- Email: [email protected]
Experience with daptomycin in an infectious diseases service over 1 year: utility in an outpatient parenteral antibiotic programme
492
Letters to the Editor / International Journal of Antimicrobial Agents 31 (2008) 484–504
References [1] Helgason E, Okstad OA, Caugant DA, Johansen HA, Fouet A, Mock M, et al. Bacillus anthracis, Bacillus cereus and Bacillus thuringiensis—one species on the basis of genetic evidence. Appl Environ Microbiol 2000;66:2627–30. [2] Inglesby TV, O’Toole T, Henderson DA, Bartlett JG, Ascher MS, Eitzen E, et al. Working Group on Civilian Biodefense. Anthrax as a biological weapon, 2002: updated recommendations for management. JAMA 2002;287:2236–52 [Erratum: JAMA 2002;288:1849]. [3] Szybalski W, Bryson V. Genetic studies on microbial cross resistance to toxic agents. I. Cross resistance of Escherichia coli to fifteen antibiotics. J Bacteriol 1952;64:489–99. [4] Cavallo JD, Ramisse F, Girardet M, Vaissaire J, Mock M, Hernandez E. Antibiotic susceptibilities of 96 isolates of Bacillus anthracis isolated in France between 1994 and 2000. Antimicrob Agents Chemother 2002;46:2307–9. [5] Mohamed MJ, Marston CK, Popovic T, Weyant RS, Tenover F. Antimicrobial susceptibility testing of Bacillus anthracis: comparison of results obtained by using the National Committee for Clinical Laboratory Standards broth microdilution reference and Etest agar gradient diffusion methods. J Clin Microbiol 2002;40:1902–7. [6] Turnbull PCB, Sirianni NM, LeBron CI, Samaan MN, Sutton FN, Reyes AE, et al. MICs of selected antibiotics for Bacillus anthracis, Bacillus cereus, Bacillus thuringiensis and Bacillus mycoides from a range of clinical and environmental sources as determined by the Etest. J Clin Microbiol 2004;42:3626–34. [7] Luna VA, King DS, Gulledge J, Cannons AC, Amuso PT, Cattani J. Susceptibility of Bacillus anthracis, Bacillus cereus, Bacillus mycoides, Bacillus pseudomycoides and Bacillus thuringiensis to 24 antimicrobials using Sensititre automated microbroth dilution and Etest agar gradient diffusion methods. J Antimicrob Chemother 2007;60:555–67.
A. M´erens a,b,∗ Service de Biologie M´edicale, Hˆopital d’Instruction des Arm´ees B´egin, 69 avenue de Paris, 94160 Saint-Mand´e, France b Ecole du Val-de-Grˆ ace, 1 place Alphonse Laveran, 75005 Paris, France a
J. Vaissaire ´ Laboratoire d’Etudes et de Recherches en Pathologie Animale et Zoonoses (LERPAZ), Agence Fran¸caise de S´ecurit´e Sanitaire des Aliments (AFSSA), 23 avenue du g´en´eral de Gaulle, 94700 Maisons-Alfort, France J.-D. Cavallo c,d de Biologie M´edicale, Hˆopital d’Instruction des Arm´ees B´egin, 69 avenue de Paris, 94160 Saint-Mand´e, France d Ecole du Val-de-Grˆ ace, 1 place Alphonse Laveran, 75005 Paris, France c Service
C. Le Doujet ´ Laboratoire d’Etudes et de Recherches en Pathologie Animale et Zoonoses (LERPAZ), Agence Fran¸caise de S´ecurit´e Sanitaire des Aliments (AFSSA), 23 avenue du g´en´eral de Gaulle, 94700 Maisons-Alfort, France C. Gros Service de Biologie M´edicale, Hˆopital d’Instruction des Arm´ees B´egin, 69 avenue de Paris, 94160 Saint-Mand´e, France
C. Bigaillon e,f de Biologie M´edicale, Hˆopital d’Instruction des Arm´ees B´egin, 69 avenue de Paris, 94160 Saint-Mand´e, France f Ecole du Val-de-Grˆ ace, 1 place Alphonse Laveran, 75005 Paris, France e Service
J.-C. Paucod Centre de Recherche du Service de Sant´e des Arm´ees, 38700, La Tronche, France F. Berger Ecole du Val-de-Grˆace, 1 place Alphonse Laveran, 75005 Paris, France E. Valade D. Vidal Centre de Recherche du Service de Sant´e des Arm´ees, 38700, La Tronche, France ∗ Corresponding
author. Tel.: +33 1 43 98 47 34; fax: +33 1 43 98 53 36. E-mail address: [email protected] (A. M´erens) doi: 10.1016/j.ijantimicag.2008.01.005
Experience with daptomycin in an infectious diseases service over 1 year: utility in an outpatient parenteral antibiotic programme Sir, Daptomycin is a novel cyclic lipopeptide with rapid cidal activity against Gram-positive organisms. In Glasgow hospitals, daptomycin is approved for restricted use, on the recommendation of an infectious diseases physician or microbiologist, for those patients with serious Grampositive infections (excluding primary pulmonary infections) when glycopeptides are failing or contraindicated. A retrospective review of our unit’s experience with daptomycin over 12 months was undertaken. Patients who had been managed through the infectious diseases inpatient unit or outpatient parenteral antibiotic therapy (OPAT) service from June 2006 (n = 1345) and who received at least one dose of daptomycin (n = 29) were identified and case records were reviewed. All patients were diagnosed with serious Gram-positive infections (Table 1). Eleven patients were bacteraemic (seven with Staphylococcus aureus), eight had methicillinresistant S. aureus infection, 13 had bone and joint infection and six had bacterial endocarditis. Twenty-one cases had received prior glycopeptide therapy and the indication was clinical/microbiological failure (15), allergy/intolerance (10), teicoplanin-resistant Staphylococcus epidermidis (1), to facilitate outpatient therapy (2) and empirical therapy in rapidly progressive soft tissue infection (1). Twenty patients received 6 mg/kg/day daptomycin and 17 received at least one additional agent with Gram-positive
Table 1 Individual patient summaries Diagnosis/ complications
Co-morbidity
Microbiology (site)
Antibiotic therapy prior to daptomycin
51/F
Infected total knee replacement Cellulitis
No
No
Vancomycin/ teicoplanin
Cor pulmonale
No
Aortic valve endocarditis and discitis Osteomyelitis foot Tricuspid valve endocarditis
Acute renal failure
MSSA (blood)
Flucloxacillin + clindamycin Flucloxacillin
Type 1 diabetes Short bowel and parenteral nutrition
MRSA (tissue) MRSA (blood), Candida albicans (blood) MSSA (blood)
62/F 59/M
27/F 46/F
Duration (days)
Indication for daptomycin
Dose (mg/kg/day)
Concomitant antibiotic therapy
Duration (days)
Duration of OPAT (days)
Outcome
6
Allergy
6
Rifampicin
35
35
Cured
8
Failure
4
No
13
0
Cured
40
Failure
6
Rifampicin
53
52
Cured
Teicoplanin
16
6
Rifampicin
68
68
Improved
Teicoplanin, voriconazole, linezolid and piperacillin/ tazobactam Flucloxacillin and gentamicin Vancomycin then linezolid
52
Renal failure/ intolerance Failure
6
Meropenem, ambisome
46
0
Improved
8
OPAT
6
Rifampicin
35
28
Improved
30
Failure
6
Sodium fusidate
85
28
Cured
69/F
Mitral valve endocarditis
No
66/F
Mitral valve endocarditis
MRSA (blood)
22/M
Primary bacteraemia Cellulitis
Multiple sclerosis and quadriparesis No
MSSA (blood)
Flucloxacillin
2
OPAT
6
No
4
4
Cured
Ischaemic heart disease, recent MRSA bacteraemia
Group A streptococci (blood), MRSA (carriage) MRSA (synovium)
Vancomycin then linezolid
11
Failure
4
No
29
0
Cured
Relapse/failure
6
Doxycycline
49
0
Improved
7
7
Cured
128
128
31
31
75/F
Osteomyelitis tibia/femur and septic arthritis knee
49/F
Cellulitis
64/M
OM tibia and infected aortobifemoral graft
72/M
Infected total knee replacement
HIV, sickle cell disease, previous MRSA septic arthritis Recurrent cellulitis Ischaemic heart disease, cerebrovascular disease No
Teicoplanin
0
No
Teicoplanin
10
Failure
4
No
MRSA, Enterococcus sp., C. albicans (blood)
Teicoplanin
21
Failure
6
AmBisome, ertapenem
Staphylococcus. epidermidis (tissue)
Vancomycin, teicoplanin
17
Allergy
6
Sodium fusidate
Died of surgical complications following repair of infected graft Cured 493
41/M
Letters to the Editor / International Journal of Antimicrobial Agents 31 (2008) 484–504
Age/gender
494
Table 1 (Continued ) Age/gender
Diagnosis/ complications
Co-morbidity
Microbiology (site)
Antibiotic therapy prior to daptomycin
Duration (days)
Indication for daptomycin
Dose (mg/kg/day)
Concomitant antibiotic therapy
Duration (days)
19/F
Septic arthritis knee and infected inferior vena caval thrombosis Cellulitis
Septic miscarriage
MSSA, group A streptococci (blood)
Cefotaxime, vancomycin, gentamicin, flucloxacillin
18
Failure
6
No
10
3
Ischaemic heart disease
Failure
6
Clindamycin
14
14
Cured
Osteomyelitis toe
21
Thrombocytopenia 6
Rifampicin
58
58
Improved
67/F
Tibial osteomyelitis and infected knee replacement
No
Teicoplanin
10
Failure
6
Meropenem
46
41
Failed. Required above knee amputation
58/F
Infected total hip replacement Infected knee replacement
Type 2 diabetes mellitus Multiple previous joint revisions. Previous Leuconostoc, S. epidermidis and Serratia sp. No
Teicoplanin, vancomycin, ceftriaxone Vancomycin, teicoplanin
14
72/F
Group A streptococci (wound swab) MRSA (wound swab)
MRSA (tissue)
Teicoplanin
35
Allergy
6
Rifampicin
14
14
Cured
No
Teicoplanin
9
Thrombocytopenia 6
Piperacillin/ tazobactam, ciprofloxacin, sodium fusidate
67
60
Cured
MRSA (wound swab)
Vancomycin
5
Failure
6
Clindamycin
16
5
MRSA (wound swab)
Teicoplanin
8
Allergy
6
No
12
12
Cured
S. epidermidis (tissue) Viridans streptococci (blood)
Teicoplanin
30
Allergy
6
Rifampicin
24
24
Cured
Piperacillin/ tazobactam, gentamicin, clarithromycin
12
Failure
4 (alternate days)
Meropenem
23
0
59/M
27/M
Pyomyositis
73/M
Post-operative wound infection Infected knee replacement Aortic and mitral valve endocarditis
78/M 52/F
Atrial fibrillation. Previous Serratia sp. and MRSA from tissue Hypogammaglobulinaemia, Behc¸et’s Atrial fibrillation Hypertension Renal dialysis, ventilation, septic cerebral emboli
Outcome
Improved but CPK rise and myositis
Improved
Failed. Developed daptomycinresistant enterococcal bacteraemia
Letters to the Editor / International Journal of Antimicrobial Agents 31 (2008) 484–504
61/M
Duration of OPAT (days)
Cellulitis
Congestive cardiac failure
No
71/F
Cellulitis
MRSA (wound swab)
48/F
Cellulitis and severe sepsis
32/M
Sacral osteomyelitis
Obesity, ischaemic heart disease, renal impairment Obesity, recurrent cellulites Paraplegia
50/M
Aortic valve endocarditis, perivalvular abscess and fistula Infected total knee replacement
57/M
Acute aortic valve replacement and revision Rheumatoid arthritis and methotrexate therapy
Piperacillin/ tazobactam, clindamycin, ceftriaxone, flucloxacillin Teicoplanin
Group A No streptococci (blood) MSSA/Bacteroides Vancomycin, (tissue) metronidazole, ceftriaxone Pneumococcus Cefotaxime, (blood) vancomycin, gentamicin
Teicoplaninresistant S. epidermidis (tissue)
Vancomycin
11
Allergy
4 (alternate days)
No
3
Failure
4 (alternate days)
0
Empirical
11
37
4
14
0
Improved
Clindamycin
4
0
Cutaneous reaction and renal failure
4
Clindamycin
1
0
Cured
Allergy
6
Clindamycin, metronidazole
12
0
Failure
6
No
74
0
Improved but CPK rise and myositis Improved
Resistance
6
Doxycycline
42
39
Cured
OPAT, outpatient parenteral antibiotic therapy; F, female; M, male; MSSA, methicillin-susceptible Staphylococcus aureus; MRSA, methicillin-resistant S. aureus; HIV, human immunodeficiency virus; CPK, creatine phosphokinase.
Letters to the Editor / International Journal of Antimicrobial Agents 31 (2008) 484–504
76/M
495
496
Letters to the Editor / International Journal of Antimicrobial Agents 31 (2008) 484–504
activity (Table 1). Twenty-eight patients (97%) survived beyond 6 months of hospital discharge. One died of surgical complications following repair of an infected aortic graft. One required above the knee amputation for osteomyelitis/septic arthritis (intraoperative specimens were negative). Twenty-three patients (79%) were improved or cured. Two improved substantially with 6 mg/kg but reversible myotoxicity was noted at 12 days and 15 days with creatine phosphokinase increases to 2369 IU/L and 5500 IU/L. Treatment was completed successfully with alternative agents. A further patient receiving concomitant clindamycin discontinued after clinical improvement owing to related transient cutaneous and renal toxicity (without myotoxicity) after 4 days. Daptomycin resistance was observed in a 52-year-old lady who presented with multiorgan failure, cerebral emboli and aortic and mitral valve viridans streptococcal endocarditis. She received 4 mg/kg on alternate days following clinical deterioration and failure of initial antimicrobial therapy. During intensive care admission, heavy colonisation with vancomycin-resistant enterococci was found. Daptomycinresistant enterococcal bacteraemia was identified on Day 13 (and Day 4 of daptomycin), but followed substantial clinical improvement. The patient subsequently switched to linezolid and survived beyond 6 months following discharge. The median duration of therapy was 29 days (range 1–128 days) with a median duration of inpatient therapy of 4 days (range 0–74 days). Nineteen patients were managed through OPAT, 11 (38%) without admission. Eleven (58%) of the 19 were trained to self administer or received therapy via a trained carer. There were no unplanned re-admissions. No further associated adverse events were noted in the OPAT setting with therapy up to 128 days. In the context of a restrictive prescribing policy, daptomycin was used successfully in a difficult-to-treat population with complicated Gram-positive infections failing or intolerant of glycopeptides, including those with bone and joint infections and left-sided endocarditis. Prolonged therapy (>28 days) was used in 31% and myotoxicity was observed twice. In clinical studies, this has been rare when administered at 4 mg/kg [1] and more frequent (6.7%) when dosed at 6 mg/kg [2]. In all three patients with any toxicity daptomycin was discontinued, with rapid resolution of toxicity, and all had shown rapid improvement of signs of infection. Breakthrough resistant nosocomial infection was observed in one patient probably due to underdosing in the context of prior vancomycin-resistant enterococcal colonisation and subsequent bloodstream infection. It was not possible to investigate whether the daptomycin resistance pre-dated or was a result of exposure to the agent. Resistance observed in clinical trials and in clinical practice both in S. aureus and enterococcal infections is typically associated with persistent deep foci of infection. In view of the risk of emergent resistance, it is essential to remove or debride foci of infection whenever possible, to be vigilant for line-related
sepsis and to optimise daptomycin dosing. Higher dosing may be useful in some deep-seated or complex infections. Others have administered 12 mg/kg/day for 41 days without significant toxicity [3], and in a rabbit model using S. aureus daptomycin resistance has been overcome with 10 mg/kg dosing [4]. In vitro there is synergy with a number of agents including rifampicin and gentamicin [5,6] and there is anecdotal evidence of in vivo synergy [7], hence combination therapy should be considered in complex infections. In this series, daptomycin was co-administered with another active agent in deep-seated infection whenever possible. We found daptomycin to be a particularly useful and well tolerated agent for OPAT, with once-daily dosing and early discharge achievable in the majority of patients. Our early clinical experience of daptomycin therefore supports its use in a range of serious Gram-positive infections following failure or intolerance of the glycopeptides in both the inpatient and OPAT setting. Funding: No funding sources. Competing interests: RAS is a principal investigator for the Cubist-sponsored DAP-Ost-06-02 study and for the DAP-002 Novartis–Cubist-sponsored skin and skin-structure study. RAS has also received an unrelated grant from Novartis for an investigator-initiated skin and skin-structure study, has presented at Novartis-sponsored educational symposia and has attended advisory board meetings for Novartis and Cubist. Ethical approval: Not required.
Acknowledgments The authors would like to thank Emma Bell, Lindsay Semple and Clare Kirkwood for assistance in providing data on OPAT therapy, Elspeth Lamont for providing pharmacy records and Dr Ray Fox who provided clinical care to two of the subjects in the series.
References [1] Arbeit RD, Maki D, Tally FP, Campanaro E, Eisenstein BI. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis 2004;38:1673–81. [2] Fowler Jr VJ, Boucher HW, Corey GR, Abrutyn E, Karchner AW, Rupp ME, et al. Daptomycin versus standard therapy for bacteraemia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006;355:653–65. [3] Cunha BA, Eisenstein LE, Hamid NS. Pacemaker-induced Staphylococcus aureus mitral valve acute bacterial endocarditis complicated by persistent bacteraemia from a coronary stent: cure with prolonged/high-dose daptomycin without toxicity. Heart Lung 2006;35: 207–11. [4] Rose WE, Rybak MJ, Kaatz GW. Evaluation of daptomycin treatment of Staphylococcus aureus bacterial endocarditis: an in vitro and in vivo simulation using historical and current dosing strategies. J Antimicrob Chemother 2007;60:334–40. [5] Tsujii BT, Rybak MJ. Short-course gentamicin in combination with daptomycin or vancomycin against Staphylococcus aureus in an in
Letters to the Editor / International Journal of Antimicrobial Agents 31 (2008) 484–504 vitro pharmacodynamic model with simulated endocardial vegetations. Antimicrob Agents Chemother 2005;49:2735–45. [6] Pankey G, Ashcraft D, Patel N. In vitro synergy of daptomycin plus rifampicin against Enterococcus faecium resistant to both linezolid and vancomycin. Antimicrob Agents Chemother 2005;49: 5166–8. [7] Burns C. Daptomycin–rifampicin for a recurrent MRSA joint infection unresponsive to vancomycin-based therapy. Scand J Infect Dis 2006;38:133–6.
R.A. Seaton ∗ A.A. MacConnachie Infection Unit, Brownlee Centre, Gartnavel General Hospital, 1053 Great Western Road, Glasgow G12 0YN, UK ∗ Corresponding
author. Tel.: +44 141 211 0292; fax: +44 141 211 1097. E-mail address: [email protected] (R.A. Seaton) doi: 10.1016/j.ijantimicag.2008.01.006
Indole derivatives as efflux pump inhibitors for TolC protein in a clinical drug-resistant Escherichia coli isolated from a pig farm Sir, The function of efflux pumps is to transport drugs through the bacterial envelope and to limit the intracellular accumulation of toxic compounds (e.g. antibiotics, antimicrobial peptides, metals and detergents). Drug resistance due to antibiotic efflux is an increasing problem worldwide [1]. A new molecular challenge is to combat this transport by searching for new molecules to block efflux and thus restore drug susceptibility in resistant clinical strains [2,3]. Pathogenic Escherichia coli is an important pathogenic bacterium in animals and humans. The major multidrug efflux pump AcrAB from E. coli co-operates with TolC to extrude an extremely broad range of antimicrobial compounds, including antibiotics, detergents, dyes and organic solvents, from the cell. The recent resolution of the threedimensional structures of TolC and AcrB from E. coli and MexA and OprM from Pseudomonas aeruginosa has given rise to a better understanding of the efflux mechanism in Gram-negative bacteria [4]. TolC is central to the export of diverse compounds, interacting with a specific inner membrane translocase in E. coli. Opening the periplasmic tunnel entrance is clearly key to the function of TolC, the assembled export and efflux machineries. TolC may be a better target than AcrB for the development of efflux pump inhibitors [5,6]. The aim of the present study was to identify original molecules capable of restoring susceptibility of a resistant strain to various antibiotics. In the vast heterocyclic structural space, many indole derivatives, including fused derivatives, form the basis of
497
Table 1 Determination of the ability of two small molecular indole derivative inhibitors to increase antibiotic sensitivity of Escherichia coli FJ305 Compounds (0.5 mM)
No compounda Indo 1 Indo 2
MIC (g/mL) CHL
TET
ERY
CIP
THI
FLO
256 8 4
64 16 16
64 32 4
128 8 16
64 8 8
32 8 4
MIC, minimum inhibitory concentration; CHL, chloramphenicol; TET, tetracycline; ERY, erythromycin; CIP, ciprofloxacin; THI, thiamphenicol; FLO, florfenicol; Indo 1, 3-amino-6-carboxyl-indolenine; Indo 2, 3-nitro6-amino-indolenine. a Isolate FJ305 was resistant to various antibiotics in the absence of indole inhibitors.
a range of pharmaceuticals, and a high level of activity continues in the search for new indole-based medicinal agents [7]. Some of the molecules tested in this work were able to inhibit the main efflux pump, AcrAB-TolC. The molecules 3-amino-6-carboxyl-indolenine and 3-nitro6-amino-indolenine were selected as potential inhibitors. A pair of the proton-acceptor and proton-donor was linked in the molecular skeleton. The designed molecules could link Asp and Tyr together by hydrogen bonds. Two small molecules were designed by quantum chemistry and synthesised by nitration and ammonification. The structure of the two small molecules was confirmed by proton nuclear magnetic resonance (1 H NMR), mass spectrometry and infrared spectra analysis. The clinical strain E. coli FJ305, in which TolC protein is overexpressed, was grown in Mueller–Hinton (MH) broth with aeration at 37 ◦ C. Minimum inhibitory concentration (MIC) determination for antibiotics in the presence of the two small molecules was conducted by the microtitre broth dilution method. Escherichia coli was cultured in MH liquid culture at 37 ◦ C and then inoculated into a tube at a concentration of 105 /mL. The concentration of indolenine derivatives was diluted from 0.5 mM. Chloramphenicol (CHL), erythromycin (ERY), ciprofloxacin (CIP), tetracycline (TET), thiamphenicol (THI) and florfenicol (FLO) were diluted two-fold and inoculated in tubes. All tubes were then cultured for 18 h at 37 ◦ C. The next day, the result was observed and demonstrated that the two small molecules could restore the susceptibility of FJ305 to CHL, ERY, CIP, TET, THI and FLO (Table 1). The molecules constrained the tunnel at the distal end of TolC, thus weakening drug export. In conclusion, hydrogen bonds are formed relatively easily between the designed molecules and Asp and Tyr. The two small molecules should be efficient molecules for shrinking the size of the tunnel and obstructing the export of drugs. MIC determination in the presence of the two small molecules demonstrated that the susceptibility of E. coli to CHL, ERY, CIP, TET, THI and FLO could be increased. 3-Amino-6carboxyl-indolenine and 3-nitro-6-amino-indolenine may be effective tools against the resistance to antibiotics of E. coli isolates.
Letters to the Editor / International Journal of Antimicrobial Agents 31 (2008) 484–504
References [1] Helgason E, Okstad OA, Caugant DA, Johansen HA, Fouet A, Mock M, et al. Bacillus anthracis, Bacillus cereus and Bacillus thuringiensis—one species on the basis of genetic evidence. Appl Environ Microbiol 2000;66:2627–30. [2] Inglesby TV, O’Toole T, Henderson DA, Bartlett JG, Ascher MS, Eitzen E, et al. Working Group on Civilian Biodefense. Anthrax as a biological weapon, 2002: updated recommendations for management. JAMA 2002;287:2236–52 [Erratum: JAMA 2002;288:1849]. [3] Szybalski W, Bryson V. Genetic studies on microbial cross resistance to toxic agents. I. Cross resistance of Escherichia coli to fifteen antibiotics. J Bacteriol 1952;64:489–99. [4] Cavallo JD, Ramisse F, Girardet M, Vaissaire J, Mock M, Hernandez E. Antibiotic susceptibilities of 96 isolates of Bacillus anthracis isolated in France between 1994 and 2000. Antimicrob Agents Chemother 2002;46:2307–9. [5] Mohamed MJ, Marston CK, Popovic T, Weyant RS, Tenover F. Antimicrobial susceptibility testing of Bacillus anthracis: comparison of results obtained by using the National Committee for Clinical Laboratory Standards broth microdilution reference and Etest agar gradient diffusion methods. J Clin Microbiol 2002;40:1902–7. [6] Turnbull PCB, Sirianni NM, LeBron CI, Samaan MN, Sutton FN, Reyes AE, et al. MICs of selected antibiotics for Bacillus anthracis, Bacillus cereus, Bacillus thuringiensis and Bacillus mycoides from a range of clinical and environmental sources as determined by the Etest. J Clin Microbiol 2004;42:3626–34. [7] Luna VA, King DS, Gulledge J, Cannons AC, Amuso PT, Cattani J. Susceptibility of Bacillus anthracis, Bacillus cereus, Bacillus mycoides, Bacillus pseudomycoides and Bacillus thuringiensis to 24 antimicrobials using Sensititre automated microbroth dilution and Etest agar gradient diffusion methods. J Antimicrob Chemother 2007;60:555–67.
A. M´erens a,b,∗ Service de Biologie M´edicale, Hˆopital d’Instruction des Arm´ees B´egin, 69 avenue de Paris, 94160 Saint-Mand´e, France b Ecole du Val-de-Grˆ ace, 1 place Alphonse Laveran, 75005 Paris, France a
J. Vaissaire ´ Laboratoire d’Etudes et de Recherches en Pathologie Animale et Zoonoses (LERPAZ), Agence Fran¸caise de S´ecurit´e Sanitaire des Aliments (AFSSA), 23 avenue du g´en´eral de Gaulle, 94700 Maisons-Alfort, France J.-D. Cavallo c,d de Biologie M´edicale, Hˆopital d’Instruction des Arm´ees B´egin, 69 avenue de Paris, 94160 Saint-Mand´e, France d Ecole du Val-de-Grˆ ace, 1 place Alphonse Laveran, 75005 Paris, France c Service
C. Le Doujet ´ Laboratoire d’Etudes et de Recherches en Pathologie Animale et Zoonoses (LERPAZ), Agence Fran¸caise de S´ecurit´e Sanitaire des Aliments (AFSSA), 23 avenue du g´en´eral de Gaulle, 94700 Maisons-Alfort, France C. Gros Service de Biologie M´edicale, Hˆopital d’Instruction des Arm´ees B´egin, 69 avenue de Paris, 94160 Saint-Mand´e, France
C. Bigaillon e,f de Biologie M´edicale, Hˆopital d’Instruction des Arm´ees B´egin, 69 avenue de Paris, 94160 Saint-Mand´e, France f Ecole du Val-de-Grˆ ace, 1 place Alphonse Laveran, 75005 Paris, France e Service
J.-C. Paucod Centre de Recherche du Service de Sant´e des Arm´ees, 38700, La Tronche, France F. Berger Ecole du Val-de-Grˆace, 1 place Alphonse Laveran, 75005 Paris, France E. Valade D. Vidal Centre de Recherche du Service de Sant´e des Arm´ees, 38700, La Tronche, France ∗ Corresponding
author. Tel.: +33 1 43 98 47 34; fax: +33 1 43 98 53 36. E-mail address: [email protected] (A. M´erens) doi: 10.1016/j.ijantimicag.2008.01.005
Experience with daptomycin in an infectious diseases service over 1 year: utility in an outpatient parenteral antibiotic programme Sir, Daptomycin is a novel cyclic lipopeptide with rapid cidal activity against Gram-positive organisms. In Glasgow hospitals, daptomycin is approved for restricted use, on the recommendation of an infectious diseases physician or microbiologist, for those patients with serious Grampositive infections (excluding primary pulmonary infections) when glycopeptides are failing or contraindicated. A retrospective review of our unit’s experience with daptomycin over 12 months was undertaken. Patients who had been managed through the infectious diseases inpatient unit or outpatient parenteral antibiotic therapy (OPAT) service from June 2006 (n = 1345) and who received at least one dose of daptomycin (n = 29) were identified and case records were reviewed. All patients were diagnosed with serious Gram-positive infections (Table 1). Eleven patients were bacteraemic (seven with Staphylococcus aureus), eight had methicillinresistant S. aureus infection, 13 had bone and joint infection and six had bacterial endocarditis. Twenty-one cases had received prior glycopeptide therapy and the indication was clinical/microbiological failure (15), allergy/intolerance (10), teicoplanin-resistant Staphylococcus epidermidis (1), to facilitate outpatient therapy (2) and empirical therapy in rapidly progressive soft tissue infection (1). Twenty patients received 6 mg/kg/day daptomycin and 17 received at least one additional agent with Gram-positive
Table 1 Individual patient summaries Diagnosis/ complications
Co-morbidity
Microbiology (site)
Antibiotic therapy prior to daptomycin
51/F
Infected total knee replacement Cellulitis
No
No
Vancomycin/ teicoplanin
Cor pulmonale
No
Aortic valve endocarditis and discitis Osteomyelitis foot Tricuspid valve endocarditis
Acute renal failure
MSSA (blood)
Flucloxacillin + clindamycin Flucloxacillin
Type 1 diabetes Short bowel and parenteral nutrition
MRSA (tissue) MRSA (blood), Candida albicans (blood) MSSA (blood)
62/F 59/M
27/F 46/F
Duration (days)
Indication for daptomycin
Dose (mg/kg/day)
Concomitant antibiotic therapy
Duration (days)
Duration of OPAT (days)
Outcome
6
Allergy
6
Rifampicin
35
35
Cured
8
Failure
4
No
13
0
Cured
40
Failure
6
Rifampicin
53
52
Cured
Teicoplanin
16
6
Rifampicin
68
68
Improved
Teicoplanin, voriconazole, linezolid and piperacillin/ tazobactam Flucloxacillin and gentamicin Vancomycin then linezolid
52
Renal failure/ intolerance Failure
6
Meropenem, ambisome
46
0
Improved
8
OPAT
6
Rifampicin
35
28
Improved
30
Failure
6
Sodium fusidate
85
28
Cured
69/F
Mitral valve endocarditis
No
66/F
Mitral valve endocarditis
MRSA (blood)
22/M
Primary bacteraemia Cellulitis
Multiple sclerosis and quadriparesis No
MSSA (blood)
Flucloxacillin
2
OPAT
6
No
4
4
Cured
Ischaemic heart disease, recent MRSA bacteraemia
Group A streptococci (blood), MRSA (carriage) MRSA (synovium)
Vancomycin then linezolid
11
Failure
4
No
29
0
Cured
Relapse/failure
6
Doxycycline
49
0
Improved
7
7
Cured
128
128
31
31
75/F
Osteomyelitis tibia/femur and septic arthritis knee
49/F
Cellulitis
64/M
OM tibia and infected aortobifemoral graft
72/M
Infected total knee replacement
HIV, sickle cell disease, previous MRSA septic arthritis Recurrent cellulitis Ischaemic heart disease, cerebrovascular disease No
Teicoplanin
0
No
Teicoplanin
10
Failure
4
No
MRSA, Enterococcus sp., C. albicans (blood)
Teicoplanin
21
Failure
6
AmBisome, ertapenem
Staphylococcus. epidermidis (tissue)
Vancomycin, teicoplanin
17
Allergy
6
Sodium fusidate
Died of surgical complications following repair of infected graft Cured 493
41/M
Letters to the Editor / International Journal of Antimicrobial Agents 31 (2008) 484–504
Age/gender
494
Table 1 (Continued ) Age/gender
Diagnosis/ complications
Co-morbidity
Microbiology (site)
Antibiotic therapy prior to daptomycin
Duration (days)
Indication for daptomycin
Dose (mg/kg/day)
Concomitant antibiotic therapy
Duration (days)
19/F
Septic arthritis knee and infected inferior vena caval thrombosis Cellulitis
Septic miscarriage
MSSA, group A streptococci (blood)
Cefotaxime, vancomycin, gentamicin, flucloxacillin
18
Failure
6
No
10
3
Ischaemic heart disease
Failure
6
Clindamycin
14
14
Cured
Osteomyelitis toe
21
Thrombocytopenia 6
Rifampicin
58
58
Improved
67/F
Tibial osteomyelitis and infected knee replacement
No
Teicoplanin
10
Failure
6
Meropenem
46
41
Failed. Required above knee amputation
58/F
Infected total hip replacement Infected knee replacement
Type 2 diabetes mellitus Multiple previous joint revisions. Previous Leuconostoc, S. epidermidis and Serratia sp. No
Teicoplanin, vancomycin, ceftriaxone Vancomycin, teicoplanin
14
72/F
Group A streptococci (wound swab) MRSA (wound swab)
MRSA (tissue)
Teicoplanin
35
Allergy
6
Rifampicin
14
14
Cured
No
Teicoplanin
9
Thrombocytopenia 6
Piperacillin/ tazobactam, ciprofloxacin, sodium fusidate
67
60
Cured
MRSA (wound swab)
Vancomycin
5
Failure
6
Clindamycin
16
5
MRSA (wound swab)
Teicoplanin
8
Allergy
6
No
12
12
Cured
S. epidermidis (tissue) Viridans streptococci (blood)
Teicoplanin
30
Allergy
6
Rifampicin
24
24
Cured
Piperacillin/ tazobactam, gentamicin, clarithromycin
12
Failure
4 (alternate days)
Meropenem
23
0
59/M
27/M
Pyomyositis
73/M
Post-operative wound infection Infected knee replacement Aortic and mitral valve endocarditis
78/M 52/F
Atrial fibrillation. Previous Serratia sp. and MRSA from tissue Hypogammaglobulinaemia, Behc¸et’s Atrial fibrillation Hypertension Renal dialysis, ventilation, septic cerebral emboli
Outcome
Improved but CPK rise and myositis
Improved
Failed. Developed daptomycinresistant enterococcal bacteraemia
Letters to the Editor / International Journal of Antimicrobial Agents 31 (2008) 484–504
61/M
Duration of OPAT (days)
Cellulitis
Congestive cardiac failure
No
71/F
Cellulitis
MRSA (wound swab)
48/F
Cellulitis and severe sepsis
32/M
Sacral osteomyelitis
Obesity, ischaemic heart disease, renal impairment Obesity, recurrent cellulites Paraplegia
50/M
Aortic valve endocarditis, perivalvular abscess and fistula Infected total knee replacement
57/M
Acute aortic valve replacement and revision Rheumatoid arthritis and methotrexate therapy
Piperacillin/ tazobactam, clindamycin, ceftriaxone, flucloxacillin Teicoplanin
Group A No streptococci (blood) MSSA/Bacteroides Vancomycin, (tissue) metronidazole, ceftriaxone Pneumococcus Cefotaxime, (blood) vancomycin, gentamicin
Teicoplaninresistant S. epidermidis (tissue)
Vancomycin
11
Allergy
4 (alternate days)
No
3
Failure
4 (alternate days)
0
Empirical
11
37
4
14
0
Improved
Clindamycin
4
0
Cutaneous reaction and renal failure
4
Clindamycin
1
0
Cured
Allergy
6
Clindamycin, metronidazole
12
0
Failure
6
No
74
0
Improved but CPK rise and myositis Improved
Resistance
6
Doxycycline
42
39
Cured
OPAT, outpatient parenteral antibiotic therapy; F, female; M, male; MSSA, methicillin-susceptible Staphylococcus aureus; MRSA, methicillin-resistant S. aureus; HIV, human immunodeficiency virus; CPK, creatine phosphokinase.
Letters to the Editor / International Journal of Antimicrobial Agents 31 (2008) 484–504
76/M
495
496
Letters to the Editor / International Journal of Antimicrobial Agents 31 (2008) 484–504
activity (Table 1). Twenty-eight patients (97%) survived beyond 6 months of hospital discharge. One died of surgical complications following repair of an infected aortic graft. One required above the knee amputation for osteomyelitis/septic arthritis (intraoperative specimens were negative). Twenty-three patients (79%) were improved or cured. Two improved substantially with 6 mg/kg but reversible myotoxicity was noted at 12 days and 15 days with creatine phosphokinase increases to 2369 IU/L and 5500 IU/L. Treatment was completed successfully with alternative agents. A further patient receiving concomitant clindamycin discontinued after clinical improvement owing to related transient cutaneous and renal toxicity (without myotoxicity) after 4 days. Daptomycin resistance was observed in a 52-year-old lady who presented with multiorgan failure, cerebral emboli and aortic and mitral valve viridans streptococcal endocarditis. She received 4 mg/kg on alternate days following clinical deterioration and failure of initial antimicrobial therapy. During intensive care admission, heavy colonisation with vancomycin-resistant enterococci was found. Daptomycinresistant enterococcal bacteraemia was identified on Day 13 (and Day 4 of daptomycin), but followed substantial clinical improvement. The patient subsequently switched to linezolid and survived beyond 6 months following discharge. The median duration of therapy was 29 days (range 1–128 days) with a median duration of inpatient therapy of 4 days (range 0–74 days). Nineteen patients were managed through OPAT, 11 (38%) without admission. Eleven (58%) of the 19 were trained to self administer or received therapy via a trained carer. There were no unplanned re-admissions. No further associated adverse events were noted in the OPAT setting with therapy up to 128 days. In the context of a restrictive prescribing policy, daptomycin was used successfully in a difficult-to-treat population with complicated Gram-positive infections failing or intolerant of glycopeptides, including those with bone and joint infections and left-sided endocarditis. Prolonged therapy (>28 days) was used in 31% and myotoxicity was observed twice. In clinical studies, this has been rare when administered at 4 mg/kg [1] and more frequent (6.7%) when dosed at 6 mg/kg [2]. In all three patients with any toxicity daptomycin was discontinued, with rapid resolution of toxicity, and all had shown rapid improvement of signs of infection. Breakthrough resistant nosocomial infection was observed in one patient probably due to underdosing in the context of prior vancomycin-resistant enterococcal colonisation and subsequent bloodstream infection. It was not possible to investigate whether the daptomycin resistance pre-dated or was a result of exposure to the agent. Resistance observed in clinical trials and in clinical practice both in S. aureus and enterococcal infections is typically associated with persistent deep foci of infection. In view of the risk of emergent resistance, it is essential to remove or debride foci of infection whenever possible, to be vigilant for line-related
sepsis and to optimise daptomycin dosing. Higher dosing may be useful in some deep-seated or complex infections. Others have administered 12 mg/kg/day for 41 days without significant toxicity [3], and in a rabbit model using S. aureus daptomycin resistance has been overcome with 10 mg/kg dosing [4]. In vitro there is synergy with a number of agents including rifampicin and gentamicin [5,6] and there is anecdotal evidence of in vivo synergy [7], hence combination therapy should be considered in complex infections. In this series, daptomycin was co-administered with another active agent in deep-seated infection whenever possible. We found daptomycin to be a particularly useful and well tolerated agent for OPAT, with once-daily dosing and early discharge achievable in the majority of patients. Our early clinical experience of daptomycin therefore supports its use in a range of serious Gram-positive infections following failure or intolerance of the glycopeptides in both the inpatient and OPAT setting. Funding: No funding sources. Competing interests: RAS is a principal investigator for the Cubist-sponsored DAP-Ost-06-02 study and for the DAP-002 Novartis–Cubist-sponsored skin and skin-structure study. RAS has also received an unrelated grant from Novartis for an investigator-initiated skin and skin-structure study, has presented at Novartis-sponsored educational symposia and has attended advisory board meetings for Novartis and Cubist. Ethical approval: Not required.
Acknowledgments The authors would like to thank Emma Bell, Lindsay Semple and Clare Kirkwood for assistance in providing data on OPAT therapy, Elspeth Lamont for providing pharmacy records and Dr Ray Fox who provided clinical care to two of the subjects in the series.
References [1] Arbeit RD, Maki D, Tally FP, Campanaro E, Eisenstein BI. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis 2004;38:1673–81. [2] Fowler Jr VJ, Boucher HW, Corey GR, Abrutyn E, Karchner AW, Rupp ME, et al. Daptomycin versus standard therapy for bacteraemia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006;355:653–65. [3] Cunha BA, Eisenstein LE, Hamid NS. Pacemaker-induced Staphylococcus aureus mitral valve acute bacterial endocarditis complicated by persistent bacteraemia from a coronary stent: cure with prolonged/high-dose daptomycin without toxicity. Heart Lung 2006;35: 207–11. [4] Rose WE, Rybak MJ, Kaatz GW. Evaluation of daptomycin treatment of Staphylococcus aureus bacterial endocarditis: an in vitro and in vivo simulation using historical and current dosing strategies. J Antimicrob Chemother 2007;60:334–40. [5] Tsujii BT, Rybak MJ. Short-course gentamicin in combination with daptomycin or vancomycin against Staphylococcus aureus in an in
Letters to the Editor / International Journal of Antimicrobial Agents 31 (2008) 484–504 vitro pharmacodynamic model with simulated endocardial vegetations. Antimicrob Agents Chemother 2005;49:2735–45. [6] Pankey G, Ashcraft D, Patel N. In vitro synergy of daptomycin plus rifampicin against Enterococcus faecium resistant to both linezolid and vancomycin. Antimicrob Agents Chemother 2005;49: 5166–8. [7] Burns C. Daptomycin–rifampicin for a recurrent MRSA joint infection unresponsive to vancomycin-based therapy. Scand J Infect Dis 2006;38:133–6.
R.A. Seaton ∗ A.A. MacConnachie Infection Unit, Brownlee Centre, Gartnavel General Hospital, 1053 Great Western Road, Glasgow G12 0YN, UK ∗ Corresponding
author. Tel.: +44 141 211 0292; fax: +44 141 211 1097. E-mail address: [email protected] (R.A. Seaton) doi: 10.1016/j.ijantimicag.2008.01.006
Indole derivatives as efflux pump inhibitors for TolC protein in a clinical drug-resistant Escherichia coli isolated from a pig farm Sir, The function of efflux pumps is to transport drugs through the bacterial envelope and to limit the intracellular accumulation of toxic compounds (e.g. antibiotics, antimicrobial peptides, metals and detergents). Drug resistance due to antibiotic efflux is an increasing problem worldwide [1]. A new molecular challenge is to combat this transport by searching for new molecules to block efflux and thus restore drug susceptibility in resistant clinical strains [2,3]. Pathogenic Escherichia coli is an important pathogenic bacterium in animals and humans. The major multidrug efflux pump AcrAB from E. coli co-operates with TolC to extrude an extremely broad range of antimicrobial compounds, including antibiotics, detergents, dyes and organic solvents, from the cell. The recent resolution of the threedimensional structures of TolC and AcrB from E. coli and MexA and OprM from Pseudomonas aeruginosa has given rise to a better understanding of the efflux mechanism in Gram-negative bacteria [4]. TolC is central to the export of diverse compounds, interacting with a specific inner membrane translocase in E. coli. Opening the periplasmic tunnel entrance is clearly key to the function of TolC, the assembled export and efflux machineries. TolC may be a better target than AcrB for the development of efflux pump inhibitors [5,6]. The aim of the present study was to identify original molecules capable of restoring susceptibility of a resistant strain to various antibiotics. In the vast heterocyclic structural space, many indole derivatives, including fused derivatives, form the basis of
497
Table 1 Determination of the ability of two small molecular indole derivative inhibitors to increase antibiotic sensitivity of Escherichia coli FJ305 Compounds (0.5 mM)
No compounda Indo 1 Indo 2
MIC (g/mL) CHL
TET
ERY
CIP
THI
FLO
256 8 4
64 16 16
64 32 4
128 8 16
64 8 8
32 8 4
MIC, minimum inhibitory concentration; CHL, chloramphenicol; TET, tetracycline; ERY, erythromycin; CIP, ciprofloxacin; THI, thiamphenicol; FLO, florfenicol; Indo 1, 3-amino-6-carboxyl-indolenine; Indo 2, 3-nitro6-amino-indolenine. a Isolate FJ305 was resistant to various antibiotics in the absence of indole inhibitors.
a range of pharmaceuticals, and a high level of activity continues in the search for new indole-based medicinal agents [7]. Some of the molecules tested in this work were able to inhibit the main efflux pump, AcrAB-TolC. The molecules 3-amino-6-carboxyl-indolenine and 3-nitro6-amino-indolenine were selected as potential inhibitors. A pair of the proton-acceptor and proton-donor was linked in the molecular skeleton. The designed molecules could link Asp and Tyr together by hydrogen bonds. Two small molecules were designed by quantum chemistry and synthesised by nitration and ammonification. The structure of the two small molecules was confirmed by proton nuclear magnetic resonance (1 H NMR), mass spectrometry and infrared spectra analysis. The clinical strain E. coli FJ305, in which TolC protein is overexpressed, was grown in Mueller–Hinton (MH) broth with aeration at 37 ◦ C. Minimum inhibitory concentration (MIC) determination for antibiotics in the presence of the two small molecules was conducted by the microtitre broth dilution method. Escherichia coli was cultured in MH liquid culture at 37 ◦ C and then inoculated into a tube at a concentration of 105 /mL. The concentration of indolenine derivatives was diluted from 0.5 mM. Chloramphenicol (CHL), erythromycin (ERY), ciprofloxacin (CIP), tetracycline (TET), thiamphenicol (THI) and florfenicol (FLO) were diluted two-fold and inoculated in tubes. All tubes were then cultured for 18 h at 37 ◦ C. The next day, the result was observed and demonstrated that the two small molecules could restore the susceptibility of FJ305 to CHL, ERY, CIP, TET, THI and FLO (Table 1). The molecules constrained the tunnel at the distal end of TolC, thus weakening drug export. In conclusion, hydrogen bonds are formed relatively easily between the designed molecules and Asp and Tyr. The two small molecules should be efficient molecules for shrinking the size of the tunnel and obstructing the export of drugs. MIC determination in the presence of the two small molecules demonstrated that the susceptibility of E. coli to CHL, ERY, CIP, TET, THI and FLO could be increased. 3-Amino-6carboxyl-indolenine and 3-nitro-6-amino-indolenine may be effective tools against the resistance to antibiotics of E. coli isolates.