Table 1. IC50 Values for Inhibition of Various Β-Lactamases by Commercially Available
β-Lactamase Inhibitors.
| Enzyme |
IC50 (µM) |
||
|
Clavulanic acid |
Sulbactam |
Tazobactam |
|
|
Class A |
|
|
|
|
S. aureus PC1 |
0.03 |
0.08 |
0.03 |
|
TEM-1 |
0.09 |
0.9 |
0.1 |
|
TEM-2 |
0.02 |
2.4 |
0.02 |
|
TEM-9 |
0.009 |
0.27 |
0.08 |
|
TEM-10 |
0.005 |
0.94 |
0.09 |
|
SHV-1 |
0.012 |
12 |
0.15 |
|
|
|
|
|
|
Class C |
|
|
|
|
P99 |
>100 |
5.6 |
0.008 |
|
|
|
|
|
|
Class D |
|
|
|
|
OXA-1 |
1.8 |
4.7 |
1.4 |
Table 2. Activities of the β‑lactamase Inhibitors Against Selected Bacterial Organisms
|
Organism |
Type of β ‑lactamases (gene abbreviations) |
Clavulanic acid MIC (µg/mL) |
Sulbactam MIC (µg/mL) |
Tazobactam MIC (µg/mL) |
|
Staphylococcus aureus* |
Pencillinases |
16–32 |
>128 |
32 |
|
Klebsiella pneumoniae |
Broad spectrum (SHV) |
16–64 |
32–128 |
>128 |
|
Proteus mirabilis |
Penicillinase |
32–128 |
>128 |
>128 |
|
Escherichia coli |
Broad spectrum (OXA, TEM, SHV) |
16–64 |
16– >128 |
>128 |
|
Pseudomonas aeruginosa |
Penicillinase (PSE) |
>128 |
>128 |
8.0–32 |
|
Moraxella catarrhalis |
Broad spectrum (TEM) |
4.0 |
16–128 |
< 0.5–16 |
|
Hemophilus influenzae |
Broad spectrum (TEM) |
8.0–128 |
128 |
0.5–128 |
|
Bacteroides fragilis |
Penicillinases |
16–> 64 |
32– >128 |
8.0–128 |
* methicillin‑sensitive
Compiled from references: 21,95,61,23,81,30
Table 3. NCCLS Minimum Inhibitory Concentration Breakpoints (µg/mL) for Beta‑lactamase Inhibitor/Beta‑lactam Combination Antibiotics
| Antibiotic |
Susceptible |
Intermediate |
Resistant |
| Amoxicillin/clavulanic acid (2:1 ratio) |
|
|
|
|
when testing staphylococci |
< 4/2 |
– |
> 8/4 |
|
when testing other organisms |
< 8/4 |
16/8 |
> 32/16 |
|
Ampicillin/sulbactam (2:1 ratio) |
|
|
|
|
when testing gram‑negative enterics and staphylococci |
< 8/4 |
16/8 |
> 32/16 |
|
Piperacillin/tazobactam (8:1 ratio) |
|
|
|
|
when testing P. aeruginosa |
< 64/4 |
– |
> 128/4 |
|
when testing other gram‑negatives |
< 16/4 |
32/4—64/4 |
> 128/4 |
|
when testing staphylococci |
< 8/4 |
– |
> 16/4 |
|
Ticarcillin/clavulanic acid (30:1 ratio) |
|
|
|
|
when testing P. aeruginosa |
< 64/2 |
– |
> 128/2 |
|
when testing other gram‑negatives |
< 16/2 |
32/2—64/2 |
> 128/2 |
| when testing staphylococci |
< 8/2 |
- |
>16/2 |
|
|
|
|
From NCCLS Table 2—M7‑A4 (M100‑S7) Minimum Inhibitory Concentration (MIC) Interpretive Standards (µg/mL)
for Organisms Other Than Hemophilus spp., Neisseria gonorrhoeae, and Streptococcus spp. — January, 1997 (6).
Table 4. Comparison of Residues Found In Positions ABL 69, 165, 182, 244, 275, and 276 in the Amino Acid Sequences of Β-Lactamases TEM-1 And IRT-1 To IRT-10.
| β-lactamase |
69 |
165 |
182 |
244 |
275 |
276 |
| TEM-1 |
Met |
Trp |
Met |
Arg |
Arg |
Asn |
|
IRT-1 (TEM-31)a |
|
|
|
Cys |
|
|
|
IRT-2 (TEM-30)b |
|
|
|
Ser |
|
|
|
IRT-3 (TEM-32) |
Ileu |
|
Thr |
|
|
|
|
IRT-4 (TEM-35) |
Leu |
|
|
|
|
Asp |
|
IRT-5 (TEM-33) |
Leu |
|
|
|
|
|
|
IRT-6 (TEM 34) |
Val |
|
|
|
|
|
|
IRT-7 (TEM-36) |
Val |
|
|
|
|
Asp |
|
IRT-8 (TEM-37) |
Ileu |
|
|
|
|
Asp |
|
IRT-9 (TEM-38) |
Val |
|
|
|
Leu |
|
|
IRT-10 (TEM-39) |
Leu |
Arg |
|
|
|
Asp |
|
IRT-14 (TEM-45) |
Leu |
|
|
|
G1n
|
|
a recently reported in K. pneumoniae (64)
b recently reported in P. mirabilis (15)
Table 5. Pharmacokinetics of Clavulanic Acid, Sulbactam, and Tazobactam Administered Intravenously in Normal Adults
|
Pharmacokinetic parameter |
Clavulanic acid (200 mg) |
Sulbactam (500 mg) |
Tazobactam (375 mg) |
|
Cmax (µg/mL) |
.5–14.3 |
20–43 |
29 |
|
Vdss (L/kg) |
0.16–0.25 |
0.16–0.50 |
0.18–0.33 |
|
Protein binding (%) |
20 |
38 |
20-23 |
|
AUC0‑∞(µg• hr/mL) |
15‑21 |
44 |
24 |
|
Elimination T1/2 (hr) |
0.7–1.3 |
1.0–1.7 |
0.35–0.94 |
|
Clrenal (mL/min) |
87–93 |
177–200 |
104–297 |
|
Cltotal (mL/min) |
116–227 |
200–270 |
202–418 |
Compiled from the following references: 10, 46, 86, 12, 23, 34,71, 90, 20.
Table 6. Available Formulations of the β-Lactams/β-Lactamase Inhibitor Combinations
|
Drug |
Trade Name |
Availability |
|
|
Amoxicillin/clavulanate |
Augmentin (Glaxo-SK) |
(amoxicillin trihydrate/clavulanic acid) Tablets: |
250 mg/125 mg 500 mg/125 mg 875 mg/125mg |
|
|
|
Augmentin XR tablets Chewable tablets: |
1000 mg/62.5 mg 125 mg/31.25 mg 200 mg/28.5 mg 250 mg/62.5 mg 400 mg/57 mg |
|
|
|
Powder for Oral Suspension: (per 5 ml) |
125 mg/31.25 mg 200 mg/28.5 mg 250 mg/62.5 mg 400 mg/57 mg |
|
Ampicillin/sulbactam |
Unasyn (Pfizer) |
(ampicillin/sulbactam) Powder for injection |
1.0 g/0.5 g 2.0 g/1.0 g |
|
Piperacillin/tazobactam |
Zosyn (Wyeth-Ayerst) |
(piperacillin/tazobactam) Powder for injection: |
2.0 g/0.25 g 3.0 g/0.375 g 4.0 g/0.5 g
|
|
Ticarcillin/clavulanate |
Timentin (SK-Beecham) |
(ticarcillin/clavulanic acid) Powder for injection: |
3.0 g/0.1 g |
Table 7. Cost per Dose and per Day of Usual Maximal Doses of the β-Lactam/β-lactamase Inhibitor
|
|
Maximum Adult Dosing (Cost = $ US, 2003) |
||
|
Drug |
Dose |
Cost/dose |
Cost*/day |
|
Amoxicillin/clavulanate |
875 mg po q12h |
5.75 |
10.60 |
|
Ampicillin/sulbactam |
3.0 g iv q6h |
15.85 |
95.00 |
|
Ticarcillin/clavulanate |
3.1 g iv q4h |
16.00 |
96.00 |
|
Piperacillin/tazobactam |
3.375 iv q4h |
17.32 |
104.00 |
*Cost is AWP as reported by the manufacturer and includes drug acquisition costs only (79) Costs of preparation and
administration of multiple doses are not considered.
Table 8. Usual Adult and Pediatric Doses for Mild-Moderate, and Severe Infections.
|
|
Adult Dosing (Based on ß-lactam component) |
Pediatric Dosing (Based on ß-lactam component) |
||
|
Drug |
Mild/Moderate |
Severe |
Mild/Moderate |
Severe |
|
Amoxicillin/clavulanate |
250 mg q 8 h- 500 mg q 8 h |
875-2000 mg q 12 h |
20-25 mg/kg/day divided q 8h |
40-45 mg/kg/day divided q 8h |
|
Ampicillin/sulbactam |
1.5 g q 6-8 h |
3.0 g q 6 h |
150- 300 mg/kg/day divided q 6h |
|
|
Ticarcillin/calvulante |
3.1 g q 6 h |
3.1 g q 4 h |
Not indicated in children < 12 years |
|
|
Piperacillin/tazobactam |
2.25-3.375 g q 6h |
3.375 g q 4 h-4.5 g q 6h |
Not indicated in children < 12 years |
|
Table 9. Manufacturer Recommended Doses of Β-Lactam/Β-Lactamase Inhibitor Combinations in Adult Patients
with Various Degrees of Renal Dysfunction
|
Drug |
CrCL (mL/min) |
Dose |
|
Amoxicillin/clavulanate |
>30 10-30 <10 |
500 mg q 8-12h or 875 mg q 12h 250-500 mg q12h 250-500 mg q 24h |
|
Ampicillin/sulbactam |
> 30 15-29 5-14 |
1.5-3.0 g q6-8h 1.5-3.0 g q8-12h 1.5-3.0 g q12-24h |
|
Ticarcillin/clavulanate |
> 60 30-60 10-30 <10 |
3.1 g q 4 h 2.0 g q 4h 2.0 g q 8h 2.0 g q 12h (q 24h with hepatic dysfunction) |
|
Piperacillin/tazobactam |
> 40 20-40 < 20 |
3.375 g q 4-6h 2.25 g q 6h 2.25q8 |
Table 10. Clinical and bacterial cure rates of standard therapy compared to β-lactamase inhibitor combinations for the treatment of various infections.
|
Authors |
Study Drug vs. Comparator Regimen |
No. Patients |
Clin Resp % |
Bact Cure % |
|
Intra-abdominal infections |
|
|
|
|
|
SGIA (84) |
Ampicillin/sulbactam Clindamycin+Gentamicin |
46 37 |
78 89 |
87 96 |
|
Yellin et al (105) |
Ampicillin/sulbactam Clindamycin +Gentamicin |
67 38 |
76 87 |
NR NR |
|
Polk et al (77) |
Piperacillin/tazobactam Clindamycin +Gentamicin |
104 43 |
88 77 |
86 75 |
|
Brismar et al (16) |
Piperacillin/tazobactam Imipenem/cilastatin |
69 65 |
91 70 |
93 73 |
|
Gynecological infections |
|
|
|
|
|
Senft et al (87) |
Ampicillin/sulbactam Cefoxitin |
39 36 |
87 91 |
83 59 |
|
Pastorek et al (75) |
Ticarcillin/clavulanate Cefoxitin |
47 46 |
93 84 |
NR NR |
|
Sweet et al (97) |
Piperacillin/tazobactam Clindamycin/gentamicin |
196 103 |
78 82 |
77 79 |
|
Skin and soft tissue infections
|
|
|
|
|
|
Stromberg et al (94) |
Ampicillin/sulbactam Clindamycin and tobramycin |
31 29 |
93 81 |
67 35 |
|
Tan et al (98) |
Piperacillin/tazobactam Ticarcillin/clavulanate |
153 98 |
76 77 |
77 79 |
|
Grayson et al (38) |
Ampicillin/sulbactam Imipenem/cilastatin |
48 48 |
81 85 |
67 75 |
|
Respiratory tract infections |
|
|
|
|
|
Shlaes et al (88) |
Piperacillin/tazobactam Ticarcillin/clavulanate |
177 122 |
81 68 |
84 64 |
Table 11. Dosing During Continuous Renal Replacement Therapy (Ampicillin-Sulbactam)
|
CVVH (Continuous venovenous hemofiltration): 3g IV q12h |
|
CVVHD (Continuous venovenous hemodialysis): 3g IV q8h |
|
CVVHDF (Continuous venovenous hemodiafiltration) 3g IV q8h |
Note: CVVH is mainly for fluid removal alone. Many institutions will employ
more CVVHD or CVVHDF which combine dialysis with fluid removal.
Table 12. Dosing during Continuous Renal Replacement Therapy (Ticarcillin-Clavulanate)
|
CVVH (Continuous venovenous hemofiltration): 2g IV q6-8h |
|
CVVHD (Continuous venovenous hemodialysis): 3.1g IV q6h |
|
CVVHDF (Continuous venovenous hemodiafiltration) 3.1g IV q6h |
Note: CVVH is mainly for fluid removal alone. Many institutions will employ more CVVHD or CVVHDF which
combine dialysis with fluid removal.
Table 13. Dosing during Continuous Renal Replacement Therapy (Piperacillin-Tazobactam)
|
CVVH (Continuous venovenous hemofiltration): 2.25g IV q6h |
|
CVVHD (Continuous venovenous hemodialysis): 2.25-3.375g IV q6h |
|
CVVHDF (Continuous venovenous hemodiafiltration) 2.25g-3.375g IV q6h |
Note: CVVH is mainly for fluid removal alone. Many institutions will employ more CVVHD or CVVHDF which
combine dialysis with fluid removal.