- Email: [email protected]
Successful treatment of meticillin-resistant Staphylococcus aureus (MRSA) aortic prosthetic valve endocarditis with prolonged high-dose daptomycin plus ceftaroline therapy
International Journal of Antimicrobial Agents 46 (2015) 225–228
Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
Letters to the Editor Successful treatment of meticillin-resistant Staphylococcus aureus (MRSA) aortic prosthetic valve endocarditis with prolonged high-dose daptomycin plus ceftaroline therapy Sir, Device-associated infections, e.g. prosthetic valve endocarditis (PVE), are among the most difficult therapeutic challenges. Since the pathogens are often embedded/protected in the prosthetic device’s biofilm, removal/replacement of the device is usually required for cure. Rarely, PVE has been treated successfully with antibiotics alone without prosthetic valve replacement. Recently, a patient presented a most difficult therapeutic challenge, i.e. aortic PVE due to a strain of meticillin-resistant Staphylococcus aureus (MRSA) with decreased susceptibility to vancomycin. Since the patient refused aortic valve replacement, there was no option but to use antimicrobial therapy alone. The clinical approach was based on two therapeutic principles. First, we have considerable experience treating MRSA acute bacterial endocarditis (ABE) with high-dose daptomycin, i.e. 12 mg/kg/day, without adverse effects [1]. Second, with MRSA, a -lactam combined with daptomycin optimises the effectiveness of daptomycin by increasing its penetration into S. aureus cells [2,3]. After failure to clear his persistent MRSA bacteraemia with vancomycin [minimum inhibitory concentration (MIC) = 2 g/mL], quinupristin/dalfopristin (MIC = 0.5 g/mL) and linezolid (MIC = 2 g/mL), we treated his MRSA aortic PVE with prolonged high-dose daptomycin (12 mg/kg/day) plus ceftaroline combination therapy. MRSA remains the most common pathogen causing ABE. Whilst most MRSA strains remain susceptible to vancomycin, vancomycin therapy may result in MRSA cell wall thickening manifested by increased MICs, i.e. penetration-dependent resistance to vancomycin and other antibiotics, e.g. daptomycin. MRSA isolates with reduced vancomycin susceptibility may be a therapeutic challenge. Daptomycin is a lipopeptide bactericidal against S. aureus, including MRSA vancomycin-intermediate S. aureus (VISA) strains. We present a case of MRSA aortic PVE successfully treated with 6 weeks of combination therapy with high-dose daptomycin plus ceftaroline. A 79-year-old male presented with fever, chills and hypotension. His past medical history included a bioprosthetic aortic valve replacement 10 years ago (for group B streptococcal endocarditis) and chronic renal insufficiency. Blood cultures were persistently positive (4/4) for MRSA. The MRSA isolate was initially susceptible to vancomycin (MIC = 1.0 g/mL), but MICs to vancomycin rapidly increased (MIC = 2.0 g/mL) (Table 1). A transoesophageal echocardiogram showed a vegetation on the prosthetic aortic valve. After 4 days of vancomycin the patient refused cardiac surgical
Table 1 Meticillin-resistant Staphylococcus aureus (MRSA) isolate susceptibilities (in g/mL) determined by broth microdilution assay. MRSA isolate
Hospital Day #1 Hospital Day #9 Hospital Day #19
Vancomycin
Daptomycin
Ceftaroline
MIC
MBC
MIC
MBC
MIC
MBC
1 2 2
N/D 4 4
0.5 1 1
0.5 1 1
0.5 1 1
1 1 1
MIC, minimum inhibitory concentration; MBC, minimum bactericidal concentration; N/D, not done.
intervention. He was treated with intravenous (i.v.) daptomycin 10 mg/kg every 24 h (q24h). Blood cultures remained highly positive (4/4) over the next 2 weeks of therapy. Daptomycin was discontinued and treatment began with linezolid and subsequently quinupristin/dalfopristin, both of which were unsuccessful, i.e. blood cultures remained persistently positive. He was then treated with high-dose daptomycin, i.e. 12 mg/kg i.v. q24h plus ceftaroline 600 mg i.v. every 12 h. His blood cultures became negative after 4 days of high-dose daptomycin plus ceftaroline. His blood cultures became negative and remained negative. His MRSA aortic PVE was successfully treated with a 6-week course of combination therapy with high-dose daptomycin and ceftaroline. There are in vitro data regarding potentiation of the anti-MRSA activity with combinations of daptomycin plus oxacillin or nafcillin but there is limited published clinical experience with these regimens. Ceftaroline is a -lactam with activity against MRSA via its affinity for penicillin-binding protein (PBP) 2a. -Lactams, e.g. ceftaroline, with inherent anti-MRSA activity might optimise intracellular entry/activity of daptomycin and could be effective particularly against MRSA strains with decreased susceptibility. Given the bactericidal activity of ceftaroline against MRSA, pharmacokinetic/pharmacodynamic models with daptomycin and ceftaroline found an enhanced in vitro effect against MRSA with increased cell wall thickness, a mechanism for daptomycin resistance following vancomycin exposure. Daptomycin resistance may be more complex, involving membrane fluidity and binding affinity [4]. Ceftaroline has been used alone and in combination to treat MRSA ABE as well as in one case with ceftaroline monotherapy of MRSA PVE [5]. After therapeutic failures, i.e. persistent high-grade MRSA bacteraemia susceptible to vancomycin, quinupristin/dalfopristin and linezolid, we cured this patient’s MRSA aortic PVE. This report adds to the literature of successful treatment of MRSA aortic PVE with prolonged high-dose daptomycin plus ceftaroline. Funding None.
0924-8579/© 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
226
Letters to the Editor / International Journal of Antimicrobial Agents 46 (2015) 225–228
Competing interests None declared. Ethical approval Not required. References [1] Mohan SS, McDermott BP, Cunha BA. Methicillin-resistant Staphylococcus aureus prosthetic aortic valve endocarditis with paravalvular abscess treated with daptomycin. Heart Lung 2005;34:69–71. [2] Dhand A, Bayer AS, Pogliano J, Yang SJ, Bolaris M, Nizet V, et al. Use of antistaphylococcal -lactams to increase daptomycin activity in eradicating persistent bacteremia due to methicillin-resistant Staphylococcus aureus: role of enhanced daptomycin binding. Clin Infect Dis 2011;53:158–63. [3] Mehta S, Singh C, Plata KB, Chanda PK, Paul A, Riosa S, et al. -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;56:6192–200. [4] Patel D, Husain M, Vidaillac C, Steed ME, Rybak MJ, Seo SM, et al. Mechanisms of in-vitro-selected daptomycin-non-susceptibility in Staphylococcus aureus. Int J Antimicrob Agents 2011;38:442–6. [5] Jongsma K, Joson J, Heidari A. Ceftaroline in the treatment of concomitant methicillin-resistant and daptomycin-non-susceptible Staphylococcus aureus infective endocarditis and osteomyelitis: case report. J Antimicrob Chemother 2013;68:1444–5.
Burke A. Cunha a,b,∗ Infectious Disease Division, Winthrop-University Hospital, 222 Station Plaza North (Suite #432), Mineola, NY 11501, USA b State University of New York, School of Medicine, Stony Brook, NY, USA a
Arthur Gran Infectious Disease Division, Winthrop-University Hospital, 222 Station Plaza North (Suite #432), Mineola, NY 11501, USA ∗ Corresponding
author at: Infectious Disease Division, Winthrop-University Hospital, 222 Station Plaza North (Suite #432), Mineola, NY 11501, USA. Tel.: +1 516 663 2505; fax: +1 516 663 2753. E-mail address: [email protected] (B.A. Cunha) 15 April 2015 http://dx.doi.org/10.1016/j.ijantimicag.2015.04.006
Inducible expression of erm(B) by the ketolides telithromycin and cethromycin Sir, Ketolides have generally been considered to be non-inducers of the resistance conferred by erm genes. A previous study reported that erm(B) was not induced by the ketolide telithromycin [1]. Inconsistent with this earlier result, however, it was subsequently reported that dimethylation at A2058 of 23S rRNA in a strain of Streptococcus pneumoniae with erm(B) was increased in the presence of telithromycin [2]. A recent study also showed that the ketolides telithromycin and cethromycin caused ribosome stalling at the regulatory region of erm(B) in an Escherichia coli cell-free system [3]. To resolve these conflicting results, we examined the inducibility of erm(B) by telithromycin and cethromycin using a double-disk test and erm(B)–lacZ reporter assays. A double-disk test was performed for Enterococcus faecium G123, a clinical isolate harbouring only erm(B) as an erythromycin resistance gene. The regulatory region sequence of erm(B) from E. faecium G123 was identical to that from transposon Tn917. Disks (8 mm in diameter) containing 0.2 g of telithromycin
Fig. 1. (a) Blunting of the clindamycin (Cl; 30 g) zones of inhibition proximal to the telithromycin (T; 0.2 g) and cethromycin (Ce; 0.2 g) disks. (b) Induction of erm(B)–lacZ by erythromycin (E), josamycin (J), quinupristin (Q), clindamycin (Cl), telithromycin (T) and cethromycin (Ce). Linezolid (L) and gentamicin (G) were used for comparison. The disks contained 0.1 g of the respective antibiotics. (c) Increased expressions of erm(B)–lacZ after incubation for 120 min with erythromycin (䊉), josamycin (), clindamycin (䊏), quinupristin (䊐), telithromycin () and cethromycin (♦).
(Sanofi-Aventis Korea, Seoul, South Korea) and cethromycin (SinoStandards, Chengdu, China) were placed near a disk containing 30 g of clindamycin. E. faecium G123 exhibited blunting of the clindamycin zone of inhibition proximal to the telithromycin and cethromycin disks (Fig. 1a). Bacillus subtilis EL100 carrying the lacZ reporter fused to the structural gene of erm(B) from Tn917 [4] was used for the -galactosidase induction assays. For the disk-based assay, an aliquot of overnight culture (2 × 108 CFU) was added to 10 mL of Luria–Bertani (LB) top agar containing 0.6% agar. The mixture was then poured over the surface of an LB agar plate (150 mm in diameter) containing 1.5% agar, 10 g/mL chloramphenicol and 80 g/mL X-gal. Sterile disks impregnated with 0.1 g of the various antibiotics were placed on the inoculated agar surface. Following incubation at 37 ◦ C for 24 h, narrow blue rings were observed around the zones of inhibition for the telithromycin and cethromycin disks (Fig. 1b). The colour intensity of each blue ring was quantified with CS Analyzer 3 software (ATTO, Tokyo, Japan). The colour intensity and width of the blue ring around the telithromycin disk were similar to those around the cethromycin disk. Unexpectedly, the telithromycin and cethromycin disks displayed a reproducible increase in colour intensity (1.4-fold) compared with the disk of erythromycin, a well-known inducer. Quantitative assays were performed using 2 mL of midlog-phase culture as described previously [4]. Telithromycin exhibited considerable induction activity, which was greater than clindamycin, a known inducer (Fig. 1c). Interestingly, telithromycin induced expression of the reporter at a broad range of concentrations, contrary to the results of the disk-based assay. Thus, it was thought that, in the disk-based assay, reporter expression was undetectable due to the inhibition of host growth at the
Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
Letters to the Editor Successful treatment of meticillin-resistant Staphylococcus aureus (MRSA) aortic prosthetic valve endocarditis with prolonged high-dose daptomycin plus ceftaroline therapy Sir, Device-associated infections, e.g. prosthetic valve endocarditis (PVE), are among the most difficult therapeutic challenges. Since the pathogens are often embedded/protected in the prosthetic device’s biofilm, removal/replacement of the device is usually required for cure. Rarely, PVE has been treated successfully with antibiotics alone without prosthetic valve replacement. Recently, a patient presented a most difficult therapeutic challenge, i.e. aortic PVE due to a strain of meticillin-resistant Staphylococcus aureus (MRSA) with decreased susceptibility to vancomycin. Since the patient refused aortic valve replacement, there was no option but to use antimicrobial therapy alone. The clinical approach was based on two therapeutic principles. First, we have considerable experience treating MRSA acute bacterial endocarditis (ABE) with high-dose daptomycin, i.e. 12 mg/kg/day, without adverse effects [1]. Second, with MRSA, a -lactam combined with daptomycin optimises the effectiveness of daptomycin by increasing its penetration into S. aureus cells [2,3]. After failure to clear his persistent MRSA bacteraemia with vancomycin [minimum inhibitory concentration (MIC) = 2 g/mL], quinupristin/dalfopristin (MIC = 0.5 g/mL) and linezolid (MIC = 2 g/mL), we treated his MRSA aortic PVE with prolonged high-dose daptomycin (12 mg/kg/day) plus ceftaroline combination therapy. MRSA remains the most common pathogen causing ABE. Whilst most MRSA strains remain susceptible to vancomycin, vancomycin therapy may result in MRSA cell wall thickening manifested by increased MICs, i.e. penetration-dependent resistance to vancomycin and other antibiotics, e.g. daptomycin. MRSA isolates with reduced vancomycin susceptibility may be a therapeutic challenge. Daptomycin is a lipopeptide bactericidal against S. aureus, including MRSA vancomycin-intermediate S. aureus (VISA) strains. We present a case of MRSA aortic PVE successfully treated with 6 weeks of combination therapy with high-dose daptomycin plus ceftaroline. A 79-year-old male presented with fever, chills and hypotension. His past medical history included a bioprosthetic aortic valve replacement 10 years ago (for group B streptococcal endocarditis) and chronic renal insufficiency. Blood cultures were persistently positive (4/4) for MRSA. The MRSA isolate was initially susceptible to vancomycin (MIC = 1.0 g/mL), but MICs to vancomycin rapidly increased (MIC = 2.0 g/mL) (Table 1). A transoesophageal echocardiogram showed a vegetation on the prosthetic aortic valve. After 4 days of vancomycin the patient refused cardiac surgical
Table 1 Meticillin-resistant Staphylococcus aureus (MRSA) isolate susceptibilities (in g/mL) determined by broth microdilution assay. MRSA isolate
Hospital Day #1 Hospital Day #9 Hospital Day #19
Vancomycin
Daptomycin
Ceftaroline
MIC
MBC
MIC
MBC
MIC
MBC
1 2 2
N/D 4 4
0.5 1 1
0.5 1 1
0.5 1 1
1 1 1
MIC, minimum inhibitory concentration; MBC, minimum bactericidal concentration; N/D, not done.
intervention. He was treated with intravenous (i.v.) daptomycin 10 mg/kg every 24 h (q24h). Blood cultures remained highly positive (4/4) over the next 2 weeks of therapy. Daptomycin was discontinued and treatment began with linezolid and subsequently quinupristin/dalfopristin, both of which were unsuccessful, i.e. blood cultures remained persistently positive. He was then treated with high-dose daptomycin, i.e. 12 mg/kg i.v. q24h plus ceftaroline 600 mg i.v. every 12 h. His blood cultures became negative after 4 days of high-dose daptomycin plus ceftaroline. His blood cultures became negative and remained negative. His MRSA aortic PVE was successfully treated with a 6-week course of combination therapy with high-dose daptomycin and ceftaroline. There are in vitro data regarding potentiation of the anti-MRSA activity with combinations of daptomycin plus oxacillin or nafcillin but there is limited published clinical experience with these regimens. Ceftaroline is a -lactam with activity against MRSA via its affinity for penicillin-binding protein (PBP) 2a. -Lactams, e.g. ceftaroline, with inherent anti-MRSA activity might optimise intracellular entry/activity of daptomycin and could be effective particularly against MRSA strains with decreased susceptibility. Given the bactericidal activity of ceftaroline against MRSA, pharmacokinetic/pharmacodynamic models with daptomycin and ceftaroline found an enhanced in vitro effect against MRSA with increased cell wall thickness, a mechanism for daptomycin resistance following vancomycin exposure. Daptomycin resistance may be more complex, involving membrane fluidity and binding affinity [4]. Ceftaroline has been used alone and in combination to treat MRSA ABE as well as in one case with ceftaroline monotherapy of MRSA PVE [5]. After therapeutic failures, i.e. persistent high-grade MRSA bacteraemia susceptible to vancomycin, quinupristin/dalfopristin and linezolid, we cured this patient’s MRSA aortic PVE. This report adds to the literature of successful treatment of MRSA aortic PVE with prolonged high-dose daptomycin plus ceftaroline. Funding None.
0924-8579/© 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
226
Letters to the Editor / International Journal of Antimicrobial Agents 46 (2015) 225–228
Competing interests None declared. Ethical approval Not required. References [1] Mohan SS, McDermott BP, Cunha BA. Methicillin-resistant Staphylococcus aureus prosthetic aortic valve endocarditis with paravalvular abscess treated with daptomycin. Heart Lung 2005;34:69–71. [2] Dhand A, Bayer AS, Pogliano J, Yang SJ, Bolaris M, Nizet V, et al. Use of antistaphylococcal -lactams to increase daptomycin activity in eradicating persistent bacteremia due to methicillin-resistant Staphylococcus aureus: role of enhanced daptomycin binding. Clin Infect Dis 2011;53:158–63. [3] Mehta S, Singh C, Plata KB, Chanda PK, Paul A, Riosa S, et al. -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;56:6192–200. [4] Patel D, Husain M, Vidaillac C, Steed ME, Rybak MJ, Seo SM, et al. Mechanisms of in-vitro-selected daptomycin-non-susceptibility in Staphylococcus aureus. Int J Antimicrob Agents 2011;38:442–6. [5] Jongsma K, Joson J, Heidari A. Ceftaroline in the treatment of concomitant methicillin-resistant and daptomycin-non-susceptible Staphylococcus aureus infective endocarditis and osteomyelitis: case report. J Antimicrob Chemother 2013;68:1444–5.
Burke A. Cunha a,b,∗ Infectious Disease Division, Winthrop-University Hospital, 222 Station Plaza North (Suite #432), Mineola, NY 11501, USA b State University of New York, School of Medicine, Stony Brook, NY, USA a
Arthur Gran Infectious Disease Division, Winthrop-University Hospital, 222 Station Plaza North (Suite #432), Mineola, NY 11501, USA ∗ Corresponding
author at: Infectious Disease Division, Winthrop-University Hospital, 222 Station Plaza North (Suite #432), Mineola, NY 11501, USA. Tel.: +1 516 663 2505; fax: +1 516 663 2753. E-mail address: [email protected] (B.A. Cunha) 15 April 2015 http://dx.doi.org/10.1016/j.ijantimicag.2015.04.006
Inducible expression of erm(B) by the ketolides telithromycin and cethromycin Sir, Ketolides have generally been considered to be non-inducers of the resistance conferred by erm genes. A previous study reported that erm(B) was not induced by the ketolide telithromycin [1]. Inconsistent with this earlier result, however, it was subsequently reported that dimethylation at A2058 of 23S rRNA in a strain of Streptococcus pneumoniae with erm(B) was increased in the presence of telithromycin [2]. A recent study also showed that the ketolides telithromycin and cethromycin caused ribosome stalling at the regulatory region of erm(B) in an Escherichia coli cell-free system [3]. To resolve these conflicting results, we examined the inducibility of erm(B) by telithromycin and cethromycin using a double-disk test and erm(B)–lacZ reporter assays. A double-disk test was performed for Enterococcus faecium G123, a clinical isolate harbouring only erm(B) as an erythromycin resistance gene. The regulatory region sequence of erm(B) from E. faecium G123 was identical to that from transposon Tn917. Disks (8 mm in diameter) containing 0.2 g of telithromycin
Fig. 1. (a) Blunting of the clindamycin (Cl; 30 g) zones of inhibition proximal to the telithromycin (T; 0.2 g) and cethromycin (Ce; 0.2 g) disks. (b) Induction of erm(B)–lacZ by erythromycin (E), josamycin (J), quinupristin (Q), clindamycin (Cl), telithromycin (T) and cethromycin (Ce). Linezolid (L) and gentamicin (G) were used for comparison. The disks contained 0.1 g of the respective antibiotics. (c) Increased expressions of erm(B)–lacZ after incubation for 120 min with erythromycin (䊉), josamycin (), clindamycin (䊏), quinupristin (䊐), telithromycin () and cethromycin (♦).
(Sanofi-Aventis Korea, Seoul, South Korea) and cethromycin (SinoStandards, Chengdu, China) were placed near a disk containing 30 g of clindamycin. E. faecium G123 exhibited blunting of the clindamycin zone of inhibition proximal to the telithromycin and cethromycin disks (Fig. 1a). Bacillus subtilis EL100 carrying the lacZ reporter fused to the structural gene of erm(B) from Tn917 [4] was used for the -galactosidase induction assays. For the disk-based assay, an aliquot of overnight culture (2 × 108 CFU) was added to 10 mL of Luria–Bertani (LB) top agar containing 0.6% agar. The mixture was then poured over the surface of an LB agar plate (150 mm in diameter) containing 1.5% agar, 10 g/mL chloramphenicol and 80 g/mL X-gal. Sterile disks impregnated with 0.1 g of the various antibiotics were placed on the inoculated agar surface. Following incubation at 37 ◦ C for 24 h, narrow blue rings were observed around the zones of inhibition for the telithromycin and cethromycin disks (Fig. 1b). The colour intensity of each blue ring was quantified with CS Analyzer 3 software (ATTO, Tokyo, Japan). The colour intensity and width of the blue ring around the telithromycin disk were similar to those around the cethromycin disk. Unexpectedly, the telithromycin and cethromycin disks displayed a reproducible increase in colour intensity (1.4-fold) compared with the disk of erythromycin, a well-known inducer. Quantitative assays were performed using 2 mL of midlog-phase culture as described previously [4]. Telithromycin exhibited considerable induction activity, which was greater than clindamycin, a known inducer (Fig. 1c). Interestingly, telithromycin induced expression of the reporter at a broad range of concentrations, contrary to the results of the disk-based assay. Thus, it was thought that, in the disk-based assay, reporter expression was undetectable due to the inhibition of host growth at the