Antimicrobial Activity of Ceftaroline and Other Anti-Infective Agents against Microbial Pathogens Recovered from the Surgical Intensive Care Patient Population: A Prevalence Analysis

Abstract

Background:

Ceftaroline is a new parenteral cephalosporin agent with excellent activity against methicillin-sensitive (MSSA) and resistant strains of Staphylococcus aureus (MRSA). Critically ill surgical patients are susceptible to infection, often by multi-drug-resistant pathogens. The activity of ceftaroline against such pathogens has not been described.

Methods:

Three hundred thirty-five consecutive microbial isolates were collected from surgical wounds or abscesses, respiratory, urine, and blood cultures from patients in the surgical intensive care unit (SICU) of a major tertiary medical center. Using Clinical and Laboratory Standards Institute (CLSI) standard methodology and published breakpoints, all aerobic, facultative anaerobic isolates were tested against ceftaroline and selected comparative antimicrobial agents.

Results:

All staphylococcal isolates were susceptible to ceftaroline at a breakpoint of ≤1.0 mcg/mL. In addition, ceftaroline exhibited excellent activity against all streptococcal clinical isolates and non-ESBL-producing strains of Enterobacteriaceae (93.5%) recovered from SICU patients. Ceftaroline was inactive against ESBL-producing Enterobacteriaceae, Pseudomonas aeruginosa, vancomycin-resistant enterococci, and selective gram-negative anaerobic bacteria.

Conclusions:

At present, ceftaroline is the only cephalosporin agent that is active against community and healthcare-associated MRSA. Further studies are needed to validate the benefit of this novel broad-spectrum anti-infective agent for the treatment of susceptible serious infections in the SICU patient population.

Ceftaroline, a parenteral anti-infective agent is the first β-lactam agent to express potent activity against methicillin-resistant Staphylococcus aureus [1 –3]. Ceftaroline fosamil expresses activity that includes heterogeneous vancomycin (VAN)-intermediate S. aureus (hVISA/VISA), VAN-resistant S. aureus (VRSA) and daptomycin nonsusceptibile S. aureus (DNS). This broad anti-staphylococcal activity is due to ceftaroline's affinity for multiple penicillin-binding proteins (PBP) [4]. Ceftaroline also exhibits potent activity against bacteria associated with community-acquired pneumonia and other select gram-negative microorganisms [5 –8].

The present investigation looks at the in-vitro gram-positive and gram-negative activity of ceftaroline and other anti-infective agents from sequential non-duplicate cultures obtained from a surgical intensive care unit (SICU) over a six-month interval in an academic medical center.

Materials and Methods

SICU bacterial isolates

From November 1, 2013, to April 30, 2014, a total of 355 microbial isolates were recovered from consecutive non-duplicate (one per patient) cultures representative of multiple sites of infection (surgical wounds or abscesses, respiratory, urine, and blood) obtained from SICU patients in a major tertiary medical center. All cultures were processed and identified using standard methodology at Dynacare Laboratories, Milwaukee, WI, and transported to the Surgical Microbiology Research Laboratory in the Department of Surgery for in vitro susceptibility testing [9]. Recovered isolates were assessed as either community- or healthcare-associated infection based upon criteria defined by the National Healthcare Safety Network (NHSN) [10].

Antimicrobial agents

The agents tested against collective aerobic and facultative anaerobic isolates included ceftaroline, ceftriaxone, cefepime, cefuroxime, daptomycin, moxifloxacin, pipercillin-tazobactam, meropenem, vancomycin, and tigecycline. Agents tested against selective anaerobic clinical isolates included ceftaroline, moxifloxacin, meropenem, clindamycin, and metronidazole. Ceftaroline standard powder was supplied by Forest Laboratories, Inc., (New York, NY). The other laboratory-grade powders were obtained from Sigma Chemicals (St. Louis, MO) or the United States Pharacopeial Convention, (USP, Rockville, MD). All powders were reconstituted as per manufacturer's recommendations. Ceftaroline was dissolved in 30% dimethyl sulfoxide and diluted further using 0.85% saline.

Antimicrobial susceptibility testing

Isolates were tested for susceptibility to ceftaroline and multiple comparator anti-infective agents by microbroth dilution as described by the Clinical and Laboratory Standards Institute (CLSI) M07-A9 (2012) [11]. Briefly, overnight aerobic cultures were suspended in 0.85% saline, diluted with sterile water, and added to the microdilution trays using a plastic inoculator device for a final concentration of approximately 5.7 log₁₀ colony-forming units (CFU)/ml. Isolates were tested in cation-adjusted Mueller–Hinton broth (CA-MHB). Calcium supplemented with 2.5–5.0% lysed horse blood agar was used for testing streptococci (CLSI, 2012). The 96-well trays were incubated overnight at 35°C and minimum inhibitory concentrations (MIC) were determined. The extended-spectrum β-lactamase (ESBL) phenotype for selected strains of Enterobacteriaceae was determined per CLSI guidelines (CLSI, 2013) [5,12]. Anaerobic isolates were tested using the agar-dilution procedure described in the CLSI document M11-A8E [13]. After 48 h of incubation in an anaerobic chamber, the isolates were suspended in Brucella broth, diluted to a 0.5 McFarland standard, inoculated to agar plates using a Steers apparatus (approximately 5.0 log₁₀ CFU/mL) and incubated at 35°C for 48 h. Microbroth and agar-dilution plates were prepared the day of testing. The MIC was defined as the lowest concentration of drug that inhibited completely visible growth as per endpoint interpretation. The CLSI interpretative criteria were applied according to M100-S23 (CLSI, 2013) [12]. United States Food and Drug Administration (FDA) breakpoint criteria were used for ceftaroline and tigecycline (Teflaro^® [Forest Laboratories, New York, NY] and Tygacil^® [Pfizer, Inc., New York, NY] package inserts 2012). Quality control (QC) test strains for aerobic and facultative susceptibility testing included S. aureus ATCC 29213, Enterococcus faecalis ATCC 29212, S. pneumoniae ATCC 49619, Escherichia coli ATCC 25922 and 35218; wheras Bacteroides fragilis ATCC 25285 and Clostridium difficile ATCC 700057 QC strains were used for anaerobic in-vitro testing (American Type Culture Collective, Rockville, MD). All QC values were within an appropriate range as per CLSI (CLSI, 2013) parameters.¹²

Results

A total of 323 of the 355 (90.9%) clinical isolates recovered from surgical ICU patients were characterized by NHSH criteria as healthcare- (hospital-acquired) associated microbial isolates. Table 1 reviews the demographic data and microbial recovery from each culture site. Thirty-nine percent of the isolates were recovered from surgical wound or abscess cultures, 28.1% from respiratory cultures, 18.3% from urine cultures, and 14.6% of the isolates were recovered from blood cultures; overall, gram-positive isolates outnumbered gram-negative, 213 versus 142, and the ratio of aerobic to anaerobic isolates was approximately 10:1 (323 versus 32). Tables 2A–D document the microbial recovery from cultures collected over a six-month interval from the SICU. The number of gram-positive aerobic and facultative microbial isolates recovered from surgical wound or abscess cultures (Table 2A) exceeded gram-negative isolates by a factor exceeding 2:1 (73 versus 32). Methicillin-resistant Staphylococcus aureus (MRSA) was recovered from 7.5% of wound and or abscess cultures, wheras methicillin-sensitive S. aureus was recovered from 2.8% of surgical wound or abscess cultures. Streptococcus spp. were the most frequent gram-positive isolates recovered (15.2%), followed by coagulase-negative staphylococci (11.6%). Enterobacteriaceae including ceftazidime-susceptible strains of Escherichia coli, Klebsiella pneumoniae, and K. oxytoca were recovered from 10.9% of surgical wound or abscess cultures, wheras ceftazidime-resistant K. pneumoniae accounted for 2.2% of all surgical wound or abscess cultures isolated over the six-month study period. Pseudomonas spp. accounted for 6.6% of all surgical wound or abscess isolates. Aerobic and facultative isolates outnumbered anaerobic microbial isolates by 3:1 (105 versus 33). Bacteroides fragilis complex were the predominant gram-negative anaerobic isolates recovered from surgical wound or abscess cultures, accounting for 54.5% of all anaerobic isolates. Clostridium perfringens was the second most frequent anaerobe recovered from surgical wound or abscess cultures (24.2%). Twenty-five percent of all surgical wound or abscess cultures were polymicrobial.

Table 1.

Demographics of SICU Isolates from Selective Culture Sources

			Gram stain
Source	N	%	Positive	Negative	Aerobes/Anaerobes
Surgical wound or abscess	138	39.0	84	54	105	33
Respiratory	100	28.1	58	42	100	0
Urine	65	18.3	32	33	65	0
Blood	52	14.6	39	13	52	0
Total	355	100.0	213	142	322	33

SICU=surgical intensive care unit.

Table 2A.

Percent Microbial Recovery from Surgical ICU Surgical Wound or Abscess Cultures

Isolates	N	Percent (%)
Gram-positive
Staphylococcus aureus	4	2.8
MRSA	10	7.5
Coagulase negative staphylococci	16	11.6
Enterococcus faecalis	13	9.4
Enterococcus faecium^a	9	6.4
Streptococcus spp.^b	21	15.2
		52.9
Gram-negative
Enterobacteriaceae (ceftazidime-susceptible)^c	15	10.9
Enterobacteriaceae (ceftazidime-resistant)^d	3	2.2
Moraxella catarrhalis	2	1.4
Stenotrophomonas maltophilia	1	0.7
Pseudomonas aeruginosa	8	5.9
Pseudomonas putida	1	0.7
Haemophilus parainfluenzae	2	1.4
		23.2
Anaerobes
Bacteroides fragilis complex^e	18	13.3
Prevotella spp.	3	2.2
Fusobacterium nucleatum	1	0.7
Clostridium perfringens	8	5.9
Proprionibacterium acnes	1	0.7
Peptostreptococcus anaerobius	2	1.4
		23.9
Total	138	100

Includes 6 vancomycin-resistant enterococci (VRE).

3 - S. aglactiae, 4 - S. dysgalactiae (Groups C and G), 1 - Streptococcus pneumoniae, 4 - Streptococcus anginosus group, 8 - Streptococcus viridans group, and 1 - Streptococcus mitis group.

6 - Escherichia coli, 2 – Klebsiella pneumoniae, 2 - Enterobacter cloacae, 1 - Proteus mirabilis, 1 - Citrobacter amalonaticus, 1 - Enterobacter aerogenes, 1 – K. oxytoca,

3 - K. pneumoniae.

Includes 8 – B. fragilis, 7 – B. vulgatus, 1 – B. caccae, 1 – B. uniformis, 1 – B. ovatus.

ICU=intensive care unit.

Table 2B.

Percent Microbial Recovery from Surgical ICU Respiratory Cultures

Isolates	N	Percent
Gram-positive
Staphylococcus aureus	27	27
MRSA	11	11
Coagulase negative staphylococci	2	2
Enterococcus faecalis	3	3
Enterococcus faecium	1	1
Streptococcus spp.^a	14	14
		58.0
Gram-negative
Enterobacteriaceae (ceftazidime-susceptible)^b	15	15
Enterobacteriaceae (ceftazidime-resistant)^c	1	1
Haemophilus influenzae	9	9
Stenotrophomonas maltophilia	2	2
Achromobacter xylosoxidans	2	2
Acinetobacter spp.	1	1
Pseudomonas aeruginosa	12	12
		42.0
Total	100	100

1 - S. mitis, 1 - S. oralis, 2 – S. dysgalactiae group G, 4 - S. pneumonia, 4 - Streptococcus anginosus group, and 2 - S. agalactiae.

3 - Escherichia coli. 3 - Klebsiella pneumoniae, 2 – K. oxytoca, 1 - Enterobacter cloacae, 1 -Enterobacter aerogenes, 1 - Serratia marcescens, 1 - Proteus mirabilis, 1 – E. absuriae, 1 - Morganella morganii, 1 - Hafnia alvei.

1 – K. pneumoniae.

ICU=intensive care unit; MRSA=methicillin-resistant S. aureus.

Table 2C.

Percent Microbial Recovery from Surgical ICU Urine Cultures

Isolates	N	Percent
Gram-positive
MRSA	2	3.1
Coagulase negative staphylococci	4	6.2
Enterococcus faecalis	10	15.4
Enterococcus faecium^a	10	15.4
Enterococcus avium	1	1.5
Streptococcus spp.^b	4	6.2
Aerococcus spp.	1	1.5
		49.3
Gram-negative
Enterobacteriaceae (ceftazidime-susceptible)^c	24	36.9
Stenotrophomonas maltophilia	3	4.6
Pseudomonas aeruginosa	6	9.2
		50.7
Total	65	100

Includes 7 – vancomycin-resistant enterococci (VRE).

3 - S. dysgalactiae (Group C) and 1 - Streptococcus anginosus group.

11- Escherichia coli, 5 – Klebsiella pneumoniae, 3 - Enterobacter cloacae, 2 - Citrobacter freundii, 2 -Providencia stuartii, and 1 - E. aerogenes.

ICU=intensive care unit.

Table 2D.

Percent Microbial Recovery from Surgical ICU Blood Cultures

Isolates	N	Percent
Gram-positive
Staphylococcus aureus	8	15.5
MRSA	4	7.7
Coagulase negative staphylococci	16	30.8
Enterococcus faecalis	3	5.7
Enterococcus faecium (VRE)	1	1.9
Streptococcus spp.^a	4	7.7
Micrococcus spp.	2	3.8
Corynebacterium spp.	1	1.9
		75.0
Gram-negative
Enterobacteriaceae (ceftazidime-susceptible)^b	8	15.5
Enterobacteriaceae (ceftazidime-resistant)^c	1	1.9
Haemophilus infuenzae	1	1.9
Acinetobacter spp.	1	1.9
Pseudomonas aeruginosa	2	3.8
		25.0
Total	52	100

3 - Streptococcus viridans group and 1 - S. anginosus group.

3 - Escherichia coli, 2 - K. pneumoniae, 2 - Enterobacter cloacae and 1 – E. aerogenes.

1 - K. pneumoniae.

ICU=intensive care unit; MRSA=methicillin-resistant S. aureus.

Methicillin-susceptible S. aureus was the most common isolate (27%), recovered from lower respiratory tract cultures (Table 2B), followed by ceftazidime-susceptible Enterobacteriaceae (15%), Streptococcus spp. (14%), Pseudomonas aeruginosa (12%) and MRSA (11%). Ceftazidime-susceptible Enterobacteriaceae were the most predominant isolates (36.9%) recovered from SICU urine cultures (Table 2C). Vancomycin-susceptible and vancomycin-resistant enterococci (VRE) accounted for 32.3% of all urine isolates. Pseudomonas aeruginosa was the third most common (9.2%) urinary pathogen recovered over the six-month study interval. Coagulase-negative staphylococci were the most common (30.8%) gram-positive isolates recovered from blood cultures (Table 2D), followed by MSSA (15.5%), ceftazidime-susceptible Enterobacteriaceae (15.5%), Enterococcus spp. (7.7%) and MRSA (7.7%). The gram-positive isolates outnumbered the gram-negatives by a factor of 3:1 (39 versus 13).

The in vitro activity of ceftaroline and other anti-infective agents against microbial isolates recovered from surgical wounds or abscesses, respiratory, urine, and blood cultures are presented in Table 3. Since 2011, patients admitted to the SICU at Froedtert Hospital have been screened for MRSA nasal carriage and the incidence has ranged from 4.5% to 5.5%. The overall prevalence of MRSA recovered from SICU cultures was 38.8% during the study period. The overall prevalence of ESBL-producing Enterobacteriaceae recovered over the same six-month study interval was 7.4%. Ceftaroline demonstrated excellent activity against both MSSA and MRSA. One-hundred percent of MRSA strains recovered over the six-month study period from surgical wounds or abscesses, respiratory, urine, and blood cultures were susceptible to ceftaroline (MIC₉₀:1.0 mcg/mL, range 0.25–1.0 mcg/mL). The comparative MIC₉₀ values for cefepime, ceftriaxone, and cefuroxime was >32 mcg/mL. Ceftaroline also demonstrated potent activity against coagulase-negative staphylococci (MIC₉₀: 0.5 mcg/mL compared with cefepime, ceftriaxone and cefuroxime (MIC₉₀:32 mcg/mL). Overall, ceftaroline exhibited greater potency against streptococcal isolates, including viridans Streptococcus, Streptococcus anginosus group, S. dyaglactiae (Groups C and G), S. pneumoniae, S. mitis, S. agalactiae, and S. oralis (MIC₉₀: 0.01 mcg/mL) compared with other anti-infectives, with the exception of cefepime and tigecycline (MIC₉₀ of 0.03 mcg/mL, respectively). Similar to other cephalosporins, ceftaroline exhibited reduced activity against E. faecalis (MIC ₉₀: 2 mcg/mL; range: 0.5–2.0 mcg/mL), wheras it was inactive against all E. faecium strains (MIC₉₀: >32 mcg/mL; range: 2->32 mcg/mL).

Table 3.

Activity of Ceftaroline and Comparator Antimicrobial Agents when Tested Against Consecutive, Non-Duplicate Gram-Positive and Gram-Negative Microbial Pathogens Recovered Over a Six-Month Period from Patients in the Surgical Intensive Care Unit (SICU)

	MIC (mcg/ml)
Organism and antimicrobial agent (no. of isolates tested)	MIC₅₀	MIC₉₀	Range
Gram-positive
Staphylococcus aureus (39)
Ceftaroline	0.12	0.25	≤0.06–0.25
Cefepime	1.0	4.0	0.5–16.0
Ceftriaxone	2.0	4.0	0.5–8.0
Cefuroxime	2.0	8.0	1.0–8.0
Daptomycin	0.12	0.5	0.12–5.0
Moxifloxacin	0.5	2.0	0.12–2.0
Vancomycin	1.0	1.0	0.5–1.0
Tigecycline	<0.12	0.25	≤0.06–0.5
Methicillin-resistant S. aureus (27)
Ceftaroline	0.5	0.5	0.25–1.0
Cefepime	>32.0	>32.0	8.0–>32.0
Ceftriaxone	>32.0	>32.0	16.0–>32.0
Cefuroxime	>32.0	>32.0	16.0–>32.0
Daptomycin	0.25	0.5	0.12–1.0
Moxifloxacin	4.0	>8.0	0.5–>8.0
Vancomycin	1.0	1.0	0.5–1.0
Tigecycline	0.12	0.25	≤0.06–0.5
Coagulase-negative staphylococci (38)^a
Ceftaroline	0.25	0.5	≤0.06–1.0
Cefepime	16.0	>32.0	0.5–>32.0
Ceftriaxone	16.0	>32.0	0.25–>32.0
Cefuroxime	8.0	>32.0	0.5–>32.0
Daptomycin	0.25	0.5	0.12–0.5
Moxifloxacin	0.25	>8.0	≤0.06–>8.0
Vancomycin	0.5	2.0	0.5–2.0
Tigecycline	0.12	0.25	0.12–0.25
Enterococcus faecalis (29)
Ceftaroline	0.5	2.0	0.5–2.0
Cefepime	16.0	>32.0	16.0–>32.0
Ceftriaxone	16.0	>32.0	8.0–>32.0
Cefuroxime	32.0	>32.0	16.0–>32.0
Daptomycin	0.5	0.5	0.25–1.0
Moxifloxacin	2.0	>8.0	1.0–>8.0
Piperacillin-tazobactam	2.0	4.0	1.0–16.0
Vancomycin	2.0	4.0	0.25–4.0
Tigecycline	<0.25	0.5	≤0.06–1.0
Enterococcus faecium (22)^b
Ceftaroline	32.0	>32.0	2.0–>32.0
Cefepime	>32.0	>32.0	>32.0
Ceftriaxone	>32.0	>32.0	>32.0
Cefuroxime	>32.0	>32.0	>32.0
Daptomycin	0.5	1.0	0.25–2.0
Moxifloxacin	2.0	>8.0	>8.0
Piperacillin-tazobactam	>128.0	>128.0	8.0>128.0
Vancomycin	2.0	>16.0	0.5–>16.0
Tigecycline	0.25	0.25	0.06–0.5
Streptococcus spp. (43)^c
Ceftaroline	≤0.01	≤0.01	≤0.01–0.25
Cefepime	0.03	0.03	0.03–0.5
Ceftriaxone	≤0.01	2.0	≤0.01–4
Cefuroxime	0.12	0.25	0.12–8.0
Daptomycin	≤0.01	0.12	≤0.01–0.25
Clindamycin	0.12	>32.0	0.5–>32.0
Moxifloxacin	0.25	1.0	0.12–1.0
Tigecycline	≤0.01	0.03	≤0.01–0.12
Gram-Negative
Enterobacteriaceae (ceftazidime-susceptible) (62)^d
Ceftaroline	0.03	0.5	≤0.01–4.0
Cefepime	0.03	1.0	0.1–16.0
Ceftriaxone	0.12	0.25	≤0.1–2.0
Cefuroxime	0.12	0.25	≤0.01–4.0
Meropenem	0.06	0.06	0.06–0.5
Moxifloxacin	0.12	4.0	0.12–8.0
Piperacillin-tazobactam	1.0	2.0	0.12–>128
Enterobacteriaceae (ceftazidime-resistant) (5)^e
Ceftaroline			32.0–> 32.0
Cefepime			>32.0
Ceftriaxone			>32.0
Cefuroxime			>32.0
Meropenem			0.12–4
Moxifloxacin			0.3–>8.0
Piperacillin-tazobactam			>128.0
Haemophilus spp. (12)^f
Ceftaroline	0.03	0.03	≤0.01–0.06
Cefepime	0.5	0.5	0.12–0.5
Ceftriaxone	0.06	0.06	≤0.1–0.12
Cefuroxime	0.5	2.0	0.03–0.12
Meropenem	≤0.01	0.25	≤0.01–0.25
Moxifloxacin	≤0.01	0.06	≤0.01–0.06
Piperacillin-tazobactam	0.25	0.25	0.25–0.5
Moraxella catarrhalis (2)
Ceftaroline			≤0.01
Cefepime			0.12
Ceftriaxone			0.06
Cefuroxime			0.06
Moxifloxacin			0.01
Piperacillin-tazobactam			0.12
Pseudomonas spp. (29)^g
Ceftaroline	16.0	32.0	2.0–>32.0
Cefepime	8.0	16.0	4.0–>32.0
Ceftriaxone	16.0	>32.0	8.0–>32.0
Cefuroxime	16.0	>32.0	16.0–>32.0
Meropenem	0.5	16.0	0.1–>8.0
Moxifloxacin	0.5	4.0	0.25–>8.0
Piperacillin-tazobactam	4.0	128.0	1.0–>128.0
Miscellaneous gram-negatives (10)^h
Ceftaroline	>32.0	>32.0	1.0–>32.0
Cefepime	32.0	>32.0	2.0–>32.0
Ceftriaxone	>32.0	>32.0	2.0>32.0
Cefuroxime	32.0	>32.0	1.0–>32.0
Meropenem	>32.0	>32.0	0.5–>32.0
Moxifloxacin	1.0	8.0	0.06–>8.0
Piperacillin-tazobactam	64.0	128.0	0.5–>128.0
Anaerobes gram-negative
Bacteroides fragilis complex (10)
Ceftaroline	2.0	>32.0	1.0–>32.0
Moxifloxacin	4.0	8.0	0.25–8.0
Meropenem	0.25	4.0	0.06–4.0
Clindamycin	2.0	>32.0	0.25–>32.0
Metronidazole	0.12	0.5	0.25–2.0
Prevotella spp. (3)
Ceftaroline			8.0–16
Moxifloxacin			0.5–1.0
Meropenem			0.25–0.5
Clindamycin			2.0–4.0
Metronidazole			0.12–1
Fusobacterium nucleatum (1)
Ceftaroline			0.01
Moxifloxacin			0.25
Meropenem			0.03
Clindamycin			0.12
Metronidazole			0.06
Gram-positive
Clostridium perfringens (8)
Ceftaroline			≤0.01–0.2
Moxifloxacin			0.25–2.0
Meropenem			0.12–0.25
Clindamycin			2.0–8.0
Metronidazole			0.12–2.0
Miscellaneous gram-positive anaerobes (2)^J
Ceftaroline			≤0.01–0.12
Moxifloxacin			≤0.01
Meropenem			≤0.01
Clindamycin			0.12
Metronidazole			0.50–>32.0

Includes 14 - methicillin-resistant S. epidermidis (MRSE).

Includes 14 - vancomycin-resistant (VRE) isolates.

Includes 11 - Streptococcus viridans, 10 – S. anginosus, 9 - S. dysgalactiae, 5 - S. aglactiae, 5 - S. pneumoniae, 1 - S. mitis, 1 – S. oralis.

Includes 24 - Escherichia coli, 12 - Klebsiella pneumoniae, 8 - Enterobacter cloacae, 4 – E. aerogenes, 3 - K oxytoca, 2 - Proteus mirabilis, 2 - Citrobacter freundii, 2 - Providencia stuartii, 1 – E. absuriae, 1 - Morganella morganii, 1 - C. amalonaticus, 1 - Serratia marcescens and 1 - Hafnia alvei.

Includes 5 - K. pneumoniae.

Includes 10 - Haemophilus influenzae (8 β-lactamase producing strains) and 2 - Haemophilus parainfluenzae.

Includes 28 - Pseudomonas aeruginosa, 1 – P. putida.

Includes 6 - Stenotrophomonas maltophilia, 2 - Acinetobacter spp. 2 - Achromobacter xylosoxidans.

Includes 8 – Bacteroides fragilis, 7 – B. vulgatus, 1 – B. caccae, 1 – B. uniformis, 1 – B. ovatus.

Includes 2 - Peptostreptococcus anaerobius, 1 - Propionibacterium acnes.

Ceftaroline was active against 93.5% of Enterobacteriaceae isolates (MIC₉₀: 0.5 mcg/mL; range <0.01–4 mcg/mL) including all (ceftazidime-susceptible) E. coli and 11 of 12 K. pneumoniae isolates. Alternatively, all ceftazidime-resistant K. pneumoniae as with, other cephalopsorins, exhibited resistance to ceftaroline. Similarly, all pseudomonal and selective miscellaneous gram-negative isolates (i.e., Stenotrophomonas maltophilia, Acinetobacter spp., and Achromobacter xylosoxidans) demonstrated resistance to ceftaroline and other anti-infective test agents. Both Haemophilus spp. and Moraxella catarrhalis isolates were highly susceptible to ceftaroline (MIC₉₀: 0.03 mcg/mL). Similar to other cephalsporins, ceftaroline exhibited reduced activity against selective anaerobic gram-negative bacilli. However, certain gram-positive anaerobic (i.e., C. perfringens) bacteria demonstrated susceptibility to ceftaroline, exhibiting activity similar to meropenem and moxifloxacin.

Discussion

Approximately 5–10% of surgical patients are at risk for healthcare-associated infections (HAIs) during the course of their hospitalizations. These infections can manifest from minor complications to serious disability or death and represent a wide variety of microbial pathogens. Many of these infections involve gram-positive pathogens such as MSSA, MRSA, and coagulase-negative staphylococci. Therapeutic options are limited when the infection involves a multi-drug-resistant strain of staphylococci, such as MRSA. Ceftaroline was approved by the FDA in 2010 for the treatment of community-acquired pneumonia and acute bacterial skin and skin structure infections, including those infections caused by MRSA [14 –17]. In addition to activity against MRSA, ceftaroline's spectrum of activity includes α, β, and non-hemolytic streptococci, Haemophilus influenzae (including β-lactamase producing strains) and common non-ESBL-producing strains of Enterobacteriaceae. The drug is not active against P. aeruginosa, Acinetobacter spp. or S. maltophilia. Within the context of the surgical ICU patient population, ceftaroline would appear to be an appropriate agent for the treatment of selected skin and skin structure infections not involving abdominal structures where the likelihood of a mixed anaerobic flora or enterococci is present. Pre-market clinical analysis documented that ceftaroline was effective in the treatment of cellulitis, major abscess, and infected wounds involving single or multiple pathogens [16]. Ceftaroline was as effective as combination therapy (vancomycin plus aztreonam) in the treatment of patients having a polymicrobial infection (91.6% versus 96.4%) [18]. An analysis of the microbial recovery from multiple sites of infection in SICU patients suggests that excluding selected gram-negative bacilli. (i.e., ESBL-producers) and enterococci, the majority of recovered SICU isolates were susceptible to ceftaroline. In an era of profound antimicrobial resistance, ceftaroline would appear to provide a reasonable alternative to an agent such as vancomycin for the treatment of healthcare-associated MRSA infection. Furthermore, two recent publications have documented that ceftaroline exhibits wide geographic activity against North American, Asian, and South African strains of MRSA [8,19]. At present, ceftaroline is the only cephalosporin to demonstrate documented bactericidal activity against healthcare- and community-associated strains of S. aureus and methicillin-resistant S. epidermidis [1,5,20]. It is interesting to note that two recent reports have documented that the diminished activity of ceftaroline against ESBL-producing strains of Enterobacteriaceae would appear to be mitigated in the presence of avibactam, a non-β-lactam β-lactamase inhibitor [21,22]. Further studies are warranted to assess the benefits of combining ceftaroline with a non-β-lactam β-lactamase inhibitor to enhance the range and scope of therapeutic efficacy.

Although previous studies have assessed the in vitro activity of ceftaroline against a broad range of microbial isolates, this is the first study to examine the comparative activity of ceftaroline against microbial isolates from a surgical ICU patient population over a six-month time interval. In the present analysis, ceftaroline demonstrated potent in vitro activity against a broad range of gram-positive and gram-negative microbial pathogens recovered from a surgical critical care patient population. Further studies are warranted to validate the therapeutic efficacy of this novel broad-spectrum agent for the treatment of infections in the SICU patient population.

Footnotes

Acknowledgments

The design and editorial comments represents the collective opinions of the authors. No outside agency was involved in the composition of this manuscript.

Author Disclosure Statement

Authors CJK, DL, NAL, TLM, MBG, CL, PJR, KRB, and GRS have no competing relationships to report. The study was supported partially by an unrestricted grant from Forest Laboratories, New York, NY (CEE).

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