Table 1.  IC50 Values for Inhibition of Various Β-Lactamases by Commercially Available

                β-Lactamase Inhibitors. 

Enzyme

IC50 (M)

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 (g/mL)

 

Sulbactam

MIC (g/mL)

 

Tazobactam

MIC (g/mL)

 

Staphylococcus aureus*

 

Pencillinases

 

1632

 

>128

 

32

 

Klebsiella pneumoniae

 

Broad spectrum (SHV)

 

1664

 

32128

 

>128

 

Proteus mirabilis

 

Penicillinase

 

32128

 

>128

 

>128

 

Escherichia coli

 

Broad spectrum (OXA, TEM, SHV)

 

1664

 

16 >128

 

>128

 

Pseudomonas aeruginosa

 

Penicillinase (PSE)

 

>128

 

>128

 

8.032

 

Moraxella catarrhalis

 

Broad spectrum (TEM)

 

4.0

 

16128

 

< 0.516

 

Hemophilus influenzae

 

Broad spectrum (TEM)

 

8.0128

 

128

 

0.5128

 

Bacteroides fragilis

 

Penicillinases

 

16> 64

 

32 >128

 

8.0128

* methicillin‑sensitive

Compiled from references: 21,95,61,23,81,30

 

 

Table 3. NCCLS Minimum Inhibitory Concentration Breakpoints (g/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

32/464/4

> 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

32/264/2

> 128/2

when testing staphylococci

< 8/2

-

>16/2

From NCCLS Table 2M7‑A4 (M100‑S7)  Minimum Inhibitory Concentration (MIC) Interpretive Standards (g/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

 

 

Text Box:  

 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 (g/mL)

 

.514.3

 

2043

 

29

Vdss (L/kg)

0.160.25

0.160.50

0.180.33

Protein binding (%)

20

38

20-23

AUC0‑∞(g hr/mL)

15‑21

44

24

Elimination T1/2 (hr)

0.71.3

1.01.7

0.350.94

Clrenal (mL/min)

8793

177200

104297

Cltotal (mL/min)

116227

200270

202418

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 -lactam component)

 Pediatric Dosing

(Based on -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.