- Email: [email protected]
soft tissue infections
Anaerobe 17 (2011) 213e215
Contents lists available at ScienceDirect
Anaerobe journal homepage: www.elsevier.com/locate/anaerobe
Clinical Microbiology
Anti-anaerobic activity of serum from patients treated with tigecycline for skin/soft tissue infections G.E. Stein a, *, K.L. Tyrrell b, L.A. Dybas a, D.M. Citron b, D.P. Nicolau c, E.J.C. Goldstein b a
Michigan State University, Department of Medicine, B323 Life Science Bldg., East Lansing, MI 48824, USA R.M. Alden Research Laboratory, Culver City, CA 90230, USA c Center for Anti-Infective Research, Hartford Hospital, Hartford, CT 06102, USA b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 September 2010 Received in revised form 15 January 2011 Accepted 2 February 2011 Available online 3 March 2011
To gain additional data concerning the anti-anaerobic activity of tigecycline in serum, we analyzed blood samples from six patients with a complicated skin/soft tissue infection who were receiving IV tigecycline 50 mg every 12 h. Venous blood samples were obtained after multiple doses of tigecycline at 1, 6 and 12 h after the initiation of a 1 h IV infusion. Sera from these samples were tested to determine serum inhibitory and bactericidal activity over time against 4 anaerobic bacteria (Bacteroides fragilis, Peptoniphilus asaccharolyticus, Prevotella bivia and Finegoldia magna). An analysis of serum titers found that tigecycline exhibited early (1 h) and prolonged (12 h) inhibitory activity against each study isolate. Moreover, it provided bactericidal activity for 12 h against these strains with the exception of F. magna. Tigecycline was found to exhibit antibacterial activity at serum concentrations below the MICs of the anaerobic bacteria tested. This finding further supports that the antimicrobial activity of tigecycline can be greater than that suggested by the free fraction of drug and that serum appears to enhance this antibacterial activity. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Tigecycline Anaerobes Bactericidal Bacteroides
1. Introduction Tigecycline is a broad-spectrum glycylcycline antibiotic which possesses good in vitro activity against both gram-positive and gram-negative anaerobic bacteria [1,2]. In vitro studies have shown that tigecycline exhibits a time-dependent pattern of antibacterial activity [3]. This finding has also been observed in a neutropenic mouse thigh-infection model [4]. The drug exposure to produce 80% of maximal effect was calculated as a free drug time greater than MIC of more than 50% of the dosing interval for tigecycline. This study also found that the drug exposure to clear various bacterial species may be different. Anaerobic bacteria were not studied in these investigations. When given intravenously, tigecycline is extensively distributed into tissues such as skin, bone, gallbladder, colon and lung [5]. Its protein binding ranges from 73 to 79% when measured by ultracentrifugation. Tigecycline circulates primarily as unchanged drug, and its major route of elimination is through feces, via biliary excretion. Urine excretion of unchanged drug accounts for <20% of the dose. Its serum values, following 100 mg loading dose and 50 mg every 12 h, are low [6]. The concentration maximum (Cmax)
* Corresponding author. Tel.: þ1 517 353 5126; fax: þ1 517 353 1922. E-mail address: [email protected] (G.E. Stein). 1075-9964/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.anaerobe.2011.02.006
of tigecycline in serum is less than 1.0 mg/L following multiple doses. In this investigation, we analyzed the antimicrobial activity of tigecycline in patient sera against anaerobic bacteria associated with skin/soft tissue infections. 2. Patients & methods 2.1. Patients Sera were obtained from six adult (3 male and 3 female) inpatients being treated with tigecycline for a complicated skin/soft tissue infection. Each patient gave written informed consent prior to treatment with tigecycline. These patients had a mean age of 57 years (range, 43e78 years) and a mean weight of 75 kg (range, 51e104 kg). Their mean albumin level was 1.8 g/dL (range, 1.4e2.1 g/dL). 2.2. Drug administration Each patient received a 100 mg loading dose of tigecycline. This was followed by doses of 50 mg every 12 h. Each dose was given intravenously over a 1 h infusion period. No other antibiotics were administered.
214
G.E. Stein et al. / Anaerobe 17 (2011) 213e215
2.3. Serum samples Venous blood samples were obtained after at least three doses of tigecycline. These occurred at 1, 6, and 12 h after the initiation of a 50 mg infusion. Following centrifugation, serum samples were aliquoted and stored at 70 C until the time of analysis. The concentration of tigecycline in serum samples was measured by a validated high-performance liquid chromatographic method [7].
2.4. Bacterial strains The minimum inhibitory concentrations of tigecycline were determined by agar dilution as recommended by Clinical and Laboratory Standards Institute (CLSI) [8]. Susceptibility testing of anaerobic organisms was performed using Brucella agar supplemented with hemin, vitamin K, and 5% laked sheep blood. Isolates were suspended in Brucella broth to a density equal to a 0.5 McFarland standard. The suspensions were applied to the antibiotic plates at 105 CFU/spot; plates were incubated in an anaerobic chamber at 36 C for 44e48 h. The MIC was defined as the lowest concentration of antibiotic that prevented a change in growth. The anaerobes tested included recent clinical isolates of Bacteroides fragilis, Peptoniphilus asaccharolyticus, Prevotella bivia, and Finegoldia magna (R.M. Alden Research Laboratory) from skin/soft tissue infections. The control strain tested was B. fragilis strain ATCC 25285.
2.5. Bacterial titers in serum Inhibitory and bactericidal titers in serum were determined according to CLSI standards [9]. Each determination was performed in duplicate. Wells with no visible growth and the first growth well were sub-cultured to Brucella agar plates that were incubated for 3 days prior to counting colonies. Isolates were tested against serum collected at each time period for all subjects. They were also incubated in human serum without drug. The bactericidal titer (up to 1:32)-in serum endpoint was determined as the highest dilution of serum yielding 99.9% killing. The median and geometric mean inhibitory and bactericidal titers at each time period (n ¼ 6) were calculated and used to determine the duration of inhibitory and bactericidal activity.
3. Results The mean peak (Cmax) and trough (Cmin) serum concentrations of tigecycline in these patients were 0.58 0.32 mg/L and 0.24 0.14 mg/L, respectively. These values are similar to those observed in other patient studies [5]. Each of the study organisms, except the P. asaccharolyticus, had a tigecycline MIC ¼ 0.5 mg/L. The strain of P. asaccharolyticus had a MIC ¼ 0.25 mg/L. Each of these isolates would be considered “susceptible” to tigecycline based upon the current FDA breakpoint (4 mg/L) for anaerobes. Tigecycline produced early (1 h) and prolonged (12 h) serum inhibitory activity against each of the tested isolates (Table 1). There was no growth inhibition in serum without drug. Tigecycline also produced early and prolonged serum bactericidal activity against these strains with the exception of F. magna. A median bactericidal titer of at least 1:4 was observed at each time period for B. fragilis, P. bivia and P. asaccharolyticus. The median bactericidal titer for F. magna was <1:2 at each time period.
Table 1 Median serum inhibitory and bactericidal titers over time for tigecycline against anaerobic bacteria. Organism and Time point (h) B. fragilis 14718 1 6 12 F. magna 16352 1 6 12 P. bivia 16157 1 6 12 P. asaccharolyticus 15684 1 6 12
SIT (range)
SBT (range)
1:8 (1:8e1:16) 1:8 (1:8) 1:8 (1:4e1:8)
1:8 (1:4e1:16) 1:4 (1:4e1:8) 1:4 (1:4e1:8)
1:8 (1:8e1:32) 1:8 (1:4e1:32) 1:4 (1:4e1:16)
<1:2 (<1:2e1:8) <1:2 (<1:2e1:8) <1:2 (<1:2e1:4)
1:16 (1:4e1:16) 1:8 (1:4e1:8) 1:4 (<1:2e1:8)
1:8 (1:4e1:16) 1:4 (1:2e1:8) 1:4 (<1:2e1:8)
1:16 (1:8e1:32) 1:8 (1:8e1:16) 1:4 (1:4e1:16)
1:16 (1:8e1:32) 1:8 (1:8e1:16) 1:4 (1:4e1:16)
SIT; Serum inhibitory titer, SBT; Serum bactericidal titer.
4. Discussion In this study, tigecycline provided inhibitory as well as bactericidal activity, with the exception of F. magna, in serum for its entire dosing interval (12 h) against anaerobic bacteria associated with complicated skin/soft tissue infections. This prolonged duration of antibacterial activity has been shown to be a good predictor of the antimicrobial effect of tigecycline [3,4]. Furthermore, this ex vivo pharmacodynamic model integrates antimicrobial activity with human pharmacokinetic parameters as well as serum factors, such as antibodies, complement, and protein binding. However, the serum bactericidal test does not predict either bacteriologic success or clinical outcome [10]. The reason for the lack of bactericidal activity against F. magna is unclear and deserves further study. Some strains of F. magna bind human serum albumin which may prevent their eradication [11]. The clinical efficacy of tigecycline against anaerobic pathogens has been evaluated in patients with complicated skin/soft tissue infections and complicated intra-abdominal infections [12e14]. The microbial eradication rates against anaerobic bacteria (eg. B. fragilis, Clostridium perfringens and Petostreptococcus spp.) in these tissues was found to range from 76% to 100%. In patients with secondary bacteremia, clinical cure rates were observed in 4 of 6 patients with B. fragilis isolated from the blood [15]. None of these patients had persistent bacteremia. The antimicrobial activity of tigecycline against B. fragilis isolates in bacteremic patients and in our serum bactericidal studies was not expected. Clinical isolates of B. fragilis have a median (MIC50) MIC ¼ 0.5 mg/L [12e14]. This MIC concentration is well above the free (w25%) fraction of tigecycline in serum, albeit our patients had low albumin levels which may have increased the amount of unbound tigecycline. We observed bactericidal activity with serum tigecycline concentrations that were diluted below the MIC of the B. fragilis isolate utilized in this study (Fig. 1). This finding suggests that tigecycline can produce killing against anaerobic bacteria that is enhanced by the addition of serum [6]. In addition, Alou et al. observed that physiological concentrations of human albumin did not diminish the antibacterial activity of tigecycline against several aerobic bacteria [16]. This finding further supports that the antimicrobial activity of tigecycline can be greater than that suggested by the free fraction of the drug. At present, the “susceptible” breakpoint concentration for tigecycline against anaerobes is approximately 3-fold higher than maximal serum levels. The findings from this investigation have shed some light on this paradox. Tigecycline was found to exhibit antibacterial activity at diluted serum concentrations that were
G.E. Stein et al. / Anaerobe 17 (2011) 213e215
Bacteroides fragilis (MIC = 0.5 mg/L) [3]
16
Median 1/titer
14
[4]
12 10
SIT
8
SBT
6
[5] [6]
4 [7]
2 0 0
2
4
6
8
10
12
Time (h) Fig. 1. Serum inhibitory and bactericidal titers of tigecycline against a strain of B. fragilis.
several-fold below the MICs of the anaerobic bacteria that were analyzed. The overall ability of tigecycline to eradicate anaerobic pathogens in serum as well as tissues will require additional study. Acknowledgment This study was funded by the R.M. Alden Research Laboratory, Culver City, CA and Pfizer, Inc.
[8]
[9] [10] [11] [12]
[13]
[14]
References [15] [1] Goldstein EJC, Citron DM, Merriam CV, Warren Y, Tyrrell K. Comparative in vitro activities of GAR-936 against aerobic and anaerobic animal and human bite wound pathogens. Antimicrob Agents Chemother 2000;44:2747e51. [2] Goldstein EJC, Citron DM, Merriam CV, Warren Y, Tyrrell K, Fernandez HT. Comparative in vitro susceptibilities of 396 unusual anaerobic strains to
[16]
215
tigecycline and eight other antimicrobial agents. Antimicrob Agents Chemother 2006;50:3507e13. Meagher AK, Ambrose PG, Grasela TH, Ellis-Grosse EJ. The pharmacokinetic and pharmacodynamic profile of tigecycline. Clin Infect Dis 2005;41(Suppl. 5):333e40. van Ogtrop ML, Andes D, Stamstad TJ, Conklin B, Weiss WJ, Craig WA, et al. In vivo pharmacodynamic activities of two glycylcyclines (GAR-936 and WAY 152,288) against various gram-positive and gram-negative bacteria. Antimicrob Agents Chemother 2000;44:943e9. MacGowan AP. Tigecycline pharmacokinetic/pharmacodynamic update. J Antimicrob Chemother 2008;62(suppl. 1):11e6. Agwuh KN, MacGowan A. Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines. J Antimicrob Chemother 2006;58: 256e65. Li C, Sutherland CA, Nighingale CH, Nicolau DP. Quantitation of tigecycline, a novel glycylcycline, by liquid chromatography. J Chromatogr B 2004;811: 225e9. Clinical and Laboratory Standards Institute. Methods for antimicrobial susceptibility testing of anaerobic bacteria. Approved standard. CLSI document M11eA7. 7th ed. Wayne, PA: CLSI; 2007. Clinical and Laboratory Standards Institute. Methodology for the serum bactericidal test. Approved guideline M21-A. Wayne, PA: CLSI; 1999. Ackerman BH, Dello Buono FA. In vitro testing of antibiotics. Pharmacotherapy 1996;16:201e21. Myre EB. Surface receptors for human serum albumin in Peptococcus magnus strains. J Med Microbiol 1984;18:189e95. Ellis-Grosse EJ, Babinchak T, Dartois N, Rose G, Loh E. The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double-blind phase 3 comparison studies with vancomycin-aztreonam. Clin Infect Dis 2005;41(Suppl. 5):S34e53. Fomin P, Beuran M, Gradauskas A, Baravskas G, Datenko A, Darois N, et al. Tigecycline is efficacious in the treatment of complicated intra-abdominal infections. Intern J Surg 2005;3:35e47. Babinchak T, Ellis-Grosse E, Dartois N, Rose GM, Loh E. The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infections: analysis of pooled clinical trial data. Clin Infect Dis 2005;41(Suppl. 5):S354e66. Gardiner D, DuKart G, Cooper A, Babinchak T. Safety and efficacy of intravenous tigecycline in subjects with secondary bacteremia: pooled results from 8 Phase III clinical trials. Clin Infect Dis 2010;50:229e38. Alou L, Gimenez M-J, Cafini F, Aguilar L, Sevillano D, Gonzalez N, et al. In vitro effect of physiological concentrations of human albumin on the antibacterial activity of tigecycline. J Antimicrob Chemother 2009;64:1230e3.
Contents lists available at ScienceDirect
Anaerobe journal homepage: www.elsevier.com/locate/anaerobe
Clinical Microbiology
Anti-anaerobic activity of serum from patients treated with tigecycline for skin/soft tissue infections G.E. Stein a, *, K.L. Tyrrell b, L.A. Dybas a, D.M. Citron b, D.P. Nicolau c, E.J.C. Goldstein b a
Michigan State University, Department of Medicine, B323 Life Science Bldg., East Lansing, MI 48824, USA R.M. Alden Research Laboratory, Culver City, CA 90230, USA c Center for Anti-Infective Research, Hartford Hospital, Hartford, CT 06102, USA b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 September 2010 Received in revised form 15 January 2011 Accepted 2 February 2011 Available online 3 March 2011
To gain additional data concerning the anti-anaerobic activity of tigecycline in serum, we analyzed blood samples from six patients with a complicated skin/soft tissue infection who were receiving IV tigecycline 50 mg every 12 h. Venous blood samples were obtained after multiple doses of tigecycline at 1, 6 and 12 h after the initiation of a 1 h IV infusion. Sera from these samples were tested to determine serum inhibitory and bactericidal activity over time against 4 anaerobic bacteria (Bacteroides fragilis, Peptoniphilus asaccharolyticus, Prevotella bivia and Finegoldia magna). An analysis of serum titers found that tigecycline exhibited early (1 h) and prolonged (12 h) inhibitory activity against each study isolate. Moreover, it provided bactericidal activity for 12 h against these strains with the exception of F. magna. Tigecycline was found to exhibit antibacterial activity at serum concentrations below the MICs of the anaerobic bacteria tested. This finding further supports that the antimicrobial activity of tigecycline can be greater than that suggested by the free fraction of drug and that serum appears to enhance this antibacterial activity. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Tigecycline Anaerobes Bactericidal Bacteroides
1. Introduction Tigecycline is a broad-spectrum glycylcycline antibiotic which possesses good in vitro activity against both gram-positive and gram-negative anaerobic bacteria [1,2]. In vitro studies have shown that tigecycline exhibits a time-dependent pattern of antibacterial activity [3]. This finding has also been observed in a neutropenic mouse thigh-infection model [4]. The drug exposure to produce 80% of maximal effect was calculated as a free drug time greater than MIC of more than 50% of the dosing interval for tigecycline. This study also found that the drug exposure to clear various bacterial species may be different. Anaerobic bacteria were not studied in these investigations. When given intravenously, tigecycline is extensively distributed into tissues such as skin, bone, gallbladder, colon and lung [5]. Its protein binding ranges from 73 to 79% when measured by ultracentrifugation. Tigecycline circulates primarily as unchanged drug, and its major route of elimination is through feces, via biliary excretion. Urine excretion of unchanged drug accounts for <20% of the dose. Its serum values, following 100 mg loading dose and 50 mg every 12 h, are low [6]. The concentration maximum (Cmax)
* Corresponding author. Tel.: þ1 517 353 5126; fax: þ1 517 353 1922. E-mail address: [email protected] (G.E. Stein). 1075-9964/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.anaerobe.2011.02.006
of tigecycline in serum is less than 1.0 mg/L following multiple doses. In this investigation, we analyzed the antimicrobial activity of tigecycline in patient sera against anaerobic bacteria associated with skin/soft tissue infections. 2. Patients & methods 2.1. Patients Sera were obtained from six adult (3 male and 3 female) inpatients being treated with tigecycline for a complicated skin/soft tissue infection. Each patient gave written informed consent prior to treatment with tigecycline. These patients had a mean age of 57 years (range, 43e78 years) and a mean weight of 75 kg (range, 51e104 kg). Their mean albumin level was 1.8 g/dL (range, 1.4e2.1 g/dL). 2.2. Drug administration Each patient received a 100 mg loading dose of tigecycline. This was followed by doses of 50 mg every 12 h. Each dose was given intravenously over a 1 h infusion period. No other antibiotics were administered.
214
G.E. Stein et al. / Anaerobe 17 (2011) 213e215
2.3. Serum samples Venous blood samples were obtained after at least three doses of tigecycline. These occurred at 1, 6, and 12 h after the initiation of a 50 mg infusion. Following centrifugation, serum samples were aliquoted and stored at 70 C until the time of analysis. The concentration of tigecycline in serum samples was measured by a validated high-performance liquid chromatographic method [7].
2.4. Bacterial strains The minimum inhibitory concentrations of tigecycline were determined by agar dilution as recommended by Clinical and Laboratory Standards Institute (CLSI) [8]. Susceptibility testing of anaerobic organisms was performed using Brucella agar supplemented with hemin, vitamin K, and 5% laked sheep blood. Isolates were suspended in Brucella broth to a density equal to a 0.5 McFarland standard. The suspensions were applied to the antibiotic plates at 105 CFU/spot; plates were incubated in an anaerobic chamber at 36 C for 44e48 h. The MIC was defined as the lowest concentration of antibiotic that prevented a change in growth. The anaerobes tested included recent clinical isolates of Bacteroides fragilis, Peptoniphilus asaccharolyticus, Prevotella bivia, and Finegoldia magna (R.M. Alden Research Laboratory) from skin/soft tissue infections. The control strain tested was B. fragilis strain ATCC 25285.
2.5. Bacterial titers in serum Inhibitory and bactericidal titers in serum were determined according to CLSI standards [9]. Each determination was performed in duplicate. Wells with no visible growth and the first growth well were sub-cultured to Brucella agar plates that were incubated for 3 days prior to counting colonies. Isolates were tested against serum collected at each time period for all subjects. They were also incubated in human serum without drug. The bactericidal titer (up to 1:32)-in serum endpoint was determined as the highest dilution of serum yielding 99.9% killing. The median and geometric mean inhibitory and bactericidal titers at each time period (n ¼ 6) were calculated and used to determine the duration of inhibitory and bactericidal activity.
3. Results The mean peak (Cmax) and trough (Cmin) serum concentrations of tigecycline in these patients were 0.58 0.32 mg/L and 0.24 0.14 mg/L, respectively. These values are similar to those observed in other patient studies [5]. Each of the study organisms, except the P. asaccharolyticus, had a tigecycline MIC ¼ 0.5 mg/L. The strain of P. asaccharolyticus had a MIC ¼ 0.25 mg/L. Each of these isolates would be considered “susceptible” to tigecycline based upon the current FDA breakpoint (4 mg/L) for anaerobes. Tigecycline produced early (1 h) and prolonged (12 h) serum inhibitory activity against each of the tested isolates (Table 1). There was no growth inhibition in serum without drug. Tigecycline also produced early and prolonged serum bactericidal activity against these strains with the exception of F. magna. A median bactericidal titer of at least 1:4 was observed at each time period for B. fragilis, P. bivia and P. asaccharolyticus. The median bactericidal titer for F. magna was <1:2 at each time period.
Table 1 Median serum inhibitory and bactericidal titers over time for tigecycline against anaerobic bacteria. Organism and Time point (h) B. fragilis 14718 1 6 12 F. magna 16352 1 6 12 P. bivia 16157 1 6 12 P. asaccharolyticus 15684 1 6 12
SIT (range)
SBT (range)
1:8 (1:8e1:16) 1:8 (1:8) 1:8 (1:4e1:8)
1:8 (1:4e1:16) 1:4 (1:4e1:8) 1:4 (1:4e1:8)
1:8 (1:8e1:32) 1:8 (1:4e1:32) 1:4 (1:4e1:16)
<1:2 (<1:2e1:8) <1:2 (<1:2e1:8) <1:2 (<1:2e1:4)
1:16 (1:4e1:16) 1:8 (1:4e1:8) 1:4 (<1:2e1:8)
1:8 (1:4e1:16) 1:4 (1:2e1:8) 1:4 (<1:2e1:8)
1:16 (1:8e1:32) 1:8 (1:8e1:16) 1:4 (1:4e1:16)
1:16 (1:8e1:32) 1:8 (1:8e1:16) 1:4 (1:4e1:16)
SIT; Serum inhibitory titer, SBT; Serum bactericidal titer.
4. Discussion In this study, tigecycline provided inhibitory as well as bactericidal activity, with the exception of F. magna, in serum for its entire dosing interval (12 h) against anaerobic bacteria associated with complicated skin/soft tissue infections. This prolonged duration of antibacterial activity has been shown to be a good predictor of the antimicrobial effect of tigecycline [3,4]. Furthermore, this ex vivo pharmacodynamic model integrates antimicrobial activity with human pharmacokinetic parameters as well as serum factors, such as antibodies, complement, and protein binding. However, the serum bactericidal test does not predict either bacteriologic success or clinical outcome [10]. The reason for the lack of bactericidal activity against F. magna is unclear and deserves further study. Some strains of F. magna bind human serum albumin which may prevent their eradication [11]. The clinical efficacy of tigecycline against anaerobic pathogens has been evaluated in patients with complicated skin/soft tissue infections and complicated intra-abdominal infections [12e14]. The microbial eradication rates against anaerobic bacteria (eg. B. fragilis, Clostridium perfringens and Petostreptococcus spp.) in these tissues was found to range from 76% to 100%. In patients with secondary bacteremia, clinical cure rates were observed in 4 of 6 patients with B. fragilis isolated from the blood [15]. None of these patients had persistent bacteremia. The antimicrobial activity of tigecycline against B. fragilis isolates in bacteremic patients and in our serum bactericidal studies was not expected. Clinical isolates of B. fragilis have a median (MIC50) MIC ¼ 0.5 mg/L [12e14]. This MIC concentration is well above the free (w25%) fraction of tigecycline in serum, albeit our patients had low albumin levels which may have increased the amount of unbound tigecycline. We observed bactericidal activity with serum tigecycline concentrations that were diluted below the MIC of the B. fragilis isolate utilized in this study (Fig. 1). This finding suggests that tigecycline can produce killing against anaerobic bacteria that is enhanced by the addition of serum [6]. In addition, Alou et al. observed that physiological concentrations of human albumin did not diminish the antibacterial activity of tigecycline against several aerobic bacteria [16]. This finding further supports that the antimicrobial activity of tigecycline can be greater than that suggested by the free fraction of the drug. At present, the “susceptible” breakpoint concentration for tigecycline against anaerobes is approximately 3-fold higher than maximal serum levels. The findings from this investigation have shed some light on this paradox. Tigecycline was found to exhibit antibacterial activity at diluted serum concentrations that were
G.E. Stein et al. / Anaerobe 17 (2011) 213e215
Bacteroides fragilis (MIC = 0.5 mg/L) [3]
16
Median 1/titer
14
[4]
12 10
SIT
8
SBT
6
[5] [6]
4 [7]
2 0 0
2
4
6
8
10
12
Time (h) Fig. 1. Serum inhibitory and bactericidal titers of tigecycline against a strain of B. fragilis.
several-fold below the MICs of the anaerobic bacteria that were analyzed. The overall ability of tigecycline to eradicate anaerobic pathogens in serum as well as tissues will require additional study. Acknowledgment This study was funded by the R.M. Alden Research Laboratory, Culver City, CA and Pfizer, Inc.
[8]
[9] [10] [11] [12]
[13]
[14]
References [15] [1] Goldstein EJC, Citron DM, Merriam CV, Warren Y, Tyrrell K. Comparative in vitro activities of GAR-936 against aerobic and anaerobic animal and human bite wound pathogens. Antimicrob Agents Chemother 2000;44:2747e51. [2] Goldstein EJC, Citron DM, Merriam CV, Warren Y, Tyrrell K, Fernandez HT. Comparative in vitro susceptibilities of 396 unusual anaerobic strains to
[16]
215
tigecycline and eight other antimicrobial agents. Antimicrob Agents Chemother 2006;50:3507e13. Meagher AK, Ambrose PG, Grasela TH, Ellis-Grosse EJ. The pharmacokinetic and pharmacodynamic profile of tigecycline. Clin Infect Dis 2005;41(Suppl. 5):333e40. van Ogtrop ML, Andes D, Stamstad TJ, Conklin B, Weiss WJ, Craig WA, et al. In vivo pharmacodynamic activities of two glycylcyclines (GAR-936 and WAY 152,288) against various gram-positive and gram-negative bacteria. Antimicrob Agents Chemother 2000;44:943e9. MacGowan AP. Tigecycline pharmacokinetic/pharmacodynamic update. J Antimicrob Chemother 2008;62(suppl. 1):11e6. Agwuh KN, MacGowan A. Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines. J Antimicrob Chemother 2006;58: 256e65. Li C, Sutherland CA, Nighingale CH, Nicolau DP. Quantitation of tigecycline, a novel glycylcycline, by liquid chromatography. J Chromatogr B 2004;811: 225e9. Clinical and Laboratory Standards Institute. Methods for antimicrobial susceptibility testing of anaerobic bacteria. Approved standard. CLSI document M11eA7. 7th ed. Wayne, PA: CLSI; 2007. Clinical and Laboratory Standards Institute. Methodology for the serum bactericidal test. Approved guideline M21-A. Wayne, PA: CLSI; 1999. Ackerman BH, Dello Buono FA. In vitro testing of antibiotics. Pharmacotherapy 1996;16:201e21. Myre EB. Surface receptors for human serum albumin in Peptococcus magnus strains. J Med Microbiol 1984;18:189e95. Ellis-Grosse EJ, Babinchak T, Dartois N, Rose G, Loh E. The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double-blind phase 3 comparison studies with vancomycin-aztreonam. Clin Infect Dis 2005;41(Suppl. 5):S34e53. Fomin P, Beuran M, Gradauskas A, Baravskas G, Datenko A, Darois N, et al. Tigecycline is efficacious in the treatment of complicated intra-abdominal infections. Intern J Surg 2005;3:35e47. Babinchak T, Ellis-Grosse E, Dartois N, Rose GM, Loh E. The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infections: analysis of pooled clinical trial data. Clin Infect Dis 2005;41(Suppl. 5):S354e66. Gardiner D, DuKart G, Cooper A, Babinchak T. Safety and efficacy of intravenous tigecycline in subjects with secondary bacteremia: pooled results from 8 Phase III clinical trials. Clin Infect Dis 2010;50:229e38. Alou L, Gimenez M-J, Cafini F, Aguilar L, Sevillano D, Gonzalez N, et al. In vitro effect of physiological concentrations of human albumin on the antibacterial activity of tigecycline. J Antimicrob Chemother 2009;64:1230e3.