2 (70) | 1422 | — | — | 0/1 | DAP + CPT |
| 14 | 10.3 (67) | 1188 | — | — | 0/1 | DAP + CPT |
| 15 | 9.4 (70) | 1036 | — | — | 0/1 | DAP + CPT |
| 16 | — | — | — | — | 0/1 | DAP + CPT |
| 17 | — | — | 4.9 | 102 | — | DAP + CPT |
| 18 | 8.5 (61) | 674 | — | — | — | DAP + CPT |
CPT, ceftaroline; CRP, C-reactive protein; DAP, daptomycin; ESR, erythrocyte sedimentation rate; MRSA, methicillin-resistant Staphylococcus aureus; VAN, vancomycin; WBC, white blood cell count
*Resolution of fevers.
The initial nidus of her infection was likely from the skin, leading to the cellulitis, fasciitis, myositis, and bacteremia. This proinflammatory state likely led to the development of a deep venous thrombosis that became a septic thrombus in the setting of the bacteremia, leading to septic pulmonary emboli. She did not show clinical improvement until ceftaroline was added to daptomycin. She was discharged on day 18 to complete a 6-week total course of daptomycin (starting from the negative blood culture on day 13) given the endovascular foci of infection. The ceftaroline was continued for 4 weeks from the same start date for synergy. The enoxaparin was transitioned to warfarin prior to discharge when her internal normalized ratio reached the target range of 2 to 3. At subsequent follow-up appointments her CRP gradually normalized and her symptoms abated as she was able to return to all previous activities. After being on anticoagulation for 3 months, follow-up venous duplex imaging revealed resolution of her thrombus, and warfarin was discontinued.
Discussion
The patient described above was deemed to have failed vancomycin treatment, which we speculate was related to the elevated minimal inhibitory concentration of 2 mg/L and delay in achieving target serum concentrations. Clinical practice guidelines for the treatment of refractory MRSA bacteremia and vancomycin treatment failure recommend large-dose daptomycin (10 mg/kg/day) if the organism is susceptible, plus a second agent with a β-lactam being an option.5 β-Lactams have been shown to act synergistically with daptomycin in the treatment of MRSA in vitro by reducing the cell net positive charge that may increase the binding of daptomycin to the cell surface. In addition, the combination may prevent the selection of daptomycin-resistant strains.6 A case series of 7 adult patients with MRSA bacteremia refractory to vancomycin- and daptomycin-based regimens showed that the addition of antistaphylococcal β-lactams (nafcillin or oxacillin) to daptomycin resulted in rapid bacteremia clearance.3
Limited evidence is available comparing different β-lactams paired with daptomycin, but ceftaroline is an attractive option given its bactericidal activity against MRSA.7 MRSA strains have been shown to be nearly 100% susceptible to ceftaroline in 2 large pediatric studies (99.4% by Pfaller et al8 and 99.8% by Sader et al9). Ceftaroline has been approved by the US Food and Drug Administration (FDA) for the treatment of acute bacterial skin and skin structure infections as well as community-acquired bacterial pneumonia in children.10 It has not been approved for the treatment of MRSA bacteremia in children or adults, but several published adult cases have shown favorable outcomes with the use of ceftaroline monotherapy for this indication.11,12 Daptomycin is newly FDA approved for use in pediatrics in complicated skin and soft tissue infections and S aureus bacteremia.13 Previous reports have shown evidence for its use in invasive Gram-positive infections in children, and a randomized controlled trial demonstrated daptomycin to be comparable to the standard of care (primarily with vancomycin or cefazolin used) in the treatment of S aureus bacteremia.14,15
In vitro studies have shown that the combination of daptomycin plus ceftaroline improves antibacterial activity.1–3 The addition of ceftaroline increases daptomycin cell membrane binding and increases killing by cathelicidin LL-37 and neutrophils.2–4 This combination has even restored daptomycin susceptibility in nonsusceptible strains.1,3 An in vitro study evaluating 2 strains of MRSA (one daptomycin susceptible and heterogeneous vancomycin intermediate, and the other daptomycin nonsusceptible and vancomycin intermediate) compared ceftaroline plus daptomycin to ceftaroline plus vancomycin and each as monotherapy in the treatment of MRSA bacteremia, and favored the combination of daptomycin plus ceftaroline.4 Another model showed that the combination of ceftaroline and daptomycin had more rapid and sustained activity compared with ceftaroline, daptomycin, or vancomycin monotherapy.16
Rose et al1 reported a case of an adult patient with endocarditis and 11 consecutive positive blood cultures for MRSA while on treatment with daptomycin, with eventual development of reduced daptomycin susceptibility. Ceftaroline was subsequently added to daptomycin, with clearance of the bacteremia within 4 days along with reduction in size of the cardiac vegetation. Sakoulas et al2 reviewed a case series of 26 adult patients with refractory staphylococcal bacteremia that had a median duration of bacteremia of 10 days, with a median clearance time of 2 days after the addition of ceftaroline to daptomycin. In the case described, ceftaroline was chosen as the second agent instead of other β-lactams to add to daptomycin, given its independent bactericidal activity against MRSA (felt to be important in the setting of pulmonary involvement) and support from these in vitro studies and adult reports.
Summary
This literature review provides support that coadministered ceftaroline plus daptomycin may be a viable option for the treatment of refractory MRSA bacteremia in adult patients, with this case report showing promise in a pediatric patient as well. All of the in vivo data are retrospective, and prospective studies looking at this combination versus monotherapy in addition to other combinations are much needed. It is possible that β-lactams in general provide synergy to daptomycin as a class without special benefit for ceftaroline. Given ceftaroline's bactericidal nature against MRSA, however, and the growing evidence of use in adult patients with MRSA bacteremia, ceftaroline may be a worthwhile addition to daptomycin in these difficult-to-treat pediatric patients.
Acknowledgment
An abstract of this case was presented at the 2016 Pediatric Hospital Medicine Conference, Chicago, Illinois, July 2016.
ABBREVIATIONS
- CRP
C-reactive protein
- FDA
US Food and Drug Administration
- MRSA
methicillin-resistant Staphylococcus aureus
Footnotes
Disclosures The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria.
REFERENCES
- 1.Rose WE, Schulz LT, Andes D et al. Addition of ceftaroline to daptomycin after emergence of daptomycin-nonsusceptible Staphylococcus aureus during therapy improves antibacterial activity. Antimicrob Agents Chemother. 2012;56(10):5296–5302. doi: 10.1128/AAC.00797-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Sakoulas G, Moise PA, Casapao AM et al. Antimicrobial salvage therapy for persistent staphylococcal bacteremia using daptomycin plus ceftaroline. Clin Ther. 2014;36(10):1317–1333. doi: 10.1016/j.clinthera.2014.05.061. [DOI] [PubMed] [Google Scholar]
- 3.Dhand A, Bayer AS, Pogliano J et al. Use of antistaphylococcal beta-lactams to increase daptomycin activity in eradicating persistent bacteremia due to methicillin-resistant Staphylococcus aureus role of enhanced daptomycin binding. Clin Infect Dis. 2011;53(2):158–163. doi: 10.1093/cid/cir340. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Werth BJ, Sakoulas G, Rose WE et al. Ceftaroline increases membrane binding and enhances the activity of daptomycin against daptomycin-nonsusceptible vancomycin-intermediate Staphylococcus aureus in a pharmacokinetic/pharmacodynamic model. Antimicrob Agents Chemother. 2013;57(1):66–73. doi: 10.1128/AAC.01586-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Liu C, Bayer A, Cosgrove SE et al. Clinical practice guidelines by the infectious diseases society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52(3):e18–e55. doi: 10.1093/cid/ciq146. [DOI] [PubMed] [Google Scholar]
- 6.Mehta S, Singh C, Plata KB et al. Beta-Lactams increase the antibacterial activity of daptomycin against clinical methicillin-resistant Staphylococcus aureus strains and prevent selection of daptomycin-resistant derivatives. Antimicrob Agents Chemother. 2012;56(12):6192–6200. doi: 10.1128/AAC.01525-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Steed ME, Rybak MJ. Ceftaroline: a new cephalosporin with activity against resistant gram-positive pathogens. Pharmacotherapy. 2010;30(4):375–389. doi: 10.1592/phco.30.4.375. [DOI] [PubMed] [Google Scholar]
- 8.Pfaller MA, Mendes RE, Castanheira M et al. Ceftaroline activity tested against bacterial isolates causing community-acquired respiratory tract infections and skin and skin structure infections in pediatric patients from United States hospitals: 2012–2014. Pediatr Infect Dis J. 2017;36(5):486–491. doi: 10.1097/INF.0000000000001477. [DOI] [PubMed] [Google Scholar]
- 9.Sader HS, Mendes RE, Farrell DJ et al. Ceftaroline activity tested against bacterial isolates from pediatric patients: results from the assessing worldwide antimicrobial resistance and evaluation program for the United States (2011–2012) Pediatr Infect Dis J. 2014;33(8):837–842. doi: 10.1097/INF.0000000000000307. [DOI] [PubMed] [Google Scholar]
- 10.Teflaro (ceftaroline fosamil) [prescribing information]. Revised 2016. St Louis, MO: Forest Pharmaceuticals Inc; [Google Scholar]
- 11.Ho TT, Cadena J, Childs LM et al. Methicillin-resistant Staphylococcus aureus bacteraemia and endocarditis treated with ceftaroline salvage therapy. J Antimicrob Chemother. 2012;67(5):1267–1270. doi: 10.1093/jac/dks006. [DOI] [PubMed] [Google Scholar]
- 12.Paladino JA, Jacobs DM, Shields RK et al. Use of ceftaroline after glycopeptide failure to eradicate methicillin-resistant Staphylococcus aureus bacteraemia with elevated vancomycin minimum inhibitory concentrations. Int J Antimicrob Agents. 2014;44(6):557–563. doi: 10.1016/j.ijantimicag.2014.07.024. [DOI] [PubMed] [Google Scholar]
- 13.Cubicin (daptomycin) [prescribing information]. Revised 2017. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; [Google Scholar]
- 14.Ardura MI, Mejías A, Katz KS et al. Daptomycin therapy for invasive gram-positive bacterial infections in children. Pediatr Infect Dis J. 2007;26(12):1128–1132. doi: 10.1097/INF.0b013e31814523f8. [DOI] [PubMed] [Google Scholar]
- 15.Arrieta AC, Bradley JS, Popejoy MW et al. Randomized multicenter study comparing safety and efficacy of daptomycin versus standard of care in pediatric patients with staphylococcal bacteremia. Pediatr Infect Dis J. 2018;37(9):893–890. doi: 10.1097/INF.0000000000001926. [DOI] [PubMed] [Google Scholar]
- 16.Werth BJ, Barber KE, Ireland CE, Rybak MJ. Evaluation of ceftaroline, vancomycin, daptomycin, or ceftaroline plus daptomycin against daptomycin-nonsusceptible methicillin-resistant Staphylococcus aureus in an in vitro pharmacokinetic/pharmacodynamic model of simulated endocardial vegetations. Antimicrob Agents Chemother. 2014;58(6):3177–3181. doi: 10.1128/AAC.00088-14. [DOI] [PMC free article] [PubMed] [Google Scholar]