Ceftaroline for MRSA Bacteremia

Yvonne Burnett, PharmD PGY-2 Infectious Diseases Pharmacy Resident

South Texas Veterans Health Care System University of Texas Health Science Center at San Antonio

University of Texas at Austin College of Pharmacy

Pharmacotherapy Grand Rounds October 3, 2014

Learning Objectives:

1. Review epidemiology and pathophysiology of methicillin-resistant Staphylococcus aureusbacteremia (MRSAB)

2. Evaluate current therapeutic options for MRSAB3. Assess ceftaroline as a potential treatment option for MRSAB4. Evaluate evidence of use of ceftaroline for treatment of MRSAB

She Doesn’t Even Go Here!

 

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Staphylococcus Aureus

I. Staphylococcus aureus1-2 a. Microbiology: gram-positive cocci in clusters

i. Golden colonies, catalase positive ii. Odor: sweaty gym socks

b. Natural colonizer of skin and respiratory tract i. 3/10 people will grow S. aureus in their nares2

c. Types of infections i. Skin and soft tissue (SSTI) ii. Bacteremia and infective endocarditis iii. Bone and joint infections

1. Osteomyelitis 2. Prosthetic joint infections

iv. Pneumonia v. Meningitis vi. Food poisoning

d. Resistance to antibiotics develops quickly3

i. Penicillin Resistance: narrow spectrum β-lactamase production ii. Methicillin-resistant S. aureus (MRSA) confers resistance to (almost) all β-lactam

antibiotics via alterations in penicillin binding proteins (PBP) iii. Vancomycin-intermediate S. aureus (VISA): increased thickening of cell walls

and loss of gene regulator of virulence pathways iv. Vancomycin-resistant S. aureus (VRSA): acquired vanA gene from an

Enterococcal plasmid

Figure 1

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MRSA

I. Epidemiology4-7 a. Substantial cause of healthcare associated infections b. Historically seen in hospitalized patients or those with healthcare exposure c. MRSA prevalence in intensive care units (ICU) doubled from 1992 to 20037

II. Community-acquired MRSA (CA-MRSA)8-9 a. Mid-2000s, MRSA seen in patients without healthcare exposure b. Different strain than seen in healthcare-associated MRSA (HA-MRSA) c. Typically SSTI in young, otherwise healthy people d. Spread by close physical contact: athletes involved in football and wrestling, soldiers kept

in close quarters, inmates, childcare workers, and residents of long-term care facilities

III. MRSA Incidence2,10 a. Despite increases previously seen in HA-MRSA and CA-MRSA, the overall incidence of

MRSA from 2005 to 2011 has declined by 31%

b. Largest declines were seen in hospitalized patients (54%) c. CA-MRSA infections increased rapidly in the past decade, and while these increases are

slowing, they are not on the same downward trend as HA-MRSA

IV. CDC Threat Report: Antimicrobial Resistance – October 201311 a. MRSA is classified as a serious threat

i. 80,461 severe MRSA infections per year in the US ii. 11, 285 deaths per year in the US

b. Although overall incidence of MRSA is decreasing, MRSA infections remain common

Figure 3

Figure 2

35.9

64.4

0 20 40 60 80

1992 2003

S. aureus Isolates with Methicillin Resistance (%)

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MRSA Bacteremia

I. Epidemiology4-6, 10, 12 a. MRSA bacteremia and endocarditis are serious diseases b. Blood stream infections are a leading cause of death in US

i. S. aureus responsible for 20% nosocomial blood stream infections12 ii. MRSA accounts for 50% of S. aureus strains in nosocomial infections12

c. MRSAB is associated with: i. High morbidity and mortality rates ii. MRSA endocarditis mortality rates 30-37%6 iii. Increased hospital length of stay iv. Increased healthcare costs

d. MRSAB has a greater likelihood of persistence vs MSSA i. Median time to clearance: 8-9 days vs 3 days5 ii. Increases likelihood of metastatic infection leading to poorer outcomes

e. Factors associated with increased risk of death in MRSAB i. Older age ii. Nursing home residence iii. Severe bacteremia iv. Organ dysfunction

II. Types of MRSA bacteremia5 a. Uncomplicated MRSA bacteremia

i. Exclusion of endocarditis ii. No implanted prosthetics iii. Clearance of bacteremia within 2-4 days iv. Defervescence within 72 hours of therapy v. No evidence of metastatic sites of infection

b. Complicated MRSA bacteremia i. Bacteremia that does not meet the above criteria for uncomplicated bacteremia

III. Treatment of MRSA bacteremia5

a. Antibiotic treatment - duration dictated by type of bacteremia Table 1

MRSA Bacteremia Treatment Options Duration of Treatment

Uncomplicated

Vancomycin 15-20 mg/kg Q8-12H (target trough 15-20 mcg/mL) 2 weeks

Daptomycin 6 mg/kg daily

Complicated

Vancomycin 15-20 mg/kg Q8-12H (target trough 15-20 mcg/mL)

4-6 weeks Daptomycin 6 mg/kg daily (some experts recommend higher

doses of 8-10 mg/kg)

Figure 4

Antibiotic Treatment Source Control Surveillance

Blood Cultures Echocardiogram

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b. Surveillance blood cultures i. Additional blood cultures 2-4 days after initial positive blood cultures and as

needed thereafter until clearance of bacteremia ii. Documentation of clearance determines start time of therapy

c. Source control i. Clinical assessment to identify source and extent of infection ii. Source control performed if possible

d. Echocardiogram i. Echocardiography is recommended in all patients with bacteremia to evaluate for

endocarditis ii. Transesophageal echocardiogram (TEE) is preferred over transthoracic

echocardiogram (TTE) as it is a more sensitive test

IV. Vancomycin5, 12-15 a. Glycopeptide bactericidal antibiotic that binds to the D-alanyl-D-alanine terminating

pentapeptide, preventing cross-linking of the cell membrane and inhibiting cell wall synthesis, thereby causing cell death

b. Gold standard for MRSA bacteremia c. Dosing: target trough level of 15-20 mcg/mL d. Treatment failures and poor outcomes have been seen with vancomycin

i. Variable dosing/levels ii. Limited penetration of bone, lung epithelial fluid, CSF iii. Slowly bactericidal, especially a concern with higher innocula

e. Treatment failures with minimum inhibitory concentration (MIC) > 2 mcg/mL f. Resistant strains - VISA, VRSA

V. Daptomycin5, 12-16 a. Cyclic bactericidal lipopeptide antibiotic that binds to bacterial cell membranes, causing

cell death by inducing rapid depolarization of membrane potential and leading to disruption of DNA, RNA, and protein synthesis

b. Emergence of reduced susceptibilities to daptomycin has been observed in several patients who experienced treatment failure

c. Correlations have been seen between daptomycin nonsusceptibility (NS) and increasing vancomycin MICs

d. Concentration dependent killing – may need higher doses up to 8-10 mg/kg

VI. MIC Breakpoints1

MIC (mcg/mL)

S I R Vancomycin ≤ 2 4 – 8 ≥ 16 Daptomycin ≤ 1 NS NS

VII. MRSA Resistance/Treatment failures5, 12-15, 17

a. Persistent MRSA bacteremia i. Challenging clinical situation, especially if source control is not possible ii. Increased risk on individual patient outcomes such as morbidity and increased

health care utilization iii. Selection pressure on bacteria in a persistent high-inoculum focus of infection

can drive antibiotic resistance

Table 2

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b. Bacteremia that is not cleared at/around day 7 of adequate treatment, should be assessed to determine whether a change in therapy is indicated

i. Patient’s overall clinical response ii. Vancomycin trough serum concentrations iii. Results of susceptibility testing iv. Presence of/ability to remove other foci of infection

c. Vancomycin treatment failures i. Slow bactericidal activity ii. Emergence of strains with reduced susceptibility iii. Inadequate debridement or retention of prosthetic device iv. At this time, no alternative regimen has proven to be superior to vancomycin in

achieving clinical cure or sterilizing blood cultures

VIII. Alternative treatment options for vancomycin resistant strains5, 15, 17 a. Recommend change in therapy rather than addition of other agents b. Daptomycin

i. Isolates with vancomycin MIC ≥ 2 mcg/mL are associated with daptomycin NS strains with MICs > 1 mcg/mL

ii. May need to use higher doses of 10 mg/kg/day iii. Potential combination with trimethoprim-sulfamethoxazole

IX. Alternative treatment options for vancomycin resistant and daptomycin nonsusceptible strains5, 15, 17 a. Quinupristin-dalfopristin IV 7.5 mg/kg Q8H

i. Used successfully as salvage therapy in patients with vancomycin treatment failure, although response rates are lower for patients with endocarditis or bacteremia of unknown source

b. Trimethoprim-sulfamethoxazole IV 5mg/kg BID i. Bactericidal in vitro, but inferior to vancomycin for treatment of S. aureus ii. Potential combination with daptomycin

c. Linezolid 600mg PO/IV BID i. Has been used with success in MRSA infections, however treatment failures

have been seen d. Telavancin IV 10 mg/kg daily

i. One case of MRSA bacteremia and tricuspid valve endocarditis was successfully treated

e. Vancomycin or daptomycin + β-lactam i. Vancomycin combination has been shown to be synergistic in vitro and in vivo for

VISA and VRSA ii. Similar observations have been seen with daptomycin in combination with β-

lactams due to daptomycin nonsusceptible strains

X. Newer MRSA Treatment Options14-15, 17 a. Ceftaroline b. Dalbavancin c. Oritavancin d. Tedizolid

All have MRSA activity, however there is little to no data available for their use in bacteremia  

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Table 3

Ceftaroline fosamil (Teflaro ®)

I. Ceftaroline18-22 a. Extended spectrum or 5th generation cephalosporin b. First β-lactam available with MRSA activity

II. Mechanism of action a. Bactericidal action via binding to essential PBPs, thereby preventing cell wall synthesis b. MRSA activity: can bind PBP2a, unlike any other β-lactam

III. Spectrum of activity a. Gram positives, including MRSA, and common gram negatives b. NOT active against: ESβL or AmpC β-lactamases, Pseudomonas aeurginosa

IV. Approved uses a. Community acquired pneumonia (CAP) b. Acute bacterial skin and skin structure infection (ABSSSI)

V. Dose a. 600mg Q12H administered over 1 hour b. Requires renal adjustment for CrCl < 50 mL/min

Renal Function Ceftaroline Dose CrCl >30-50 mL/min 400mg Q12H CrCl 15-30 mL/min 300mg Q12H CrCl < 15 mL/min 200mg Q12H

ESRD on HD 200mg Q12H

VI. Adverse Reactions a. Diarrhea, nausea, rash, hypokalemia, ↑ LFTs b. Direct Coombs’ seroconversion

VII. Monitoring Parameters: renal function

VIII. Drug Interactions: minimal potential for interactions – not an inducer, inhibitor or substrate of CYP450 enzymes

IX. Resistance is expected to be minimal; however, ~2-3% are nonsusceptible at baseline

X. MIC Breakpoints1,18

MIC (mcg/mL) S I R

Vancomycin ≤ 2 4 – 8 ≥ 16 Daptomycin ≤ 1 NS NS Ceftaroline ≤ 1 2 ≥ 4

Table 4

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XI. Pharmacokinetics18 PK Parameter Value

Cmax 21 mcg/mL Tmax 1 hr AUC 56 mcg/mL/hr

Vd 20 L Protein binding 20%

T1/2 2.7 hrs Excretion Urine (88%); feces (6%)

XII. Pharmacodynamics18-19 a. Bactericidal time-dependent killing

i. f %T>MIC = percentage of time during the dosing interval that free-drug concentrations remain above MIC

ii. Goal f %T>MIC > 50% b. Van Wart et al23

i. Monte Carlo simulations: evaluated PK-PD target attainment by MIC in simulated patients following IV administration of ceftaroline 600mg Q12H and simulated patients with renal impairment administered various dosing regimens

ii. Bacterial Reduction Endpoints

f %T>MIC Bacterial Reduction Endpoint ≥ 26 Bacterial stasis ≥ 36 1-log10 CFU reduction ≥ 51 2-log10 CFU reduction

iii. Target attainment for ceftaroline 600mg Q12H for normal renal function (CrCl ≥ 80 mL/min)

1. MRSA with an MIC of 1 treated with ceftaroline 600mg Q12H in normal renal function resulted in 97% target attainment of f %T>MIC ≥ 51

2. MIC distribution was based on contemporary surveillance data iv. Conclusions

1. Ceftaroline dosed at 600mg Q12H in normal renal function attains appropriate PK-PD targets required for efficacy

2. Similar results were seen in renally adjusted ceftaroline dosing regimens

Table 5

Table 6

Figure 5

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XIII. Why even think about using ceftaroline for MRSA bacteremia? a. MRSA coverage b. Ceftaroline is a β-lactam c. Favorable PK/PD d. High barrier to resistance e. No need to monitor drug levels

XIV. Why are we even talking about ceftaroline? 5,24 a. β-lactams have better outcomes in MSSA bacteremia compared to vancomycin

i. Vancomycin kills staphylococci more slowly than β-lactams ii. Per guidelines “clearly inferior to β-lactams for MSSA bacteremia and

endocarditis” iii. Superior to vancomycin in preventing recurrence of bacteremia iv. Associated with lower mortality rates

b. Ceftaroline is a β-lactam

XV. FDA Approval Trials a. CANVAS I & II 25

i. Determine noninferiority of clinical cure rate with ceftaroline monotherapy, compared with that achieved with vancomycin plus aztreonam combination therapy for the treatment of complicated SSTIs

ii. Ceftaroline achieved high clinical cure rates and was efficacious against complicated SSTIs caused by MRSA and other common SSTI pathogens

iii. Small MRSA bacteremia subpopulation 1. In pooled analysis: trend towards higher clinical cure rate for vancomycin

plus aztreonam arm

Cure Rate, n/n (%)

Ceftaroline Vancomycin

plus aztreonam

MRSA Bacteremia 6/7 (85.7) 2/2 (100)

b. FOCUS I & II 26 i. Ceftaroline was evaluated for treatment of CAP in 2 randomized, double-blinded,

multicenter trials versus ceftriaxone ii. Ceftaroline was found to be noninferior to ceftriaxone iii. No MRSA bacteremia subgroup

Literature Review – Ceftaroline Monotherapy

I. Ho et al, 2012 a. Case series of 6 patients in which ceftaroline was utilized as salvage monotherapy for

persistent MRSAB or endocarditis II. Polenakovik et al, 2013

a. Retrospective chart review of 31 patients with MRSAB treated with ceftaroline III. Casapao et al, 2014

a. Retrospective observational multicenter study that analyzed clinical and microbiological outcomes of 527 patients treated with ceftaroline ≥ 72 hours

Table 7

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Ho et al, J Antimicrob Chemother. 2012;67:1267-127027

I. Case series of 6 patients in which ceftaroline was utilized as salvage monotherapy for persistent MRSAB or endocarditis a. Therapy was initiated with ceftaroline 600mg Q8H after multiple doses of MRSA-active

therapy i. Rationale for dosing: PD models and severity of infections

1. Ensure optimal %T>MIC

Source of MRSAB Days of Prior

Therapy (Agent)

Duration of Bacteremia

(days)

Ceftaroline Duration of Therapy (weeks)

Clinical Outcome

1 Endocarditis 13 (VAN) then 4 (DAP) 18* 6 Resolution

2 Endocarditis 15 (VAN) 15 3 (+ LZD x 3) Resolution

3 SSTI, uveitis, endocarditis 22 (VAN) 2** 3 (+

LZD x 3) Resolution

4 UTI 11 (VAN) 11 1.5 Death

5 Uveitis, ethmoid osteomyelitis 12 (VAN) 13 2 (+

VAN x 3) Resolution

6 Prostatitis, septic thrombophlebitis 8 (VAN) 13 3 (+

DAP for home IV) Resolution

* Bacteremia cleared after 13 days, but relapsed at day 17. Cleared again on day 18, day 1 of ceftaroline. ** Cleared bacteremia on day 2 of vancomycin, however developed uveitis on day 22 and was switched to ceftaroline

b. Characteristics of ceftaroline therapy i. Conversion to ceftaroline

1. Previous treatment: vancomycin or daptomycin 2. Median duration of previous therapy: 13.5 days 3. Short duration of bacteremia after switch to ceftaroline

ii. Complications 1. Acute respiratory failure that required intubation, evidence of GI bleed

! patient expired a. Factors not thought to be associated with infection

2. Limited patient follow-up information suggests clinical and microbiological cure with no relapses or emergence of resistance

c. Take Home Message i. First case series to report on use of ceftaroline for MRSAB ii. All patients received multiple doses of MRSA-active therapy prior to initiation with

ceftaroline and subsequently cleared their bacteremia iii. Limited follow-up does not give insight into long-term adverse events related to

prolonged duration of therapy with ceftaroline

Table 8

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Polenakovik et al. Internet J Antimicrob Agents. 2013;42:450-45528

I. Retrospective chart review of 31 patients with MRSAB treated with ceftaroline a. Inclusion/Exclusion

II. Sources

Source of Bacteremia Number of patients

Central venous catheter 7

Complicated ABSSSI 6

IVDU 5

Pneumonia 3

Arteriovenous graft 2

Orthopedic implant 1

Unknown 8 Met criteria for endocarditis 9

III. Most common rationales for ceftaroline use a. Vancomycin MIC ≥ 2 mcg/mL b. Persistent bacteremia c. Poor clinical response to therapy as documented by treating ID physician

IV. Characteristics of ceftaroline therapy

Ceftaroline Therapy Result, n (range)

Median duration of previous MRSA therapy, days 5 (1-30+)

Median duration of ceftaroline therapy, days 30 (7-60)

Median total daily dose of ceftaroline, mg 1200 (400-1800)

Patients receiving ceftaroline (n=112)

Patients meeting inclusion criteria (n=31)

Excluded (n=81) - No MRSAB (n=72) - Non-evaluable (n=4) - < 7 days of therapy - Bloodstream co-infection (n=2)

Table 9

Figure 6

Table 10

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V. Outcomes

Outcome Result, n (%) (n=31)

Clinical success 23 (74.2) Microbiological cure 20 (64.2)

Median time to clearance of bacteremia on ceftaroline, days 3 (1-8) Mortality 2 (6.5)

Recurrent bacteremia 3 (9.7)

VI. Adverse Events

Adverse Event N (%) (n=30)

Requiring cessation of treatment 3 (9.7) Antibiotic-associated diarrhea 2 (6.5)

Rash 1 (3.2) Eosinophilic pneumonia 1 (3.2) Peripheral eosinophilia* 2 (6.5)

*resolved without cessation of ceftaroline

VII. Take Home Message a. Larger case series in which ceftaroline was used successfully as salvage treatment b. Ceftaroline is a relatively safe drug when used for an extended period of time; however

clinicians need to be aware of rare occurrence of eosinophilia pneumonia

Table 11

Table 12

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Casapao et al. Antimicrob Agents and Chemother. 2014;58(5):2541-629

I. Retrospective observational multicenter study that analyzed clinical and microbiological outcomes of 527 patients treated with ceftaroline ≥ 72 hours a. Exclusion: ceftaroline was used for

i. Prophylactic therapy ii. Infection caused by an agent known to be resistant to ceftaroline alone without

MRSA infection

II. Characterization of Types of Infections

Characteristics Patients, n(%) (N=527)

S. aureus Infection

ABSSSI 175 (35.1) Bacteria 148 (28.1)

Pneumonia 99 (18.8) Bone and joint 81 (15.4)

Other 14 (2.7) Positive Culture Results S. aureus 327 (62)

MRSA 271/327 (89) Previous Antibiotic Use Vancomycin, daptomycin, or linezolid 422 (80.1)

III. Ceftaroline Usage

Ceftaroline Usage Patients, n(%) (N=527)

Rationale for ceftaroline use Disease progression on prior therapy 253 (48)

Simplified regimen for multiple indications 95 (18) Anticipated risk of toxicity 79 (15)

Ceftaroline dosing 600mg Q12H or renally adjusted

equivalent 452 (85.5)

600mg Q8H 76 (14.4)

IV. S. aureus Bacteremia Subpopulation

S. aureus Bacteremia Subpopulation Patients, n/n (%) or

n (range) (N=133)

S. aureus bacteremia 133/148 (90)

MRSA bacteremia 123/133 (92.5)

Off-label dosing (600mg Q8H) 44 (33.1)

Median duration of ceftaroline treatment during hospitalization, days 9 (4-16)

MRSA treatment prior to ceftaroline 143/148 (96.6)

Time to switch to ceftaroline, days 6 (3-11)

Time to clearance of bacteremia on ceftaroline, days 2.5

Table 13

Table 14

Table 15

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V. Outcomes

Overall Outcomes Overall S. aureus Bacteremia Clinical success rate 426/484 (88) 101/129 (78.3)

Microbiological cure -- 21/148 (14.8) Mortality during hospitalization 40/527 (7.6) 109/120 (90.8)

VI. Outcomes by Dosing Strategy in Bacteremia Subgroup

VII. Adverse Reactions

Result Experienced any adverse reaction, n/n (%) 41/527 (8)

Patient in bacteremia subgroup with adverse reaction, n/n (%) 19/148 (13) Patients receiving off-label dosing with adverse reaction, n/n (%) 13/76 (17) Median duration of ceftaroline to onset of adverse reaction, days 6

Most common adverse reactions

Renal failure*, diarrhea, vomiting, nausea, rash*, hypokalemia, C. difficile

associated diarrhea

*adverse reaction more common and occurred in patients receiving off-label dosing

VIII. Take Home Message a. Large observational analysis of patients receiving ceftaroline with a high MRSA

bacteremia population b. Similar success rates and time to clearance of bacteremia to those in previous case

reports/series c. No difference in clinical cure in MRSA bacteremia using standard or off-label dosing d. Ceftaroline was also well tolerated with low frequencies of adverse events

i. More adverse events were seen in off-label dosing ii. No reports of treatment cessation

e. A longer duration of ceftaroline therapy is warranted to fully evaluate tolerability f. Use of off-label dosing, 600mg Q8H, may have potential in treatment of severe infections

but deserves further investigations, especially in bacteremia

79%

20%

79%

20% 0

20

40

60

80

100

Clinical Cure Clinical Failure

Standard Dosing

Off-label Dosing

Table 16

Figure 7

Table 17

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Ceftaroline and Daptomycin Combination Therapy

I. Daptomycin plus β-lactam synergy30-33 a. Guidelines mention combination of daptomycin and anti-staphylococcal β-lactams as an

option for salvage therapy b. In vitro studies have shown enhanced killing using the combination c. Daptomycin plus ceftaroline – In vitro data shows that the combination appears to be

potent, with rapid and sustained bactericidal activity II. Sakoulas et al34

a. Retrospective analysis of 26 cases of refractory staphylococcal bacteremia treated with daptomycin and ceftaroline as salvage therapy

b. Types of Infections

Infection Characteristics Results, n (%) or median (range)

(n=26)

Staphylococcal Infection

MRSA 20 (76) MSSA 2 (8) VISA 2 (8)

Methicillin-resistant S. epidermidis 2 (8) Patients with MRSAB and endocarditis 10/20 (50)

Daptomycin + ceftaroline salvage therapy

Second-line therapy 8 (31) Third-line therapy 13 (50)

Fourth-line therapy 5 (19) Bacteremia duration prior to combination therapy, days 10 (3-23)

c. Ceftaroline Usage

Ceftaroline Usage Results, n (%) or median (range)

(n=26)

Ceftaroline dosing Q8H 5 (19)

Q12H 19 (73) Q24H 2 (8)

Duration of combination therapy, days 16 (3-16) Duration of combination therapy plus follow-up antibiotics, days 42 (8-132) Duration of bacteremia after combination therapy, days 2 (1-6)

d. Outcomes i. Survival: 25/26 patients (96%) ii. Adverse Effects

1. No adverse effects attributed to ceftaroline 2. Eosinophilic pneumonia attributed to daptomycin

iii. In Vitro Testing: 1. Combination demonstrated considerable synergy over each drug alone 2. Ceftaroline induces daptomycin binding in MSSA and MRSA comparably

to nafcillin 3. Significantly enhances neutrophilic killing of MRSA

e. Take Home Message i. Combination therapy with daptomycin and ceftaroline appears to rapidly clear

bacteremia in two days 1. Results are similar to those seen in ceftaroline monotherapy case series

ii. No adverse effects were attributed to ceftaroline; however, eosinophilic pneumonia was seen in ceftaroline monotherapy

Table 18

Table 19

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Controversies with Ceftaroline

I. Controversies a. Where is ceftaroline’s place in MRSAB therapy? b. What is the optimal dose? c. When should ceftaroline monotherapy be used versus combination therapy?

II. Pros/Cons

Pros Cons Bactericidal agent with good MRSA activity

even against vancomycin resistant and daptomycin nonsusceptible strains

Off-label dosing (600mg Q8H)

Clearance of bacteremia is quick (2-3 days)

Faster clearance of bacteremia was seen after many days of vancomycin or daptomycin,

unsure of effect of previous therapy

Regimens have been well tolerated Limited follow up data - unknown side effects of

prolonged course of therapy required for bacteremia and higher off-label dosing strategy

Favorable PK/PD profile Lack of randomized control trials, only case reports/series

III. Where does ceftaroline fit in? a. Vancomycin or daptomycin are still first line b. Ceftaroline is an option for salvage treatment for MRSAB

i. Take into account the clinical scenario and condition of the patient ii. Bacteremia persists > 7 days and received adequate treatment iii. Vancomycin resistance and daptomycin nonsusceptibility iv. Allergies or intolerance of vancomycin or daptomycin

IV. What is the optimal dose for ceftaroline? a. FDA approved dose is 600mg Q12H for ABSSSI and CAP b. Dose was validated by PK-PD studies previously mentioned c. However – Vidaillac et al conducted an in vitro PK-PD study comparing Q12H vs Q8H35

i. Target f %T>MIC > 50% for bactericidal effect ii. 12 hour regimen: f %T>MIC = 83% iii. 8 hour regimen: f %T>MIC = 100% iv. This was in the strains with an MIC = 0.5 mcg/mL v. No difference in time-kill curves between Q12H versus Q8H

1. Except ceftaroline was superior in VISA/VRSA strains

V. Potential for more adverse events with higher dose a. Concern with longer treatment durations required for bacteremia and endocarditis b. Casapao et al showed higher incidence of adverse events with off-label dosing c. Eosinophilic pneumonia

i. Required treatment cessation in one patient in Polenakovik et al ii. Attributed to daptomycin in combination therapy case series

d. Hematologic toxicities i. Jain et al36

1. Retrospective review of 12 cases treated with ceftaroline for refractory staphylococcal infections

2. 9/12 (75%) discontinued due to adverse effects

Table 20

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3. 7/12 discontinued due to hematologic toxicities – neutropenia or anemia 4. Average time to discontinuation: 22 days

ii. Furtek et al37 1. Retrospective analysis of 41 patients that received at least 7 days of

ceftaroline 2. 5 (12%) patients developed neutropenia requiring treatment cessation

iii. Neurotoxicty38 1. Higher doses of cefepime in mild renal impairment leading to higher

troughs, was associated with neurotoxicity 2. Will there be similar results with ceftaroline?

VI. Ceftaroline monotherapy versus combination therapy with daptomycin a. In vitro studies have shown the combination of daptomycin and ceftaroline to be potently

bactericidal, more so than using either agent alone b. No difference in time to clearance of bacteremia using the combination therapy vs

ceftaroline alone seen in case series c. Potential for additive side effects using prolonged therapy with both agents d. Expensive regimen e. Would be interesting to see if combination therapy can be used to clear bacteremia and

then de-escalate to a single agent

Conclusions

I. Vancomycin or daptomycin remain first line therapies for MRSA bacteremia II. Ceftaroline is an valid option for salvage therapy in the populations described

a. Bacteremia persists > 7 days and received adequate treatment b. Vancomycin resistance and daptomycin nonsusceptibility c. Allergies or intolerance of vancomycin or daptomycin

III. Dosing is controversial as there is potential for increase of adverse events with prolonged duration of high dose therapy a. Available data doesn’t seem to show a difference between Q12H and Q8H dosing b. Many of the patients in the case series were treated successfully with Q8H c. Prefer Q8H dosing, especially in these very ill patients, until there is more data

IV. At this time, I would not recommend use of ceftaroline and daptomycin combination therapy over ceftaroline monotherapy a. No advantage over ceftaroline in clearance of bacteremia

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