CAMERA2 Trial: Combination Antibiotic

Therapy for Methicillin Resistant

Staphylococcus Aureus Infection
Maddie Tompkins, PharmD
PGY1 Pharmacy Resident
March 26th, 2020
 Epidemiology
Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia
is associated with 20-30% mortality

120,00 MRSA
bacteremia 20,000
cases associated
deaths

2
MMWR Morb Mortal Wkly Rep. 2019;68(9):214-219.
 Resistance Mechanisms
MRSA expression of
mecA gene encodes
an alternative mecA:
penicillin-binding PBP2a
protein (PBP2a)
blaZ:
penicillinase

3
Peacock SJ, et al. Annu Rev Biochem. 2015;84:577-601
 Standard Therapy
Poor tissue Cost
penetration
VS Inactivation
Slow
bactericidal by
activity surfactant
Vancomycin and daptomycin have multiple disadvantages
In vitro and ex vivo studies suggest synergy with the addition
of a beta-lactam
4
Liu C, et al. Clin Infect Dis. 2011;52(3):e18-e55.
 Seesaw Effect
Alterations in the cell surface Beta-lactam
which improves vancomycin-cell MICs
wall interactions
Reduction in cell wall thickness Glycopeptide
Prevention of vancomycin MICs
sequestration

5
Tran KN, et al. Antimicrob Agents Chemother. 2018 May 25;62(6).
 Hagihara et al.

6
Hagihara M, et al. Antimicrob Agents Chemother. 2012 Jan;56(1):202-7.
 Retrospective Trials
Study Cohorts Outcomes Results Conclusion
Casapao Vancomycin Composite: 30-day 30% vs 24.6% Associated with
et al. monotherapy vs mortality, persistent (p=0.552) expedited
vancomycin + bacteremia, bacteremia bacteremia
beta-lactam relapse, change in clearance
therapy due to
worsening
Median duration of 4 vs 3 days
bacteremia (p=0.048)

Dilworth Vancomycin Persistent bacteremia 43.9% vs 26.7% Reduction in

et al. monotherapy vs. (P=0.027) persistent
vancomycin + bacteremia with
AKI 7.6% vs 18.9%
beta-lactam a nonsignificant
(P=0.062)
trend towards
AKI
7
Casapao AM, et al. Pharmacotherapy. 2017 Nov;37(11):1347-1356.
Dilworth TJ, et al. Antimicrob Agents Chemother. 2019 Feb 26;63(3).
 CAMERA Pilot Trial
Davis et al. 2016
Objective • To determine and compare the average duration of MRSA bacteremia in each
treatment arm
Outcomes • Duration of MRSA bacteremia in days
• Combined safety endpoint: nephrotoxicity, hepatotoxicity, 28- and 90-day
mortality, relapsed bacteremia, metastatic complications, ICU admission,
development of septic shock
Methods • Multicenter, open-label, parallel-group RCT
• Vancomycin with goal mean trough of 15 mg/L or vancomycin + flucloxacillin for
the first 7 days
Results • Duration of bacteremia: 3 days vs 1.94 days (P=0.06)
• No difference in secondary safety endpoints

8
Davis et al. Clin Infect Dis. 2016 Jan 15;62(2):173-180.
Objectives
• To determine whether the combination of an
antistaphylococcal beta-lactam with standard therapy is more
effective than monotherapy in patients with MRSA bacteremia

Study Design
• Multicenter, open-label, randomized controlled trial
• Conducted from August 2015 to July 2018

Interventions
• Standard therapy: IV vancomycin (trough goal 15-20 mg/dL) or
IV daptomycin 6-10 mg/kg/day
• Standard therapy + IV flucloxacillin, cloxacillin, or cefazolin for
7 days
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Primary Outcome Measures
Composite outcome at 90 days
All-cause mortality
Persistent bacteremia at ≥ day 5
Microbiological relapse – positive blood culture for MRSA at
least 72 hours after a negative culture
Microbiological treatment failure – positive sterile site culture
for MRSA at least 14 days after randomization

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Secondary Outcome Measures
All-cause mortality at 14, 42, and 90 days
Proportion with persistent bacteremia at day 2
Persistent bacteremia at ≥ day 5
Proportion with AKI within the first 7 days OR new need for any
form of RRT in the first 90 days
Microbiological relapse and treatment failure
Duration of IV antibiotic treatment

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Inclusion/Exclusion Criteria
- Age ≥ 18 years
- ≥1 set of blood cultures
positive for MRSA
- Randomized within 72
hours of blood culture
collection
- Remain inpatient for 7 days
following randomization
- Previous type 1
hypersensitivity to beta-
lactams
- Polymicrobial bacteremia
- Known pregnancy
- Current beta-lactam
therapy cannot be ceased or
substituted
- Moribund (expected death
within 48 hours)
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Statistics
Sample size of 440 to detect an absolute reduction in the primary
endpoint of 12.5%
Modified intention-to-treat analysis
Categorical data: Fischer exact test
Continuous data: Mann-Whitney U test or t test
Post hoc analyses adjusted for randomization variables (study site and
hemodialysis) via mixed-effects models
No assumptions made about missing data
No adjustments made for multiple comparisons
Planned interim analysis after 220 patients 13
Planned Interim Analysis
Increased
rates of Early termination
AKI of recruitment

Further
collection
of serum
creatinine
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 Baseline Characteristics
Characteristic Combination Therapy Standard Therapy
(n=174) (n=178)
Maintenance dialysis, No. (%) 25 (14) 30 (17)
Pitt bacteremia score, median 2 (2-3) 2 (2-3)
(IQR)
SOFA score, median (IQR) 2 (1-4) 1 (0-4)
Indwelling vascular device, 95 (55) 97 (54)
No. (%)
Indwelling prosthetic valve or 20 (11) 14 (8)
cardiac device, No. (%)
IV drug use in last 30 days, 14 (8) 16 (9)
No. (%) 15
 Baseline Characteristics
Infection Foci, No. (%) Combination Therapy Standard Therapy
(n=178) (n=178)
SSTI 40 (23) 50 (28)
Primary blood stream 34 (20) 35 (20)
Native osteoarticular 31 (18) 27 (15)
CLABSI 25 (14) 22 (12)
Pleuropulmonary 13 (7) 11 (6)
infection
Device related 9 (5) 9 (5)
Infective endocarditis 9 (5) 6 (3)
Infective endocarditis 26 (15) 16 (9) 16
 Baseline Characteristics
Vancomycin MIC, No. (%) Combination Therapy Standard Therapy
≤ 1 mcg/mL 152/160 (95) 153/161 (95)
2 mcg/mL 8/160 (5) 8/161 (5)

Characteristics, No. (%) Combination Therapy Standard Therapy

Vancomycin 171 (98) 178 (100)
Daptomycin 7 (4) 6 (3)
Nonstudy antibiotics 53 (30) 48 (27)
days 1-7
Infected source removed 77/106 (73) 84/105 (80)
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Time to source control 0 (-1 to 2) 0 (-1 to 2)
Primary Outcomes
59 (35%) in the
combination therapy
Standard
group and 68 (39%) in
the standard therapy
group met the primary
outcome at day 90 Combination

(-4.2%; 95% CI, -14.3%

to 6.0%; P=0.42) 10 20 30 40 50

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 Secondary Outcomes
Outcomes Combination Standard P-Value
All-cause mortality
Day 14 13/170 (8%) 13/174 (7%) 0.95
Day 42 25/170 (15%) 19/174 (11%) 0.29
Day 90 35/170 (21%) 28/174 (16%) 0.28
Persistent bacteremia

Day 2 50/167 (30%) 61/173 (35%) 0.29

Day 5 19/166 (11%) 35/172 (20%) 0.02
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 Secondary Outcomes
Outcomes Combination Standard P-Value
Microbiological relapse 14/169 (8%) 18/175 (10%) 0.52
Microbiological treatment 16/170 (9%) 17/175 (10%) 0.92
failure
AKI 34/145 (23%) 9/145 (6%) <0.001
Duration of IV antibiotics, 29.3 (19.5) 28.1 (17.4) 0.72
mean (SD), days

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Occurrence of AKI
AKI Combination Standard Therapy
Therapy (n=145) (n=145)
None 109 (75%) 132 (91%)
Stage 1 18 (12%) 8 (6%)
Stage 2 7 (5%) 3 (2%)
Stage 3 11 (8%) 2 (1%)

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 Subgroup Analyses for Primary Outcome
Subgroup Analysis Combination Standard P-value for
Therapy, No (%) Therapy, No (%) interaction
Backbone drug 0.39
Vancomycin 56/165 (34%) 67/172 (39%)
Daptomycin 3/5 (60%) 1/3 (33%)
Dialysis 0.23
Not receiving 52/145 (36%) 54/145 (37%)
Receiving 7/25 (28%) 14/30 (47%)
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Discussion/Conclusion
• No statistically
significant difference in the
composite 90-day primary
outcome

• Early termination
due to higher rates of AKI
in the combination therapy
group

23
Strengths
• Included hemodialysis patients
• Reported vancomycin MIC data
• Addressed source control and time to source
control
• Evaluated almost all patients for endocarditis
Limitations
• Vancomycin trough dosing; goal 15-20 mcg/mL
• Underpowered
• Small proportion of patients with endocarditis
• No adjustments made for multiple comparisons
• Few patients received cefazolin which may be less
nephrotoxic 24
Clinical Impact
Additional studies should be conducted to compare vancomycin
AUC dosing with the addition of a beta-lactam (cefazolin or
nafcillin) for the first 7 days
Outcome measures should include mortality, persistent
bacteremia, and AKI

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CAMERA2 Trial: Combination Antibiotic
Therapy for Methicillin Resistant
Staphylococcus Aureus infection
Maddie Tompkins, PharmD
PGY1 Pharmacy Resident
March 26th, 2020
Resources
 Peacock SJ, Paterson GK. Mechanisms of Methicillin Resistance in Staphylococcus aureus. Annu Rev
Biochem. 2015;84:577-601. doi: 10.1146/annurev-biochem-060614-034516
 Liu C, Bayer A, Cosgrove SE, et al; Infectious Diseases Society of America. 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
 Tran KN, et al. β-Lactam Combinations with Vancomycin Show Synergistic Activity against Vancomycin-
Susceptible Staphylococcus aureus, Vancomycin-Intermediate S. aureus (VISA), and Heterogeneous VISA.
Antimicrob Agents Chemother. 2018 May 25;62(6).
 Tong SYC, Lye DC, Yahav D, et al. Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal
β-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: A
Randomized Clinical Trial. JAMA. 2020;323(6):527–537. doi:10.1001/jama.2020.0103
 Hagihara M, Wiskirchen DE, Kuti JL, Nicolau DP. In vitro pharmacodynamics of vancomycin and cefazolin
alone and in combination against methicillin-resistant Staphylococcus aureus. Antimicrob Agents
Chemother. 2012 Jan;56(1):202-7.

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Resources
 Casapao AM, Jacobs DM, Bowers DR, Beyda ND, Dilworth TJ; REACH-ID Study Group. Early administration
of adjuvant β-lactam therapy in combination with vancomycin among patients with methicillin-resistant
Staphylococcus aureus bloodstream infection: a retrospective, multicenter analysis. Pharmacotherapy.
2017;37(11):1347-1356
 Dilworth TJ, Casapao AM, Ibrahim OM, Jacobs DM, Bowers DR, Beyda ND, Mercier RC. Adjuvant β-Lactam
Therapy Combined with Vancomycin for Methicillin-Resistant Staphylococcus aureus Bacteremia: Does β-
Lactam Class Matter? Antimicrob Agents Chemother. 2019 Feb 26;63(3).
 Davis JS, Sud A, O'Sullivan MVN, et al. Combination of Vancomycin and β-Lactam Therapy for Methicillin-
Resistant Staphylococcus aureus Bacteremia: A Pilot Multicenter Randomized Controlled Trial. Clin Infect
Dis. 2016 Jan 15;62(2):173-180.

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