Timentin (Ticarcillin Disodium / Clavulanate Potassium) - Description and Clinical Pharmacology

To reduce the development of drug-resistant bacteria and maintain the effectiveness of TIMENTIN (ticarcillin disodium and clavulanate potassium) and other antibacterial drugs, TIMENTIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

TIMENTIN is a sterile injectable antibacterial combination consisting of the semisynthetic antibiotic ticarcillin disodium, and the beta-lactamase inhibitor clavulanate potassium (the potassium salt of clavulanic acid) for intravenous administration. Ticarcillin is derived from the basic penicillin nucleus, 6-amino-penicillanic acid.

Chemically, ticarcillin disodium is N -(2-Carboxy-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-6-yl)-3-thiophenemalonamic acid disodium salt and may be represented as:

Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus . It is a beta-lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of beta-lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid-mediated beta-lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins.

Chemically, clavulanate potassium is potassium (Z)-(2 R ,5 R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylate and may be represented structurally as:

TIMENTIN is supplied as a white to pale yellow powder for reconstitution. TIMENTIN is very soluble in water, its solubility being greater than 600 mg/mL. The reconstituted solution is clear, colorless or pale yellow, having a pH of 5.5 to 7.5.

For the 3.1-gram dosage of TIMENTIN, the theoretical sodium content is 4.51 mEq (103.6 mg) per gram of TIMENTIN. The theoretical potassium content is 0.15 mEq (6 mg) per gram of TIMENTIN.

CLINICAL PHARMACOLOGY

After an intravenous infusion (30 min.) of 3.1 grams of TIMENTIN, peak serum concentrations of both ticarcillin and clavulanic acid are attained immediately after completion of infusion. Ticarcillin serum levels are similar to those produced by the administration of equivalent amounts of ticarcillin alone with a mean peak serum level of 330 mcg/mL. The corresponding mean peak serum level for clavulanic acid was 8 mcg/mL. (See following table.)

SERUM LEVELS IN ADULTS

AFTER A 30-MINUTE IV INFUSION OF TIMENTIN^®

TICARCILLIN SERUM LEVELS (mcg/mL)

Dose	0	15 min.	30 min.	1 hr.	1.5 hr.	3.5 hr.	5.5 hr.
3.1 gram	324	223	176	131	90	27	6
	(293 to 388)	(184 to 293)	(135 to 235)	(102 to 195)	(65 to 119)	(19 to 37)	(5 to 7)

CLAVULANIC ACID SERUM LEVELS (mcg/mL)

Dose	0	15 min.	30 min.	1 hr.	1.5 hr.	3.5 hr.	5.5 hr.
3.1 gram	8.0	4.6	2.6	1.8	1.2	0.3	0
	(5.3 to 10.3)	(3.0 to 7.6)	(1.8 to 3.4)	(1.6 to 2.2)	(0.8 to 1.6)	(0.2 to 0.3)

The mean area under the serum concentration curve was 485 mcg•hr/mL for ticarcillin and 8.2 mcg•hr/mL for clavulanic acid.

The mean serum half-lives of ticarcillin and clavulanic acid in healthy volunteers are 1.1 hours and 1.1 hours, respectively.

In pediatric patients receiving approximately 50 mg/kg of TIMENTIN (30:1 ratio ticarcillin to clavulanate), mean ticarcillin serum half-lives were 4.4 hours in neonates (n = 18) and 1.0 hour in infants and children (n = 41). The corresponding clavulanate serum half-lives averaged 1.9 hours in neonates (n = 14) and 0.9 hour in infants and children (n = 40). Area under the serum concentration time curves averaged 339 mcg•hr/mL in infants and children (n = 41), whereas the corresponding mean clavulanate area under the serum concentration time curves was approximately 7 mcg•hr/mL in the same population (n = 40).

Approximately 60% to 70% of ticarcillin and approximately 35% to 45% of clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single dose of TIMENTIN to normal volunteers with normal renal function. Two hours after an intravenous injection of 3.1 grams of TIMENTIN, concentrations of ticarcillin in urine generally exceed 1,500 mcg/mL. The corresponding concentrations of clavulanic acid in urine generally exceed 40 mcg/mL. By 4 to 6 hours after injection, the urine concentrations of ticarcillin and clavulanic acid usually decline to approximately 190 mcg/mL and 2 mcg/mL, respectively. Neither component of TIMENTIN is highly protein bound; ticarcillin has been found to be approximately 45% bound to human serum protein and clavulanic acid approximately 25% bound.

Somewhat higher and more prolonged serum levels of ticarcillin can be achieved with the concurrent administration of probenecid; however, probenecid does not enhance the serum levels of clavulanic acid.

Ticarcillin can be detected in tissues and interstitial fluid following parenteral administration.

Penetration of ticarcillin into bile and pleural fluid has been demonstrated. The results of experiments involving the administration of clavulanic acid to animals suggest that this compound, like ticarcillin, is well distributed in body tissues.

An inverse relationship exists between the serum half-life of ticarcillin and creatinine clearance. The dosage of TIMENTIN need only be adjusted in cases of severe renal impairment. (See DOSAGE AND ADMINISTRATION.)

Ticarcillin may be removed from patients undergoing dialysis; the actual amount removed depends on the duration and type of dialysis.

Microbiology

Ticarcillin is a semisynthetic antibiotic with a broad spectrum of bactericidal activity against many gram-positive and gram-negative aerobic and anaerobic bacteria.

Ticarcillin is, however, susceptible to degradation by beta-lactamases, and therefore, the spectrum of activity does not normally include organisms which produce these enzymes.

Clavulanic acid is a beta-lactam, structurally related to the penicillins, which possesses the ability to inactivate a wide range of beta-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid-mediated beta-lactamases frequently responsible for transferred drug resistance.

The formulation of ticarcillin with clavulanic acid in TIMENTIN protects ticarcillin from degradation by beta-lactamase enzymes and effectively extends the antibiotic spectrum of ticarcillin to include many bacteria normally resistant to ticarcillin and other beta-lactam antibiotics. Thus, TIMENTIN possesses the distinctive properties of a broad-spectrum antibiotic and a beta-lactamase inhibitor. Ticarcillin/clavulanic acid has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Gram-Positive Aerobes

Staphylococcus aureus (beta-lactamase and non−beta-lactamase−producing)^*

Staphylococcus epidermidis (beta-lactamase and non−beta-lactamase−producing)^*

^*Staphylococci that are resistant to methicillin/oxacillin must be considered resistant to ticarcillin/clavulanic acid.  

Gram-Negative Aerobes

Citrobacter species (beta-lactamase and non−beta-lactamase−producing)

Enterobacter species including E. cloacae (beta-lactamase and non−beta-lactamase−producing)

(Although most strains of Enterobacter species are resistant in vitro, clinical efficacy has been demonstrated with TIMENTIN in urinary tract infections and gynecologic infections caused by these organisms.)

Escherichia coli (beta-lactamase and non−beta-lactamase−producing)

Haemophilus influenzae (beta-lactamase and non−beta-lactamase−producing)^† 

Klebsiella species including K. pneumoniae (beta-lactamase and non−beta-lactamase−producing)

Pseudomonas species including P. aeruginosa (beta-lactamase and non−beta-lactamase−producing)

Serratia marcescens (beta-lactamase and non−beta-lactamase−producing) 

^† beta-lactamase−negative, ampicillin-resistant (BLNAR) strains of H. influenzae must be considered resistant to ticarcillin/clavulanic acid.

Anaerobic Bacteria

Bacteroides fragilis group (beta-lactamase and non−beta-lactamase−producing)

Prevotella (formerly Bacteroides ) melaninogenicus (beta-lactamase and non−beta-lactamase−producing)

The following in vitro data are available, but their clinical significance is unknown.

The following strains exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ticarcillin/clavulanic acid. However, with the exception of organisms shown to respond to ticarcillin alone, the safety and effectiveness of ticarcillin/clavulanic acid in treating infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Gram-Positive Aerobes

Staphylococcus saprophyticus (beta-lactamase and non−beta-lactamase− producing)

Streptococcus agalactiae ^‡ (Group B)

Streptococcus bovis ^‡

Streptococcus pneumoniae ^‡ (penicillin-susceptible strains only) 

Streptococcus pyogenes ^‡

Viridans group streptococci^‡

Gram-Negative Aerobes

Acinetobacter baumannii (beta-lactamase and non−beta-lactamase−producing)

Acinetobacter calcoaceticus (beta-lactamase and non−beta-lactamase−producing)

Acinetobacter haemolyticus (beta-lactamase and non−beta-lactamase−producing)

Acinetobacter lwoffi (beta-lactamase and non−beta-lactamase−producing)

Moraxella catarrhalis (beta-lactamase and non−beta-lactamase−producing)

Morganella morganii (beta-lactamase and non−beta-lactamase−producing)

Neisseria gonorrhoeae (beta-lactamase and non−beta-lactamase−producing)

Pasteurella multocida (beta-lactamase and non−beta-lactamase−producing)

Proteus mirabilis (beta-lactamase and non−beta-lactamase−producing)

Proteus penneri (beta-lactamase and non−beta-lactamase−producing)

Proteus vulgaris (beta-lactamase and non−beta-lactamase−producing)

Providencia rettgeri (beta-lactamase and non−beta-lactamase−producing)

Providencia stuartii (beta-lactamase and non−beta-lactamase−producing)

Stenotrophomonas maltophilia (beta-lactamase and non−beta-lactamase−producing)

Anaerobic Bacteria

Clostridium species including C. perfringens , C. difficile, C. sporogenes, C. ramosum, and C. bifermentans (beta-lactamase and non−beta-lactamase−producing)

Eubacterium species

Fusobacterium species including F. nucleatum and F. necrophorum (beta-lactamase and non−beta-lactamase−producing)

Peptostreptococcus species^‡

Veillonella species^‡

^‡These are non−beta-lactamase−producing strains, and therefore, are susceptible to ticarcillin.

In vitro synergism between TIMENTIN and gentamicin, tobramycin, or amikacin against multiresistant strains of Pseudomonas aeruginosa has been demonstrated.

Susceptibility Testing

Dilution Techniques

Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method^1,3 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ticarcillin/clavulanate potassium powder.

The recommended dilution pattern utilizes a constant level of 2 mcg/mL clavulanic acid in all tubes with varying amounts of ticarcillin. MICs are expressed in terms of the ticarcillin concentration in the presence of clavulanic acid at a constant 2 mcg/mL. The MIC values should be interpreted according to the following criteria:

RECOMMENDED RANGES FOR TICARCILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING^*

For Pseudomonas aeruginosa:

MIC (mcg/mL)	Interpretation
≤64	Susceptible (S)
≥128	Resistant (R)

For Enterobacteriaceae:

MIC (mcg/mL)	Interpretation
≤16	Susceptible (S)
32-64	Intermediate (I)
≥128	Resistant (R)

For Staphylococci^† :

MIC (mcg/mL)	Interpretation
≤8	Susceptible (S)
≥16	Resistant (R)

^* Expressed as concentration of ticarcillin in the presence of clavulanic acid at a constant 2 mcg/mL.

^† Staphylococci that are susceptible to ticarcillin/clavulanic acid but resistant to methicillin/oxacillin must be considered as resistant.

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard ticarcillin/clavulanate potassium powder should provide the following MIC values:

Microorganism		MIC (mcg/mL) ‡
Escherichia coli	ATCC 25922	4-16
Escherichia coli	ATCC 35218	4-16
Pseudomonas aeruginosa	ATCC 27853	8-32
Staphylococcus aureus	ATCC 29213	0.5-2

^†¡ Expressed as concentration of ticarcillin in the presence of clavulanic acid at a constant 2 mcg/mL.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure^2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 85 mcg of ticarcillin/clavulanate potassium (75 mcg ticarcillin plus 10 mcg clavulanate potassium) to test the susceptibility of microorganisms to ticarcillin/clavulanic acid.

Reports from the laboratory providing results of the standard single-disk susceptibility test with an 85 mcg of ticarcillin/clavulanate potassium (75 mcg ticarcillin plus 10 mcg clavulanate potassium) disk should be interpreted according to the following criteria:

RECOMMENDED RANGES FOR TICARCILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING

For Pseudomonas aeruginosa:

Zone Diameter (mm)	Interpretation
≥15	Susceptible (S)
≤14	Resistant (R)

For Enterobacteriaceae:

Zone Diameter (mm)	Interpretation
≥20	Susceptible (S)
15-19	Intermediate (I)
≤14	Resistant (R)

For Staphylococci^§:

Zone Diameter (mm)	Interpretation
≥23	Susceptible (S)
≤22	Resistant (R)

^§Staphylococci that are resistant to methicillin/oxacillin must be considered as resistant to ticarcillin/clavulanic acid.

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for ticarcillin/clavulanic acid.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 85 mcg of ticarcillin/clavulanate potassium (75 mcg ticarcillin plus 10 mcg clavulanate potassium) disk should provide the following zone diameters in these laboratory test quality control strains:

Microorganism		Zone Diameter (mm)
Escherichia coli	ATCC 25922	24-30
Escherichia coli	ATCC 35218	21-25
Pseudomonas aeruginosa	ATCC 27853	20-28
Staphylococcus aureus	ATCC 25923	29-37

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to ticarcillin/clavulanic acid can be determined by standardized test methods.^3,4 The MIC values obtained should be interpreted according to the following criteria:

RECOMMENDED RANGES FOR TICARCILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING^||

MIC (mcg/mL)	Interpretation
≤32	Susceptible (S)
64	Intermediate (I)
≥128	Resistant (R)

^||Expressed as concentration of ticarcillin in the presence of clavulanic acid at a constant 2 mcg/mL.

Interpretation is identical to that stated above for results using dilution techniques.

As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized ticarcillin/clavulanate potassium powder should provide the following MIC values:

		Agar dilution	Broth microdilution
		MIC Range	MIC Range
Microorganism		(mcg/mL) ||	(mcg/mL) †‘
Bacteroides thetaiotaomicron	ATCC 29741	0.5-2	0.5-2
Eubacterium lentum	ATCC 43055	16-64	8-32

^†‘Expressed as concentration of ticarcillin in the presence of clavulanic acid at a constant 2 mcg/mL.

CLINICAL STUDIES

TIMENTIN has been studied in a total of 296 pediatric patients (excluding neonates and infants less than 3 months) in 6 controlled clinical trials. The majority of patients studied had intra-abdominal infections, and the primary comparator was clindamycin and gentamicin with or without ampicillin. At the end-of-therapy visit, comparable efficacy was reported in the trial arms using TIMENTIN and an appropriate comparator.

TIMENTIN was also evaluated in an additional 408 pediatric patients (excluding neonates and infants less than 3 months) in 3 uncontrolled US clinical trials. Patients were treated across a broad range of presenting diagnoses including: Infections in bone and joint, skin and skin structure, lower respiratory tract, urinary tract, as well as intra-abdominal and gynecologic infections. Patients received TIMENTIN either 300 mg/kg/day (based on the ticarcillin component) divided every 4 hours for severe infection or 200 mg/kg/day (based on the ticarcillin component) divided every 6 hours for mild to moderate infections. The efficacy rates were comparable to those obtained in the controlled trials.

The adverse event profile in these 704 pediatric patients treated with TIMENTIN was comparable to that seen in adult patients.