Antibiotic susceptibilities of
Abstract
Brucella species cause brucellosis in humans and animals, a zoonosis that can manifest not only as acute or chronic diseases but also as silent infections persisting throughout life with recurrences potentially occurring after several decades. In vitro and in vivo methods have been developed to evaluate the bacteriostatic and bactericidal activity of antibiotics against Brucella sp. Especially eukaryotic cells and animal models have been used to evaluate the ability of antibiotics, alone or in combination, to eradicate these bacteria from their intracellular reservoir. Although treatment recommendations have been established for common clinical forms of brucellosis, optimized therapeutic alternatives are still needed for severe forms of the disease, and for infections occurring in young children and pregnant women. Moreover, acquired resistance to first-line treatments of brucellosis is a current concern. This chapter will summarize current knowledge on in vitro and in vivo interactions between Brucella species and antibiotics and new therapeutic strategies that have been evaluated.
Keywords
- Brucella
- brucellosis
- antibiotic susceptibility testing
- antibiotic resistance
- treatment
1. Introduction
Most
2. Experimental models for evaluation of the activity of antibiotics against Brucella spp.
Routine antibiotic susceptibility testing (AST) of
2.1. AST in axenic media
2.1.1. Bacteriostatic activity by class of antibiotics
Current reference methods for the
In the literature, however, the multiplicity of methods used for MIC determination for
A first interesting finding is the variability in susceptibility to beta-lactams among
The tetracyclines display the lowest MICs against
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Streptomycin | US/HA | Bru, 27, (1970) | Broth microdilution (BB, NA, 10%, 37°C, 48 h) | 2.5 | 0.15->100 | [9] |
Israel/H | Bru, 31, 1978–82 | Agar dilution (CM47L, 104/mL, 10%, 37°C, 48 h) | 2 | 0.125-4 | [12] | |
Bru, 31, 1978–82 | Agar dilution (CM47L, 105/mL, 10%, 37°C, 48 h) | 8 | 0.06-8 | [12] | ||
Bru, 31, 1978–82 | Agar dilution (CM47L, 106/mL, 10%, 37°C, 48 h) | 8 | 0.25-8 | [12] | ||
Spain/H | Bm, 95, 1980–84 | Agar dilution (CM47L, 105cfu/spot, 0%, 37°C, 48 h) | 0.5 | 0.12-1 | [23] | |
US-Mexico/HA | Bru, 15, (1986) | Broth microdilution (TSB,5 × 105cfu/mL,6%,35°C,48 h) | 4 | 1-4 | [18] | |
Saudi Arabia | Bm, 47, (1989) | Broth dilution (BB,5 × 105cfu/mL, 0%, 35°C, 48 h) | 2.5 | 0.15-5 | [13] | |
Israel/H | Bm, 86, (1991) | Broth microdilution (BB, 5 × 105cfu/mL,5%,37°C,48 h) | 3.1 | NA | [33] | |
Turkey/H | Bm, 43, 1991–94 | Broth microdilution (MH-P/7,105-6cfu,0%,35°C,48 h) | 2 | 0.25-8 | [11] | |
Turkey/H | Bm, 43, 1991–94 | Broth microdilution (MH-P/5,105-6cfu,0%,35°C,48 h) | 128 | 8-256 | [11] | |
Spain/HA | Bru, 62, (1993) | Agar dilution (MH-HP,104cfu/spot,10%,35°C,48 h) | 4 | 0.1-4 | [30] | |
Spain/H | Bm, 160, 1997 | Agar dilution (MH-HP,104cfu/spot,10%,35°C,48 h) | 8 | 4-16 | [25] | |
Korea/C | Bab, 85, 1998–2006 | Broth microdilution (TSB, 0.5 McFd, 5%, 37°C, 48 h) | 2 | 0.5-2 | [19] | |
Greece/HA | Bru, 74, 1999–2005 | E-test (SB-MH, 0.5 McFd, 5%, 35°C, 48 h) | 2 | 0.125-4 | [16] | |
Egypt/H | Bm, 355, 1999–2007 | E-test (SB-MH, 0.5 McFd, 5%, NA, 48 h) | 2 | 0.125-3 | [22] | |
Syria | Bm, 100, 2004–07 | Broth microdilution (BB/7, 5 × 106 cfu/mL,37°C, 48 h) | >128 | 64->128 | [15] | |
Syria | Bm, 100, 2004–07 | Broth microdilution (BB/5, 5 × 106 cfu/mL,37°C, 48 h) | >128 | >128 | [15] | |
Turkey/H | Bru, 56, 2008–09 | E-test (SB-MH, 0.5 McFd, 0%, 35°C, 48 h) | 1 | 0.064-1.5 | [27] | |
Turkey/H | Bm, 73, 2009–11 | E-test (SB-MH, 0.5 McFd, NA, 37°C, 48 h) | 1 | 0.5-1.5 | [26] | |
Turkey/H | Bm, 76, 2001–06 | E-test (SB-MH, 1 McFd, 0%, 35°C,48 h) | 1 | 0.064-1.5 | [29] | |
US/H | Bru, 39, (2010) | Broth microdilution (BB, NA, 0%, 35°C, 48 h) | 2 | 1-8 | [10] | |
Bru, 39, (2010) | Broth microdilution (BB, NA, 5%, 35°C, 48 h) | 4 | 2-16 | [10] | ||
Gentamicin | US/HA | Bru, 27, (1970) | Broth microdilution (BB, NA, 10%, 37°C, 48 h) | 0.3 | 0.02-2.5 | [9] |
Israel/H | Bru, 31, 1978–82 | Agar dilution (CM47L, 104/mL, 10%, 37°C, 48 h) | 0.25 | 0.03-0.25 | [12] | |
Bru, 31, 1978–82 | Agar dilution (CM47L, 105/mL, 10%, 37°C, 48 h) | 1 | 0.03-1 | [12] | ||
Bru, 31, 1978–82 | Agar dilution (CM47L, 106/mL, 10%, 37°C, 48 h) | 2 | 0.03-2 | [12] | ||
US-Mexico/HA | Bru, 15, (1986) | Broth microdilution (TSB,5 × 105cfu/mL,6%,35°C,48 h) | 1 | 0.25-2 | [18] | |
Saudi Arabia | Bm, 116, (1995) | Broth dilution (MH,105-6cfu/mL, 5%, 35°C, 48 h) | 0.5 | <0.25-0.5 | [31] | |
Korea/C | Bab, 85, 1998–2006 | Broth microdilution (TSB, 0.5 McFd, 5%, 37°C, 48 h) | 1 | 0.5-2 | [19] | |
Greece/HA | Bru, 74, 1999–2005 | E-test (SB-MH, 0.5 McFd, 5%, 35°C, 48 h) | 2 | 0.03-1.5 | [16] | |
Egypt/H | Bm, 355, 1999–2007 | E-test (SB-MH, 0.5 McFd, 5%, NA, 48 h) | 1 | 0.094-3 | [22] | |
Peru/H | Bm, 48, 2000–06 | E-test (SB-MH, 0.5 McFd, NA, NA, 48 h) | 0.25 | 0.032-0.25 | [28] | |
Turkey/H | Bm, 76, 2001–06 | E-test (SB-MH, 1 McFd, 0%, 35°C,48 h) | 0.5 | 0.064-0.75 | [29] | |
US/H | Bru, 39, (2010) | Broth microdilution (BB, ND, 0%, 35°C, 48 h) | 2 | 0.5-2 | [10] | |
Bru, 39, (2010) | Broth microdilution (BB, ND, 5%, 35°C, 48 h) | 4 | 0.5-8 | [10] | ||
China/H | Bm, 19, 2010–12 | E-test (BA-MH, 0.5 McFd, 5%, 35°C, 24 h) | 0.75 | 0.5-0.75 | [17] | |
Tobramycin | US-Mexico/HA | Bru, 15, (1986) | Broth microdilution (TSB,5 × 105cfu/mL,6%,35°C,48 h) | 2 | 0.5-4 | [18] |
Kanamycin | US/HA | Bru, 27, (1970) | Broth microdilution (BB, NA, 10%, 37°C, 48 h) | 2.5 | 0.02-5 | [9] |
Amikacin | US-Mexico/HA | Bru, 15, (1986) | Broth microdilution (TSB,5 × 105cfu/mL,6%,35°C,48 h) | 4 | 1-4 | [18] |
China/H | Bm, 19, 2010–12 | E-test (BA-MH, 0.5 McFd, 5%, 35°C, 24 h) | 12 | 4-12 | [17] | |
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Tetracycline | US/HA | Bru, 27, (1970) | Broth microdilution (BB, NA, 10%, 37°C, 48 h) | 0.04 | 0.001-0.15 | [9] |
Israel/H | Bru, 31, 1978–82 | Agar dilution (CM47L, 104/mL, 10%, 37°C, 48 h) | 0.25 | ≤0.06-0.5 | [12] | |
Bru, 31, 1978–82 | Agar dilution (CM47L, 105/mL, 10%, 37°C, 48 h) | 0.5 | ≤0.06-0.5 | [12] | ||
Bru, 31, 1978–82 | Agar dilution (CM47L, 106/mL, 10%, 37°C, 48 h) | 1 | ≤0.06-2 | [12] | ||
Spain/H | Bm, 95, 1980–84 | Agar dilution (CM47L, 105cfu/spot, 0%, 37°C, 48 h) | 0.25 | 0.6-0.25 | [23] | |
Spain/H | Bm, 98, (1982) | Agar dilution (CM47L, 105cfu/spot, 0%, 37°C, 48 h) | 0.39 | 0.1-0.5 | [24] | |
US-Mexico/HA | Bru, 15, (1986) | Broth microdilution (TSB,5 × 105cfu/mL,6%,35°C,48 h) | 0.25 | ≤0.13-0.25 | [18] | |
Spain/H | Bm, 358, 1987–89 | Agar dilution (CM471, 105cfu/spot, 0%, 37°C, 48 h) | 0.25 | 0.06-0.5 | [32] | |
Saudi Arabia | Bm, 47, (1989) | Broth dilution (BB,5 × 105cfu/mL, 0%, 35°C, 48 h) | 0.04 | 0.001-0.6 | [13] | |
Spain/HA | Bru, 62, (1993) | Agar dilution (MH-HP, 104cfu/spot, 10%, 35°C, 48 h) | 0.2 | 0.01-0.2 | [30] | |
Saudi Arabia | Bm, 116, (1995) | Broth dilution (MH, 105-6cfu/mL, 5%, 35°C, 48 h) | 0.5 | <0.25-0.5 | [31] | |
Greece/HA | Bru, 74, 1999–2005 | E-test (SB-MH, 0.5 McFd, 5%, 35°C, 48 h) | 0.5 | 0.03-1.5 | [16] | |
Korea/C | Bab, 85, 1998–2006 | Broth microdilution (TSB, 0.5 McFd, 5%, 37°C, 48 h) | 0.25 | 0.125-0.5 | [19] | |
Egypt/H | Bm, 355, 1999–2007 | E-test (SB-MH, 0.5 McFd, 5%, NA, 48 h) | 0.19 | 0.023-0.75 | [22] | |
Syria | Bm, 100, 2004–07 | Broth microdilution (BB/7, 5 × 106 cfu/mL, 37°C, 48 h) | 16 | 0.25-16 | [15] | |
Syria | Bm, 100, 2004–07 | Broth microdilution (BB/5, 5 × 106 cfu/mL, 37°C, 48 h) | 16 | 0.25-16 | [15] | |
US/H | Bru, 39, (2010) | Broth microdilution (BB, ND, 0%, 35°C, 48 h) | 0.25 | 0.06-0.5 | [10] | |
Bru, 39, (2010) | Broth microdilution (BB, ND, 5%, 35°C, 48 h) | 0.25 | 0.03-0.5 | [10] | ||
Doxycycline | US/HA | Bru, 27, (1970) | Broth microdilution (BB, NA, 10%, 37°C, 48 h) | 0.3 | 0.01-0.3 | [9] |
Spain/H | Bm, 95, 1980–84 | Agar dilution (CM47L, 105cfu/spot, 0%, 37°C, 48 h) | 0.12 | 0.6-0.25 | [23] | |
Turkey/H | Bm, 43, 1991–94 | Broth microdilution (MH-P/7,105-6cfu,0%, 35°C,48 h) | <0.125 | <0.125-8 | [11] | |
Turkey/H | Bm, 43, 1991–94 | Broth microdilution (MH-P/5,105-6cfu,0%, 35°C,48 h) | 2 | <0.125-8 | [11] | |
Spain/H | Bm, 160, 1997 | Agar dilution (MH-HP, 104cfu/spot, 10%, 35°C,48 h) | 0.25 | 0.12-0.25 | [25] | |
Korea/C | Bab, 85, 1998–2006 | Broth microdilution (TSB, 0.5 McFd, 5%, 37°C, 48 h) | 0.25 | 0.063-0.5 | [19] | |
Egypt/H | Bm, 355, 1999–2007 | E-test (SB-MH, 0.5 McFd, 5%, NA, 48 h) | 0.25 | 0.016-0.5 | [22] | |
Peru/H | Bm, 48, 2000–06 | E-test (SB-MH, 0.5 McFd, NA, NA, 48 h) | 0.38 | 0.032-0.5 | [28] | |
Turkey/H | Bm, 76, 2001–06 | E-test (SB-MH, 1 McFd, 0%, 35°C,48 h) | 0.125 | 0.016-0.19 | [29] | |
Syria | Bm, 100, 2004–07 | Broth microdilution (BB/7, 5 × 106 cfu/mL, 37°C, 48 h) | 16 | 0.5-16 | [15] | |
Syria | Bm, 100, 2004–07 | Broth microdilution (BB/5, 5 × 106 cfu/mL, 37°C, 48 h) | 8 | 0.5-8 | [15] | |
Italy/H | Bru, 20, 2005–06 | E-test (SB-MH, 0.5 McFd, 5%, 37°C, 48 h) | ND | 0.06-0.125 | [21] | |
Turkey/H | Bru, 56, 2008–09 | E-test (SB-MH, 0.5 McFd, 0%, 35°C, 48 h) | 0.064 | 0.023-0.125 | [27] | |
Turkey/H | Bm, 73, 2009–11 | E-test (SB-MH, 0.5 McFd, NA, 37°C, 48 h) | 0.094 | 0.023-0.19 | [26] | |
US/H | Bru, 39, (2010) | Broth microdilution (BB, ND, 0%, 35°C, 48 h) | 0.25 | 0.06-0.5 | [10] | |
Bru, 39, (2010) | Broth microdilution (BB, ND, 5%, 35°C, 48 h) | 0.5 | 0.03-1 | [10] | ||
China/H | Bm, 19, 2010–12 | E-test (BA-MH, 0.5 McFd, 5%, 35°C, 24 h) | 32 | 8-32 | [17] | |
Minocycline | US/HA | Bru, 27, (1970) | Broth microdilution (BB, NA, 10%, 37°C, 48 h) | 0.3 | 0.01-1.25 | [9] |
Israel/H | Bm, 86, (1991) | Broth microdilution (BB, 5 × 105cfu/mL, 5%, 37°C, 48 h) | 0.4 | NA | [33] | |
Korea/C | Bab, 85, 1998–2006 | Broth microdilution (TSB, 0.5 McFd, 5%, 37°C, 48 h) | 0.125 | 0.063-0.25 | [19] | |
Tigecycline | Turkey/H | Bru, 56, 2008–09 | E-test (SB-MH, 0.5 McFd, 0%, 35°C, 48 h) | 0.094 | 0.019-0.25 | [27] |
Turkey/H | Bm, 73, 2009–11 | E-test (SB-MH, 0.5 McFd, NA, 37°C, 48 h) | 0.125 | 0.047-0.19 | [26] | |
Turkey/H | Bm, 76, 2001–06 | E-test (SB-MH, 1 McFd, 0%, 35°C, 48 h) | 0.094 | 0.023-0.5 | [29] | |
Turkey/H | Bm, 38, (2010) | E-test (SB, NA, NA, 35°C, 48 h) | 0.5 | 0.032-0.5 | [76] | |
Turkey/H | Bm, 38, (2010) | E-test (BA, NA, NA, 35°C, 48 h) | 1 | 0.0125-1 | [76] | |
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US/HA | Bru, 27, (1970) | Broth microdilution (BB, NA, 10%, 37°C, 48 h) | 1.25 | 0.02-12.5 | [9] |
Spain/H | Bm, 98, (1982) | Agar dilution (CM47L, 105cfu/spot, 0%, 37°C, 48 h) | 0.5 | 0.06-1 | [24] | |
Spain/H | Bm, 95, 1980–84 | Agar dilution (CM47L, 105cfu/spot, 0%, 37°C, 48 h) | 2 | 0.12-4 | [23] | |
US-Mexico/HA | Bru, 15, (1986) | Broth microdilution (TSB, 5 × 105cfu/mL, 6%, 35°C, 48 h) | 1 | 0.06-1 | [18] | |
Saudi Arabia | Bm, 47, (1989) | Broth dilution (BB, 5 × 105cfu/mL, 0%, 35°C, 48 h) | 1.25 | 0.02-2.5 | [13] | |
Israel/H | Bm, 86, (1991) | Broth microdilution (BB, 5 × 105cfu/mL, 5%, 37°C, 48 h) | 4 | NA | [33] | |
Turkey/H | Bm, 43, 1991–94 | Broth microdilution (MH-P/7,105-6cfu, 0%, 35°C, 48 h) | 2 | 1-32 | [11] | |
Turkey/H | Bm, 43, 1991–94 | Broth microdilution (MH-P/5,105-6cfu, 0%, 35°C, 48 h) | 1 | <0.125-1 | [11] | |
Spain/HA | Bru, 62, (1993) | Agar dilution (MH-HP, 104cfu/spot, 10%, 35°C, 48 h) | 1 | 0.1-4 | [30] | |
Saudi Arabia | Bm, 116, (1995) | Broth dilution (MH, 105-6cfu/mL, 5%, 35°C, 48 h) | 1 | 0.25-1 | [31] | |
Spain/H | Bm, 160, 1997 | Agar dilution (MH-HP, 104cfu/spot, 10%, 35°C, 48 h) | 1 | 0.5-1 | [25] | |
Korea/C | Bab, 85, 1998–2006 | Broth microdilution (TSB, 0.5 McFd, 5%, 37°C, 48 h) | 2 | 0.5-4 | [19] | |
Greece/HA | Bru, 74, 1999–2005 | E-test (SB-MH, 0.5 McFd, 5%, 35°C, 48 h) | 1 | 0.09-1.5 | [16] | |
Egypt/H | Bm, 355, 1999–2007 | E-test (SB-MH, 0.5 McFd, 5%, NA, 48 h) | 4 | 0.25-6 | [22] | |
Peru/H | Bm, 48, 2000–06 | E-test (SB-MH, 0.5 McFd, NA, NA, 48 h) | 0.75 | 0.19-1 | [28] | |
Turkey/H | Bm, 76, 2001–06 | E-test (SB-MH, 1 McFd, 0%, 35°C,48 h) | 1.5 | 0.064-3 | [29] | |
Syria | Bm, 100, 2004–07 | Broth microdilution (BB/7, 5 × 106 cfu/mL,37°C, 48 h) | 64 | 2-64 | [15] | |
Syria | Bm, 100, 2004–07 | Broth microdilution (BB/5, 5 × 106 cfu/mL,37°C, 48 h) | 64 | 2-64 | [15] | |
Italy/H | Bru, 20, 2005–06 | E-test (SB-MH, 0.5 McFd, 5%, 37°C, 48 h) | ND | 0.75-2 | [21] | |
Turkey/H | Bru, 56, 2008–09 | E-test (SB-MH, 0.5 McFd, 0%, 35°C, 48 h) | 2 | 0.5-2 | [27] | |
Turkey/H | Bm, 73, 2009–11 | E-test (SB-MH, 0.5 McFd, NA, 37°C, 48 h) | 2 | 0.38-3 | [26] | |
US/H | Bru, 39, (2010) | Broth microdilution (BB, ND, 0%, 35°C, 48 h) | 2 | 0.25-2 | [10] | |
Bru, 39, (2010) | Broth microdilution (BB, ND, 5%, 35°C, 48 h) | 2 | 0.25->8 | [10] | ||
China/H | Bm, 19, 2010–12 | E-test (BA-MH, 0.5 McFd, 5%, 35°C, 24 h) | 2 | 0.06-2 | [17] | |
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Spain/HA | Bru, 62, (1993) | Agar dilution (MH-HP, 104cfu/spot, 10%, 35°C, 48 h) | 1 | 0.2-4 | [30] |
Rifampicin is the second most active compound against
The aminoglycosides are also highly active
The combination of trimethoprim (TMP) and sulfamethoxazole (SMX) was usually tested at a ratio of 1:19, and only TMP MICs were reported (Table 2). These varied from 0.06 to 4 mg/L with the agar dilution method [23,30], 0.006 to 4 mg/L with the broth microdilution method [10,18,31], and 0.06 to 1.5 mg/L with the E-test method [16,21,22,26–29]. Similar MIC ranges (0.8–3.2 mg/L) were obtained when using TMP/SMX at a ratio of 1:5 [17]. In contrast, higher MICs (5–25 mg/L of TMP) were reported in a study from Saudi Arabia [13], using a broth dilution method with high-volume (5 mL) medium culture and a high bacterial inoculum (2.5 × 106 cfu per test).
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Penicillin G | US/HA | Bru, 27, (1970) | Broth microdilution (BB, NA, 10%, 37°C, 48 h) | 25 | 0.3->100 | [9] |
US-Mexico/HA | Bru, 15, (1986) | Broth microdilution (TSB,5 × 105cfu/mL,6%,35°C,48 h) | 4 | 0.25-8 | [18] | |
Ampicillin | US/HA | Bru, 27, (1970) | Broth microdilution (BB, NA, 10%, 37°C, 48 h) | 2.5 | 0.02-5 | [9] |
US-Mexico/HA | Bru, 15, (1986) | Broth microdilution (TSB,5 × 105cfu/mL,6%,35°C,48 h) | 4 | 0.25-8 | [18] | |
Greece/HA | Bru, 74, 1999–2005 | E-test (SB-MH, 0.5 McFd, 5%, 35°C, 48 h) | 2 | 0.09-3 | [16] | |
Korea/C | Bab, 85, 1998–2006 | Broth microdilution (TSB, 0.5 McFd, 5%, 37°C, 48 h) | 4 | 0.125-4 | [19] | |
China/H | Bm, 19, 2010–12 | E-test (BA-MH, 0.5 McFd, 5%, 35°C, 24 h) | 2 | 1.5-2 | [17] | |
Carbenicillin | US/HA | Bru, 27, (1970) | Broth microdilution (BB, NA, 10%, 37°C, 48 h) | 50 | 0.6->100 | [9] |
Cephalothin | US/HA | Bru, 27, (1970) | Broth microdilution (BB, NA, 10%, 37°C, 48 h) | 100 | 0.3->100 | [9] |
US-Mexico/HA | Bru, 15, (1986) | Broth microdilution (TSB,5 × 105cfu/mL,6%,35°C,48 h) | 32 | 1-64 | [18] | |
Cefoxitine | Spain/H | Bm, 98, (1982) | Agar dilution (CM47L, 105 cfu/spot, 0%, 37°C, 48 h) | 64 | 8-128 | [24] |
US-Mexico/HA | Bru, 15, (1986) | Broth microdilution (TSB,5 × 105cfu/mL,6%,35°C,48 h) | 16 | 2-16 | [18] | |
Cefuroxime | Spain/H | Bm, 83, (1986) | Agar dilution (CM47L, 105 cfu/spot, 0%, 37°C, 48 h) | 32 | 8-64 | [20] |
Ceftizoxime | Spain/H | Bm, 83, (1986) | Agar dilution (CM47L, 105 cfu/spot, 0%, 37°C, 48 h) | 1 | 0.5-1 | [20] |
Cefoperazone | US-Mexico/HA | Bru, 15, (1986) | Broth microdilution (TSB,5 × 105cfu/mL,6%,35°C,48 h) | 16 | ≤1-16 | [18] |
Spain/H | Bm, 83, (1986) | Agar dilution (CM47L, 105 cfu/spot, 0%, 37°C, 48 h) | 32 | 4-64 | [20] | |
Cefotaxime | US-Mexico/HA | Bru, 15, (1986) | Broth microdilution (TSB,5 × 105cfu/mL, 6%,35°C,48 h) | 2 | ≤0.5-4 | [18] |
Spain/H | Bm, 83, (1986) | Agar dilution (CM47L, 105 cfu/spot, 0%, 37°C, 48 h) | 2 | ≤0.5-2 | [20] | |
Ceftriaxone | Spain/H | Bm, 95, 1980–84 | Agar dilution (CM47L, 105cfu/spot, 0%, 37°C, 48 h) | 0.5 | 0.12-1 | [23] |
Spain/H | Bm, 83, (1986) | Agar dilution (CM47L, 105 cfu/spot, 0%, 37°C, 48 h) | 1 | ≤0.25-1 | [20] | |
Egypt/H | Bm, 355, 1999–2007 | E-test (SB-MH, 0.5 McFd, 5%, NA, 48 h) | 1 | 0.064-4 | [22] | |
Italy/H | Bru, 20, 2005–06 | E-test (SB-MH, 0.5 McFd, 5%, 37°C, 48 h) | NA | 0.064-0.38 | [21] | |
Ceftazidime | China/H | Bm, 19, 2010–12 | E-test (BA-MH, 0.5 McFd, 5%, 35°C, 24 h) | 8 | 2-8 | [17] |
Moxalactam | US-Mexico/HA | Bru, 15, (1986) | Broth microdilution (TSB,5 × 105cfu/mL, 6%,35°C,48 h) | 16 | 1-16 | [18] |
Spain/H | Bm, 83, (1986) | Agar dilution (CM47L, 105cfu/spot, 0%, 37°C, 48 h) | 16 | 4-16 | [20] | |
Aztreonam | Spain/H | Bm, 83, (1986) | Agar dilution (CM47L, 105cfu/spot, 0%, 37°C, 48 h) | >256 | 64->256 | [20] |
Thienamycin | Spain/H | Bm, 98, (1982) | Agar dilution (CM47L, 105cfu/spot, 0%, 37°C, 48 h) | 2 | 0.1-2 | [24] |
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Spain/H | Bm, 98, (1982) | Agar dilution (CM47L, 105cfu/spot, 0%, 37°C, 48 h) | 6.25 | 0.39-6.25 | [24]* |
Spain/H | Bm, 95, 1980–84 | Agar dilution (CM47L, 105cfu/spot, 0%, 37°C, 48 h) | 0.25 | 0.06-0.5 | [23] | |
US-Mexico/HA | Bru, 15, (1986) | Broth microdilution (TSB,5 × 105cfu/mL,6%,35°C,48 h) | 1 | ≤0.25-1 | [18] | |
Saudi Arabia | Bm, 47, (1989) | Broth dilution (BB,5 × 105cfu/mL, 0%, 35°C, 48 h) | 5 | 5-25 | [13] | |
Spain/HA | Bru, 62, (1993) | Agar dilution (MH-HP,104cfu/spot,10%,35°C,48 h) | 4 | 0.1-4 | [30] | |
Saudi Arabia | Bm, 116, (1995) | Broth dilution (MH, 105-6cfu/mL, 5%, 35°C, 48 h) | 1 | <0.25-1 | [31] | |
Greece/HA | Bru, 74, 1999–2005 | E-test (SB-MH, 0.5 McFd, 5%, 35°C, 48 h) | 0.75 | 0.032-1.5 | [16] | |
Egypt/H | Bm, 355, 1999–2007 | E-test (SB-MH, 0.5 McFd, 5%, NA, 48 h) | 0.19 | 0.006-0.75 | [22] | |
Peru/H | Bm, 48, 2000–06 | E-test (SB-MH, 0.5 McFd, NA, NA, 48 h) | 0.15 | 0.012-0.64 | [28] | |
Turkey/H | Bm, 76, 2001–06 | E-test (SB-MH, 1 McFd, 0%, 35°C,48 h) | 0.094 | 0.016-0.125 | [29] | |
Italy/H | Bru, 20, 2005–06 | E-test (SB-MH, 0.5 McFd, 5%, 37°C, 48 h) | ND | 0.012/0.064 | [21] | |
Turkey/H | Bru, 56, 2008–09 | E-test (SB-MH, 0.5 McFd, 0%, 35°C, 48 h) | 0.125 | 0.064-0.25 | [27] | |
Turkey/H | Bm, 73, 2009–11 | E-test (SB-MH, 0.5 McFd, NA, 37°C, 48 h) | 0.19 | 0.016-0.5 | [26] | |
China/H | Bm, 19, 2010–12 | E-test (BA-MH, 0.5 McFd, 5%, 35°C, 24 h) | 3.2 | 0.8-3.2 | [17]* | |
US/H | Bru, 39, (2010) | Broth microdilution (BB, ND, 0%, 35°C, 48 h) | 2 | 0.25-2 | [10] | |
Bru, 39, (2010) | Broth microdilution (BB, ND, 5%, 35°C, 48 h) | 2 | 0.25-4 | [10] | ||
|
US/HA | Bru, 27, (1970) | Broth microdilution (BB, NA, 10%, 37°C, 48 h) | 0.3->100 | [9] | |
Israel/H | Bru, 31, 1978–82 | Agar dilution (CM47L, 104/mL, 10%, 37°C, 48 h) | 2 | 0.125-4 | [12] | |
Bru, 31, 1978–82 | Agar dilution (CM47L, 105/mL, 10%, 37°C, 48 h) | 4 | 0.06-4 | [12] | ||
Bru, 31, 1978–82 | Agar dilution (CM47L, 106/mL, 10%, 37°C, 48 h) | 8 | 0.06-8 | [12] | ||
US-Mexico/HA | Bru, 15, (1986) | Broth microdilution (TSB,5 × 105cfu/mL,6%,35°C,48 h) | 2 | 0.25-4 | [18] | |
Korea/C | Bab, 85, 1998–2006 | Broth microdilution (TSB, 0.5 McFd, 5%, 37°C, 48 h) | 5 | 0.15-12.5 | [19] | |
|
||||||
Erythromycin | US/HA | Bru, 27, (1970) | Broth microdilution (BB, NA, 10%, 37°C, 48 h) | 0.6 | 0.02-2.5 | [9] |
US-Mexico/HA | Bru, 15, (1986) | Broth microdilution (TSB,5 × 105cfu/mL,6%,35°C,48 h) | 8 | 0.5-8 | [18] | |
Turkey/H | Bm, 43, 1991–94 | Broth microdilution (MH-P/7,105-6cfu,0%,35°C,48 h) | 128 | 0.5-256 | [11] | |
Turkey/H | Bm, 43, 1991–94 | Broth microdilution (MH-P/5,105-6cfu,0%,35°C,48 h) | >256 | 32->256 | [11] | |
Spain/HA | Bru, 62, (1993) | Agar dilution (MH-HP,104cfu/spot,10%,35°C,48 h) | 16 | 0.2-16 | [30] | |
Greece/HA | Bru, 74, 1999–2005 | E-test (SB-MH, 0.5 McFd, 5%, 35°C, 48 h) | 4 | 0.5-8 | [16] | |
Korea/C | Bab, 85, 1998–2006 | Broth microdilution (TSB, 0.5 McFd, 5%, 37°C, 48 h) | 2 | 1-4 | [19] | |
Roxithromycin | Spain/HA | Bru, 62, (1993) | Agar dilution (MH-HP,104cfu/spot,10%,35°C,48 h) | 16 | 0.1-32 | [30] |
Dirithromycin | Spain/HA | Bru, 62, (1993) | Agar dilution (MH-HP,104cfu/spot,10%,35°C,48 h) | 16 | 0.5-16 | [30] |
Clarithromycin | Spain/HA | Bru, 62, (1993) | Agar dilution (MH-HP,104cfu/spot,10%,35°C,48 h) | 8 | 0.06-8 | [30] |
Azithromycin | Spain/H | Bm, 358, 1987–89 | Agar dilution (CM471, 105cfu/spot, 0%, 37°C, 48 h) | 1 | 0.03-2 | [32] |
Turkey/H | Bm, 43, 1991–94 | Broth microdilution (MH-P/7,105-6cfu,0%,35°C,48 h) | 1 | <0.125-4 | [11] | |
Turkey/H | Bm, 43, 1991–94 | Broth microdilution (MH-P/5,105-6cfu,0%,35°C,48 h) | >256 | 16->256 | [11] | |
Spain/HA | Bru, 62, (1993) | Agar dilution (MH-HP, 104cfu/spot, 10%,35°C, 48 h) | 2 | 0.1-4 | [30] | |
Saudi Arabia | Bm, 116, (1995) | Broth dilution (MH,105-6cfu/mL, 5%, 35°C, 48 h) | 0.5 | <0.25-2 | [31] | |
Peru/H | Bm, 48, 2000–06 | E-test (SB-MH, 0.5 McFd, NA, NA, 48 h) | 0.5 | 0.064-0.5 | [28] | |
Turkey/H | Bm, 73, 2009–11 | E-test (SB-MH, 0.5 McFd, NA, 37°C, 48 h) | 8 | 0.75-16 | [26] | |
|
||||||
Norfloxacin | Greece/HA | Bru, 74, 1999–2005 | E-test (SB-MH, 0.5 McFd, 5%, 35°C, 48 h) | 3 | 0.125-4 | [16] |
Korea/C | Bab, 85, 1998–2006 | Broth microdilution (TSB, 0.5 McFd, 5%, 37°C, 48 h) | 8 | 4-16 | [19] | |
Ofloxacin | Saudi Arabia | Bm, 47, (1989) | Broth dilution (BB,5 × 105cfu/mL, 0%, 35°C, 48 h) | 0.02 | 0.02-0.3 | [13] |
Israel/H | Bm, 86, (1991) | Broth microdilution (BB, 5 × 105cfu/mL,5%,37°C,48 h) | 2.5 | ND | [33] | |
Turkey/H | Bm, 43, 1991–94 | Broth microdilution (MH-P/7,105-6cfu,0%,35°C,48 h) | 1 | <0.125-4 | [11] | |
Turkey/H | Bm, 43, 1991–94 | Broth microdilution (MH-P/5,105-6cfu,0%,35°C,48 h) | >16 | 4->16 | [11] | |
Spain/H | Bm, 160, 1997 | Agar dilution (MH-HP,104cfu/spot,10%,35°C,48 h) | 2 | 1-2 | [25] | |
Korea/C | Bab, 85, 1998–2006 | Broth microdilution (TSB, 0.5 McFd, 5%, 37°C, 48 h) | 2 | 0.5-2 | [19] | |
Levofloxacin | Spain/H | Bm, 160, 1997 | Agar dilution (MH-HP,104cfu/spot,10%,35°C,48 h) | 0.5 | 0.5 | [25] |
Greece/HA | Bru, 74, 1999–2005 | E-test (SB-MH, 0.5 McFd, 5%, 35°C, 48 h) | 0.5 | 0.06-0.75 | [16] | |
China/H | Bm, 19, 2010–12 | E-test (BA-MH, 0.5 McFd, 5%, 35°C, 24 h) | 8 | 2-8 | [17] | |
Ciprofloxacin | Spain/H | Bm, 95, 1980–84 | Agar dilution (CM47L, 105cfu/spot, 0%, 37°C, 48 h) | 0.5 | 0.12-0.5 | [23] |
Saudi Arabia | Bm, 47, (1989) | Broth dilution (BB,5 × 105cfu/mL, 0%, 35°C, 48 h) | 1.25 | 1.25-2.5 | [13] | |
Israel/H | Bm, 86, (1991) | Broth microdilution (BB,5 × 105cfu/mL,5%,37°C,48 h) | 0.8 | NA | [33] | |
Spain/H | Bm, 34, (1991) | Agar dilution (MH-HP/7,103cfu/spot,10%,35°C,48 h) | 0.5 | 0.25-0.5 | [14] | |
Spain/H | Bm, 34, (1991) | Agar dilution (MH-HP/5,103cfu/spot,10%,35°C,48 h) | 1 | 0.5-1 | [14] | |
Spain/H | Bm, 34, (1991) | Agar dilution (MH-HP/7,104cfu/spot,10%,35°C,48 h) | 0.5 | 0.25-0.5 | [14] | |
Spain/H | Bm, 34, (1991) | Agar dilution (MH-HP/5,104cfu/spot,10%,35°C,48 h) | 1 | 0.5-1 | [14] | |
Spain/H | Bm, 34, (1991) | Agar dilution (MH-HP/7,106cfu/spot,10%,35°C,48 h) | 1 | 0.5-1 | [14] | |
Spain/H | Bm, 34, (1991) | Agar dilution (MH-HP/5,106cfu/spot,10%,35°C,48 h) | 2 | 1-2 | [14] | |
Turkey/H | Bm, 43, 1991–94 | Broth microdilution (MH-P/7,105-6cfu,0%,35°C,48 h) | 2 | <0.125-8 | [11] | |
Turkey/H | Bm, 43, 1991–94 | Broth microdilution (MH-P/5,105-6cfu,0%,35°C,48 h) | >16 | 2->16 | [11] | |
Spain/H | Bm, 160, 1997 | Agar dilution (MH-HP,104cfu/spot,10%,35°C,48 h) | 1 | 0.25-1 | [25] | |
Korea/C | Bab, 85, 1998–2006 | Broth microdilution (TSB, 0.5 McFd, 5%, 37°C, 48 h) | 1 | 0.25-4 | [19] | |
Greece/HA | Bru, 74, 1999–2005 | E-test (SB-MH, 0.5 McFd, 5%, 35°C, 48 h) | 0.5 | 0.016-0.75 | [16] | |
Egypt/H | Bm, 355, 1999–2007 | E-test (SB-MH, 0.5 McFd, 5%, NA, 48 h) | 0.38 | 0.125-0.75 | [22] | |
Peru/H | Bm, 48, 2000–06 | E-test (SB-MH, 0.5 McFd, NA, NA, 48 h) | 0.25 | 0.064-0.25 | [28] | |
Turkey/H | Bm, 76, 2001–06 | E-test (SB-MH, 1 McFd, 0%, 35°C,48 h) | 0.38 | 0.064-0.5 | [29] | |
Syria | Bm, 100, 2004–07 | Broth microdilution (BB/7, 5 × 106 cfu/mL,37°C, 48 h) | 4 | 0.125-8 | [15] | |
Syria | Bm, 100, 2004–07 | Broth microdilution (BB/5, 5 × 106 cfu/mL,37°C, 48 h) | 8 | 0.125-8 | [15] | |
Italy/H | Bru, 20, 2005–06 | E-test (SB-MH, 0.5 McFd, 5%, 37°C, 48 h) | ND | 0.094-0.5 | [21] | |
Turkey/H | Bm, 73, 2009–11 | E-test (SB-MH, 0.5 McFd, NA, 37°C, 48 h) | 0.19 | 0.125-1 | [26] | |
Sparfloxacin | Israel/H | Bm, 86, (1991) | Broth microdilution (BB, 5 × 105cfu/mL,5%,37°C,48 h) | 1.5 | NA | [33] |
Moxifloxacin | Spain/H | Bm, 160, 1997 | Agar dilution (MH-HP,104cfu/spot,10%,35°C,48 h) | 1 | 1 | [25] |
Turkey/H | Bm, 76, 2001–06 | E-test (SB-MH, 1 McFd, 0%, 35°C,48 h) | 0.25 | 0.032-0.25 | [29] |
MICs determined for chloramphenicol were not consistent from one study to the other (Table 2): MICs ranged from 0.3 to higher than 100 [9], 0.25 to 4 mg/L [18], and 0.15 to 12.5 mg/L [19]. However, this antibiotic was globally considered poorly effective
The macrolides also display poor
In recent years, the fluoroquinolones proved to be very active against
2.1.2. Bactericidal activity by class of antibiotics
The bactericidal activity of antibiotics against
|
|
|
|
|
Doxycycline |
|
6 | 4–>16 | [35] |
Minocycline |
|
6 | 1–>16 | [35] |
Gentamicin |
|
6 | 0.25–1 | [35] |
Streptomycin |
|
6 | 0.25–8 | [35] |
Ciprofloxacin |
|
6 | 0.5–2 | [35] |
|
21 | 2–≥8 | [14] | |
Ofloxacin |
|
21 | ≥8 | [14] |
Sparfloxacin |
|
21 | 2–≥8 | [14] |
Temafloxacin |
|
21 | 2–≥8 | [14] |
Lomefloxacin |
|
21 | ≥8 | [14] |
Fleroxacin |
|
21 | ≥8 | [14] |
Enrofloxacin |
|
6 | 0.25–2 | [35] |
Rifampin |
|
6 | 0.25–16 | [35] |
Erythromycin |
|
6 | 2–>16 | [35] |
Spiramycin |
|
6 | 4–>16 | [35] |
Clarithromycin |
|
6 | 8–>16 | [35] |
Roxithromycin |
|
6 | 16–>16 | [35] |
2.1.3. Antibiotic combinations
The checkerboard method is considered the most accurate technique for
Using this method, Mortensen et al. [18] reported a synergistic effect of the combination of tetracycline with rifampicin, but indifference or antagonism with the combinations of tetracycline plus either streptomycin or gentamicin. Doxycycline plus rifampicin was reported to be synergistic in several studies [11,15,35,36]. A synergistic effect was also found for most
The E-test method has also been used for the evaluation of the activity of antibiotic combinations [29,37]. Mueller Hinton agar plates supplemented with 5% sheep blood were inoculated with a 0.5–1 McFarland turbidity standard suspension of
Using kill-time experiments, earlier bactericidal activity was demonstrated with the combination of streptomycin with either a tetracycline (tetracycline or doxycycline), rifampicin, or a fluoroquinolone (including ciprofloxacin) [33,35]. The same was true for the combination of rifampicin with either a fluoroquinolone (especially ciprofloxacin) or a tetracycline [33]. In some studies, the combination of rifampicin with a tetracycline was no more effective than the former antibiotic alone [34]. In contrast, the combination of ciprofloxacin and minocycline was antagonistic [33].
2.2. AST in eukaryotic cell models
Richardson et al. [39] first reported that streptomycin (at concentrations up to 50 mg/L) was not bacteriostatic against
2.3. Animal models
Several animal models have been developed to study
Early studies in guinea pigs demonstrated the
The
3. Acquired resistances to antibiotics in Brucella species
Very few studies have reported high doxycycline MICs (up to 32 mg/L) in animal and human strains of
Fluoroquinolone resistance mechanisms have been characterized in
4. Correlation between laboratory data and clinical efficacy of antibiotics
In untreated patients, brucellosis may be controlled by the immune system, but relapses and chronic evolution of the disease are frequently observed [1]. The combination of immune defenses and an appropriate antibiotic therapy allows earlier amendment of clinical symptoms and more effective control of infection. The clinical experience regarding the treatment of brucellosis has established some basic principles that remain true today [70]. To reduce the risk of recurrence, at least two antibiotics should be administrated for a minimum of 4–6 weeks. The combination of doxycycline with either rifampicin or an aminoglycoside (streptomycin or gentamicin) is the most effective
Nevertheless, relapse rates of 5%–15% are still reported in immunocompetent patients after administration of appropriate antibiotic therapy, sometimes several decades following the primary infection [73,75]. A first explanation could be the lack of eradication of
Improving our understanding of treatment failures and relapses in brucellosis patients will necessitate not only a better standardization of assessment of the antibiotic activity using both
5. New therapeutic alternatives
5.1. Novel antibiotics
Tigecycline, a glycylcycline compound derived from minocycline, displays broad ranges of MICs and higher MIC90
Among new fluoroquinolones, moxifloxacin did not display higher activity compared to ciprofloxacin
Among the new macrolide compounds, azithromycin displayed
Medicinal plants have been evaluated for their
5.2. Intracellular delivery of antibiotics
The aminoglycosides are able to penetrate eukaryotic cells, albeit very slowly, but concentrate in the acidic lysosomal compartment because of their weak base nature [43]. At acidic pH, these antibiotics are partially inactivated because of their protonation. Although intracellular pharmacokinetic studies were mostly conducted using uninfected eukaryotic cells, it is tempting to extrapolate these data to
5.3. Peptide nucleic acids
Peptide nucleic acids (PNAs) are artificially synthesized polymers similar to DNA or RNA that can be used as antisense therapies. They show high specificity in binding to complementary DNAs, resistance to nucleases and proteases, and a high stability over a wide pH range. They readily cross the bacterial cell membranes when coupled with a cell-penetrating peptide. Rajasekaran et al. [97] reported growth inhibition of
5.4. Enhancement of the host response
Multiplication within phagocytic cells is a major virulence factor of
6. Conclusion
Brucellosis remains a prevalent disease in the world, a major concern in public health and an economic burden in agriculture. Although effective vaccines are available for the livestock, treatment of brucellosis remains challenging in both animals and humans. Recommendations for treatment of common clinical forms of human brucellosis have been addressed, especially by the WHO. However, treatment optimization is still needed for severe forms of the disease and in young children and pregnant women. Moreover, current treatment recommendations could be challenged by the emergence of acquired resistances to first-line drugs in
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