Table 1. Characteristics differentiating the medically important species of the genus Nocardiaa |
|
||||||||||||||||
|
N. abscessus |
N. africana |
N. asteroides sensu stricto type VI |
N.brasiliensis |
N. brevicatena complex |
N. carnea |
N. farcinica |
N. nova |
N. otitidiscaviarum |
N. paucivorans |
N. pseudobrasiliensis |
N. transvalensis (N. asteroides type IV) |
N. transvalensis (sensu stricto) |
N. transvalensis (new taxon I) |
N. transvalensis (new taxon II) |
N. veterana |
|
Hydrolysis of: |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Acetamide |
- |
- |
V |
- |
- |
NT |
+ |
- |
- |
- |
+ |
- |
- |
- |
- |
- |
|
Adenine |
- |
- |
- |
- |
- |
- |
- |
- |
- |
- |
+ |
- |
- |
- |
- |
- |
|
Casein |
- |
+ |
- |
+ |
- |
- |
- |
- |
- |
- |
+ |
- |
- |
- |
- |
- |
|
Esculin |
- |
- |
- |
+ |
+ |
+ |
+ |
- |
+ |
V |
+ |
- |
- |
- |
- |
- |
|
Hypoxanthine |
- |
- |
- |
+ |
- |
- |
- |
- |
+ |
- |
+ |
+ |
+ |
+ |
+ |
- |
|
Tyrosine |
- |
- |
- |
+ |
- |
- |
- |
- |
- |
- |
+ |
- |
- |
- |
- |
- |
|
Xanthine |
- |
- |
- |
- |
- |
- |
|
- |
+ |
- |
- |
- |
- |
- |
- |
- |
|
Growth at or in: |
|||||||||||||||||
45°C |
V |
+ |
V |
- |
V |
- |
+ |
- |
V |
NT |
- |
NT |
NT |
NT |
NT |
NT |
|
Lysozyme broth |
+ |
+ |
+ |
+ |
V |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
|
Production of arylsulfatase |
- |
- |
- |
- |
- |
- |
- |
+ |
- |
- |
- |
- |
- |
- |
- |
- |
|
Acid production or utilization of L-rhamnose |
V |
- |
V |
- |
V |
- |
+ |
- |
- |
- |
- |
- |
- |
- |
- |
- |
|
Resistance to: |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Amikacin (MIC, >16 μg/ml) |
- |
- |
- |
- |
- |
NT |
- |
- |
- |
- |
- |
+ |
+ |
V |
V |
NT |
|
Gentamicinb (zone, <10 mm) |
- |
+ |
- |
NT |
V |
NT |
+ |
V |
NT |
NT |
NT |
+ |
+ |
+ |
+ |
NT |
|
Kanamycin (MIC, >16 μg/ml) |
- |
+ |
V |
NT |
- |
NT |
+ |
V |
NT |
NT |
NT |
+ |
+ |
+ |
+ |
NT |
|
Tobramycin b (zone, <20 mm) |
- |
NT |
- |
NT |
+ |
NT |
+ |
V |
NT |
NT |
- |
+ |
+ |
+ |
+ |
NT |
|
Ciprofloxacin (MIC, >4 μg/ml) |
+ |
NT |
- |
+ |
- |
NT |
- |
+ |
NT |
NT |
- |
NT |
NT |
NT |
NT |
NT |
|
Ampicillin (MIC, >4 μg/ml) |
I |
- |
+ |
V |
V |
NT |
+ |
- |
+ |
NT |
V |
NT |
NT |
NT |
NT |
NT |
|
Amox-clav (MIC, ≥64/32 μg/ml) |
NT |
NT |
NT |
- |
V |
NT |
- |
+ |
+ |
NT |
V |
V |
+ |
V |
- |
NT |
|
Cefamandoleb (zone, <20 mm) |
- |
NT |
- |
V |
V |
NT |
+ |
- |
NT |
NT |
NT |
NT |
NT |
NT |
NT |
NT |
|
Cefotaxime (MIC, ≥64 μg/ml) |
- |
NT |
- |
V |
- |
NT |
+ |
- |
V |
NT |
NT |
NT |
NT |
NT |
NT |
NT |
|
Ceftriaxone (MIC, ≥64 μg/ml) |
- |
NT |
- |
V |
- |
NT |
+ |
- |
V |
NT |
NT |
NT |
NT |
NT |
NT |
NT |
|
Erythromycinb (zone, <30 mm) |
+ |
- |
I |
- |
+ |
NT |
+ |
- |
+ |
NT |
- |
+ |
+ |
+ |
+ |
NT |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
a Data were derived from 12, 46, 49, 88, 108, 112, 116, 119, and 120. Abbreviations and symbols: -, 90% or more of the strains are negative; +, 90% or more of the strains are positive; V, 11 to 89% of the strains are positive; NT, not tested; I, intermediate; amox-clav, amoxicillin-clavulanate. b Disk content (µg) was as follows: gentamicin, 10 µg; tobramycin, 10 µg; cefamandole, 30 µg; and erythromycin, 30 µg. Methodology adapted from Wallace et al. (111). Briefly, the inoculum was adjusted to a turbidity equivalent to that of a 0.5 McFarland barium sulfate standard and was streaked onto a Mueller-Hinton agar plate, the plate was inoculated at 35°C, and the zone of inhibition was read at 48 h. |
Table 2. Characteristics of some
antimicrobial agents used clinically* |
|||||
Class and microbial agent (s) |
Route of administration |
Drug concentration† Intracellular/ extracellular ratio |
Mechanism of action |
Drug interactions |
Side effects |
Aminoglycoside Amikacin |
Parenteral
|
<1 (105) 2 to 4 after 72 h of incubation (103) |
Bactericidal activity results from action on 30S ribosomal subunit to produce faulty protein synthesis |
Calcium, sodium bicarbonates, β-lactams, and heparin |
Nephro- and ototoxicity |
β-Lactams |
|
|
|
|
|
Penicillins Ampicillin |
Oral/ Parenteral |
<1 in PMNs and macrophages after prolonged incubation (105)
|
Bactericidal activity results from interference with construction of bacterial cell wall by inhibition of transpeptidases responsible for catalysis of peptidoglycan cross-linking |
Allopurinol, bacteriostatic antibiotics (chloramphenicol, sulfonamides, or tetracyclines) may interfere with bactericidal effect of ampicillin and probenecid Aminoglycosides
|
Nephro-and ototoxicity |
Carbapenem Imipenem |
Parenteral
|
||||
Cephalosporins |
|
||||
Cefotaxime |
Parenteral |
||||
Ceftriaxone |
Parenteral |
||||
Cefixime |
Oral |
||||
Cefuroxime |
Oral/Parenteral |
||||
b-Lactam-b-lactamase inhibitor Amoxicillin- clavulanic acid |
Oral
|
|
Bactericidal activity results from the ability of clavulanic acid to inactivate a wide variety of β-lactamases by blocking the active sites of these enzymes and thus protects amoxicillin from degradation |
Probenecid, allopurinol, antabuse, and ampicillin |
Gastrointestinal and hypersensitivity reactions |
Macrolides Erythromycin |
Oral/Parenteral
|
16 to 32 in alveolar macrophages (55) 2 to 10 in PMNs (15) |
Bactericidal activity results from inhibition of protein synthesis by binding 50S ribosomal subunit |
Theophylline, digoxin, oral anticoagulants, ergotamine
|
Gastrointestinal irritation, transient CNS reactions, and cardiac arrhymias |
Quinolones Ciprofloxacin
|
Oral/Parenteral |
2 to 8 in macrophages and fibroblasts (15) |
Bactericidal activity results from gyrase inhibition required to fold DNA strands |
Theophylline, magnesium -aluminum antacids, and other cations (calcium, zinc, and iron) |
Gastrointestinal, CNS, and skin/allergic reactions
|
Sulfonamides |
|
|
|
|
|
Sulfamethoxazole |
Oral |
1.7 in PMNs (34) 4.1 in PMNs (34) and 9 at 37°C and 13 at 25°C (50) |
Bacteriostatic results from the inhibition of folate pathway |
Thiazides, warfarin, phenytoin, cyclosporine,and cyclosporin
|
Hepatotoxicity, myelosuppression, and gastrointestinal, allergic skin, hematologic, neurologic, and psychiatric reactions |
Trimethoprim |
Oral |
||||
TMP-SMX |
Oral/Parenteral |
||||
Tetracyclines |
|
|
|
|
|
Doxycycline |
Oral/Parenteral |
7.1 in PMNs (34) |
Bacteriostatic activity results from inhibition of protein synthesis
|
Antacids and anticoagulant therapy Bacteriostatic drugs may interfere with bactericidal action of penicillin |
Gastrointestinal reactions and renal toxicity Hypersensitivity reactions and IV minocycline may cause thrombophlebitis |
Minocyline |
Oral/Parenteral |
||||
*Adapted from Physicians Desk Reference (84) except where referenced. †PMN, polymorphonuclear leukocytes; CNS, central nervous system; and IV, intravenous. |
Table 3 Antimicrobial susceptibility of N. farcinica, N. nova, and N. asteroides sensu stricto isolates* |
||||||||||||||||||
MIC (µg/mL) in broth |
||||||||||||||||||
|
50% |
90% |
Geometric mean┼ |
Range |
Breakpoint (µg/mL) ╪ |
% Resistant isolates |
||||||||||||
|
Nf |
Nn |
Na |
Nf |
Nn |
Na |
Nf |
Nn |
Na |
Nf |
Nn |
Na |
Nf |
Nn |
Na |
Nf |
Nn |
Na |
Ampicillin |
>32 |
4 |
8 |
>32 |
8 |
>32 |
49 |
2 |
6 |
32->32 |
≤0.25-16 |
≤0.25-16 |
≥4 |
≥4 |
≥4 |
100 |
56 |
73 |
Amoxicillin/ clavulanic acid |
16/8 |
64/32 |
8/4 |
32/16 |
64/32 |
64/32 |
12/6 |
48/24 |
8/4 |
2/1-64/32 |
2/1-64/32 |
≤0.5/0.25->64/32 |
≥32/16 |
≥32/16 |
≥32/16 |
29 |
94 |
33 |
Cefuroxime |
32 |
1 |
<1 |
64 |
4 |
8 |
30 |
1 |
2 |
4->64 |
≤1-16 |
≤1-32 |
≥32 |
≥32 |
≥32 |
64 |
0 |
6 |
Cefotaxime |
64 |
4 |
2 |
>64 |
16 |
16 |
66 |
4 |
2 |
32->64 |
≤0.5-64 |
<0.5-64 |
≥64 |
≥64 |
≥64 |
82 |
6 |
2 |
Ceftriaxone |
>64 |
4 |
2 |
>64 |
16 |
8 |
45 |
5 |
2 |
8->64 |
≤1-64 |
≤1-64 |
≥64 |
≥64 |
≥64 |
86 |
11 |
2 |
Cefixime |
>64 |
64 |
16 |
>64 |
>64 |
>64 |
111 |
49 |
26 |
64->64 |
8->64 |
≤1->64 |
≥4 |
≥4 |
$4 |
100 |
100 |
87 |
Imipenem |
8 |
<0.25 |
2 |
>32 |
0.5 |
32 |
7 |
0.3 |
2 |
0.5-32 |
≤0.25-2 |
≤0.25->32 |
≥16 |
≥16 |
$16 |
36 |
0 |
23 |
Amikacin |
1 |
<0.25 |
<0.25 |
1 |
>0.25 |
1 |
1 |
0.25 |
0.4 |
≤0.25-2 |
≤0.25 |
≤0.25-4 |
≥64 |
≥64 |
≥64 |
0 |
0 |
0 |
Erythromycin |
16 |
0.25 |
4 |
>16 |
0.5 |
>16 |
14 |
0.3 |
3 |
1->16 |
≤0.13-0.3 |
≤0.13->16 |
≥8 |
≥8 |
≥8 |
86 |
0 |
40 |
Minocycline |
2 |
1 |
1 |
8 |
4 |
8 |
2 |
1.6 |
1 |
0.5-16 |
0.25-8 |
≤0.13->16 |
≥16 |
≥16 |
≥16 |
4 |
0 |
6 |
Doxycycline |
4 |
4 |
2 |
8 |
8 |
16 |
4 |
4 |
2 |
1-16 |
1->16 |
≤0.13->16 |
≥16 |
≥16 |
≥16 |
14 |
6 |
12 |
Ciprofloxacin |
1 |
8 |
8 |
8 |
>8 |
>8 |
1 |
8 |
3 |
0.25->8 |
4->8 |
≤0.06->8 |
≥4 |
≥4 |
≥4 |
32 |
100 |
62 |
Rifampin |
>32 |
2 |
32 |
>32 |
>32 |
>32 |
42 |
8 |
3 |
≤0.25->32 |
≤0.5->32 |
≤0.5->32 |
≥4 |
≥4 |
≥4 |
93 |
50 |
73 |
Sulfamethoxazole |
8 |
32 |
4 |
32 |
8 |
16 |
7 |
2.3 |
4 |
≤1-128 |
≤1->128 |
≤1-32 |
>32 |
>32 |
>32 |
11 |
11 |
0 |
Dapsone |
8 |
4 |
2 |
>32 |
8 |
32 |
8 |
3.5 |
5 |
1->32 |
≤0.5->32 |
≤0.5->32 |
>32 |
>32 |
>32 |
14 |
6 |
8 |
PS-15 |
4 |
2 |
2 |
4 |
4 |
4 |
2 |
1.8 |
2 |
≤0.063->4 |
0.5-4 |
0.5->4 |
|
|
|
|
|
|
WR99210 |
≤0.063 |
≤0.063 |
≤0.063 |
0.5 |
0.125 |
2 |
0.2 |
0.08 |
0.2 |
≤0.063-2 |
≤0.063-0.5 |
≤0.063-4 |
|
|
|
|
|
|
Cycloguanil |
512 |
64 |
256 |
>512 |
128 |
>512 |
512 |
60 |
194 |
128->512 |
16-256 |
≤8->512 |
|
|
|
|
|
|
Proguanil |
128 |
32 |
64 |
512 |
64 |
>512 |
132 |
37 |
60 |
32->512 |
16-128 |
≤8->512 |
|
|
|
|
|
|
Trimethoprim |
4 |
8 |
4 |
>32 |
32 |
>32 |
5 |
7 |
5 |
≤0.5->32 |
1->32 |
≤0.5- >32 |
≥16 |
≥16 |
≥16 |
82 |
39 |
2 |
TMP-SMX |
0.5/ 9.55 |
0.06/ 1.19 |
0.25/ 4.8 |
2/ 38 |
0.5/ 9.5 |
1/ 19 |
0.5/ 9.5 |
0.17/ 3.2 |
0.22/ 4.18 |
≤0.06/ 1.19-4/76 |
≤0.06/1.19->8/152 |
≤0.06/ 1.19-1/19 |
>2/ 38 |
>2/ 38 |
>2/ 38 |
7 |
11 |
0 |
|
|
|
|
|
|
|
Zone of inhibition (mm) on disk |
|||||||||||
|
|
|
|
|
|
|
Arithmetic mean |
Range |
Breakpoint (mm) |
% Resistant isolates |
||||||||
|
|
|
|
|
|
|
Nf |
Nn |
Na |
Nf |
Nn |
Na |
Nf |
Nn |
Na |
Nf |
Nn |
Na |
Cefamandole (30 µg) |
|
|
|
|
|
|
12
|
53 |
38 |
6-46 |
6-90 |
6-50 |
≤14 |
≤14 |
≤14 |
70 |
17 |
29 |
Tobramycin (10 µg) |
|
|
|
|
|
|
7 |
24 |
37 |
6-22 |
6-46 |
6-40 |
≤14 |
≤14 |
≤14 |
96 |
33 |
25 |
Note. Nf, N. farcinica (23 clinical isolates, five reference strains); Nn, N. nova (16 clinical isolates, two reference strains); Na, N. asteroides sensu stricto (49 clinical isolates, three reference strains). * Modified from reference 72. † Estimated value (next highest twofold value was used when calculating geometric mean of values that were greater than the highest concentration tested). ‡ Breakpoint for resistance from National Committee for Clinical Laboratory Standards (79). |
Table 4. Antimicrobial susceptibility of Nocardia abscessus and Nocardia asteroides sensu stricto type VI
MIC (ug/mL) in broth
50%
90%
Geometric mean*
Range
Breakpoint (ug/mL) % Resistant isolates
Antimicrobial agent
Na
Na (VI)
Na
Na (VI)
Na
Na (VI)
Na
Na (VI)
Na
Na (VI)
Na
Na (VI)
Ampicillin
4
32
8
>32
4
16->32
1-8
16->32
>4
>4
86
100
Amoxicillin/
clavulanic acid
4/2
32/16
16/8
64/32
3.2/1.6
20/10
<0.5/0.25-16/8
1/0.5->64/32
≥32/16
≥32/16
0
61
Cefuroxime
2
1
4
16
2
2
<1-4
<1-32
≥32
≥32
0
11
Cefotaxime
2
2
4
8
2
3
0.5-16
1-64
≥64
≥64
0
6
Ceftriaxone
<1
2
4
8
3
3
<1-16
<1-64
≥64
≥64
0
6
Cefixime
64
>64
>64
>64
32
45
0.5->64
0.5->64
≥64
≥64
71
61
Imipenem
1
4
4
16
1
5
<0.25->32
<0.25>32
≥16
≥16
14
11
Amikacin
0.5
0.5
2
1
1
0.5
<0.25-4
<0.25-1
≥16
≥16
0
0
Erythromycin
>16
16
> 16
>16
24
12
8->16
2->16
≥8
≥8
100
72
Minocycline
1
2
8
8
3
2
1-16
<0.13->16
≥16
≥16
14
6
Doxycycline
8
2
16
8
7
2
0.25->8
0.13->16
≥16
≥16
43
6
Ciprofloxacin
8
8
8
>8
4
2
0.25->8
0.13->8
≥4
≥4
71
83
Rifampin
>32
32
>32
>32
24
24
4->32
0.5->32
≥4
≥4
100
94
Sulfamethoxazole
8
4
32
16
32
5
2->32
<1-16
>32
>32
0
0
Dapsone
4
4
8
32
4
4
2-16
1->32
≥32
≥32
0
17
PS-15
2
2
2
4
2
2
1-4
1->4
WR99210
0.125
0.125
2
2
0.26
0.35
<0.063-2
<0.063-4
Cycloguanil
128
512
>512
>512
388
338
128->512
8->512
Proguanil
64
64
128
>512
97
97
32->512
8->512
Trimethoprim
8
4
16
32
9.7
6.5
2->32
2->32
≥16
≥16
43
33
TMP-SMX
0.5/9.5
0.25/4.80
0.5/9.5
0.5/9.5
0.15/2.80
0.2/4.4
<0.06/1.19-1/19
<0.06/1.19-1/19
>2/38
>2/32
0
0
Zone of inhibition (mm) on disk
Arithmetic mean
Range
Breakpoint (mm)
% Resistant isolates
Cefamandole
(30 μg)
35
47
0-50
0-50
<14
<14
57
89
Tobramycin
(10 μg)
40
45
0-34
0-40
<14
<14
86
89
Note: Na, N. abscessus (7 clinical isolates); Na (VI) (18 clinical isolates).
*Estimated value (next highest twofold value was used when calculating geometric mean of values that were greater than the highest concentration tested).
HBreakpoint for resistance from National Committee for Clinical Laboratory Standards (79).
Table 5. Treatment for Pulmonary Nocardiosis
Drugs |
|
Dose |
Synergistic/Additive with* |
References |
Trimethoprim/Sulfamethoxazole (TMP/SMX) |
Parenteral oral |
160mg/800mg q6h 2 tabs DS BID** |
Imipenem (S) Amikacin (S/A) |
Gombert, 1983, Gombert, 1983 Kanemitsu, 2003 |
Sulfonamides |
Oral |
1.5-2 mg BID |
|
|
Minocycline |
Oral |
100 to 200 mg BID |
Amikacin (A) |
Kanemitsu, 2003 |
Amoxicillin-clavulanate |
Oral |
875 BID |
|
|
Amikacin |
Parenteral |
5-7.5 mg/kg 1 12 h |
TMP/SMX (S/A) Cefotaxime (S/A) Imipenem (S/A) Minocycline (A) |
Gombert 1983 Gombert 1983 Gombert 1983 |
Cefotaxime |
Parenteral |
2g q 6h |
Imipenem (S) Amikacin (S/A) |
Gombert 1983 Gombert 1983 Kanemitsu, 2003 |
Ceftriaxone |
Parenteral |
1 g 2 12 h |
|
|
Imipenem |
Parenteral |
500 mg q 6 h |
TMP/SMX (S) Cefotaxime (S) Amikacin (S/A) |
Gombert 1983 Gombert 1983 Gombert 1983 Kanemitsu, 2003 |
Meropenem |
Parenteral |
1 g 8h |
|
|
Linezolid |
0ral/Parenteral |
600mg BID |
|
|
Sparfloxacin*** |
|
|
Amikacin (S) |
Kanemitsu, 2003 |
* Against Nocardia asteroids (AAC 1983, Tohoku J Exp 2003) S: Synergistic A: Additive BID: Twice a day q: Every h: Hour(s)
**TMP 10-20mg/kg SMX 50-100mg /kg in two divided doses
***ZagamŽ no longer available in the United States.