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Mechanism Of Action
TIMENTIN is an antibacterial drug.
After an intravenous infusion (30 minutes) of 3.1 grams of TIMENTIN, peak serum concentrations of both ticarcillin and clavulanic acid were attained immediately after completion of the infusion. Ticarcillin serum levels were similar to those produced by the administration of equivalent amounts of ticarcillin alone with a mean peak serum level of 324 mcg/mL. The corresponding mean peak serum level for clavulanic acid was 8 mcg/mL. (See Table 2.)
Table 2: Mean Peak Serum Levels (mcg/mL) in Adults
After a 30-Minute IV Infusion of 3.1 grams of TIMENTIN
|Time||Ticarcillin Peak (Range)||Clavulanic Acid Peak (Range)|
|0||324 (293 - 388)||8.0 (5.3 - 10.3)|
|15 minutes||223 (184 -293)||4.6 (3.0 -7.6)|
|30 minutes||176 (135 -235)||2.6 (1.8 -3.4)|
|1 hour||131 (102 - 195)||1.8 (1.6 -2.2)|
|1.5 hours||90 (65 - 119)||1.2 (0.8 - 1.6)|
|3.5 hours||27 (19 -37)||0.3 (0.2 -0.3)|
|5.5 hours||6 (5 -7)||0|
The mean area under the serum concentration curve was 485 mcg•hr/mL for ticarcillin and 8.2 mcg•hr/mL for clavulanic acid.
Ticarcillin has been found to be approximately 45% bound to human serum protein and clavulanic acid approximately 25% bound. Ticarcillin can be detected in tissues and interstitial fluid following parenteral administration.
Distribution 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.
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.
The mean serum half-life of both ticarcillin and clavulanic acid in healthy volunteers was 1.1 hours.
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).
An inverse relationship exists between the serum half-life of ticarcillin and creatinine clearance. The half-life of ticarcillin in patients with renal failure is approximately 13 hours. 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.
Mechanism of Action
Ticarcillin disrupts bacterial cell wall development by inhibiting peptidoglycan synthesis and/or by interacting with penicillin-binding proteins.
Ticarcillin is susceptible to degradation by P-lactamases, so the spectrum of activity does not normally include organisms which produce these enzymes.
Clavulanic acid is a β-lactam, structurally related to the penicillins, which inactivates some β-lactamase enzymes that are commonly found in bacteria resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid-mediated β-lactamases frequently responsible for transferred drug resistance.
The formulation of ticarcillin with clavulanic acid in TIMENTIN protects ticarcillin from degradation by β-lactamase enzymes, effectively extending the antibacterial spectrum of ticarcillin to include many bacteria normally resistant to ticarcillin and other β-lactam antibacterials.
Interaction With Other Antimicrobials
In vitro synergism between TIMENTIN and gentamicin, tobramycin, or amikacin against multi-resistant isolates of Pseudomonas aeruginosa has been demonstrated.
Ticarcillin/clavulanic acid has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see INDICATIONS AND USAGE].
Susceptibility to ticarcillin/clavulanic acid will vary with geography and time; local susceptibility data should be consulted, if available.
Staphylococcus aureus (methicillin-susceptible
Staphylococcus epidermidis (methicillin-susceptible isolates only)
Bacteroides fragilis group
a Some extended spectrum P-lactamase (ESBL)-producing isolates are resistant to ticarcillin/clavulanic acid. Most carbapenemase-producing isolates are resistant to ticarcillin/clavulanic acid.
b β-lactamase-negative, ampicillin-resistant (BLNAR) isolates of H. influenzae must be considered resistant to ticarcillin/clavulanic acid.
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ticarcillin/clavulanic acid. However, the efficacy of ticarcillin/clavulanic acid in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.
Staphylococcus saprophyticus (methicillin-susceptible
Streptococcus agalactiae (Group B)
Streptococcus pneumoniae (penicillin-susceptible isolates only)
Streptococcus spp. viridans group (penicillin-susceptible isolates only)
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method2,4 (broth and/or agar). The MIC values should be interpreted according to criteria provided in Table 3.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.3,4 These procedures use paper disks impregnated with 85 mcg of ticarcillin/clavulanate potassium (75 mcg ticarcillin plus 10 mcg clavulanate potassium) to test the susceptibility of bacteria to ticarcillin/clavulanic acid. The disc diffusion interpretive criteria are provided in Table 3.
Anaerobic Techniques: For anaerobic bacteria, susceptibility to ticarcillin/clavulanic acid can be determined by standardized test methods.4,5 The MIC values obtained should be interpreted according to the criteria in Table 3.
Table 3:Susceptibility Test Interpretive Criteria for
|Microorganism||Minimum Inhibitory Concentration (mcg/mL)||Disc Diffusion (Zone Diameter mm)|
|Anaerobes||≤ 32/2||64/2||≥ 128/2||-||-||-|
|Enterobacteriaceae||≤ 16/2||32/2 - 64/2||≥ 128/2||≥ 20||15 - 19||≤ 14|
|Pseudomonas aeruginosa||≤ 16/2||32/2 - 64/2||≥ 128/2||≥ 24||16 -23||≤ 15|
Susceptibility of staphylococci to ticarcillin/clavulanate may be deduced by testing penicillin and either oxacillin or cefoxitin.4
A report of “Susceptible” indicates the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the bacterium 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 product is physiologically concentrated or in situations where a high dosage of the drug product 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 antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.
Quality Control: Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the tests.2,3,4,5 Standard ticarcillin/clavulanic acid powder should provide the following range of MIC values noted in Table 4. For the diffusion technique using the 85 mcg of ticarcillin/clavulanate potassium (75 mcg ticarcillin plus 10 mcg clavulanate potassium), the criteria in Table 4 should be achieved.
Table 4: Acceptable Quality Control Ranges for
Ticarcillin/ Clavulanic Acid
|QC Strain||Broth MIC (mcg/mL)||Zone Diameter (mm)||Agar Dilution MIC (mcg/mL)|
|Bacteroides thetaiotaomicron ATCC 29741||0.5/2 - 2/2||-||0.5/2 -2/2|
|Clostridium difficile ATCC 700057||-||-||16/2 - 64/2|
|Enterococcus faecalis ATCC 29212||16/2 - 64/2||-||-|
|Escherichia coli ATCC 25922||4/2 - 16/2||24 -30||-|
|Escherichia coli ATCC 35218||8/2 - 32/2||21 -25||-|
|Eubacterium lentum ATCC 43055||8/2 - 32/2||-||16/2 - 64/2|
|Pseudomonas aeruginosa ATCC 27853||8/2 - 32/2||20 -28||-|
|Staphylococcus aureus ATCC 29213||0.5/2 - 2/2||-||-|
|Staphylococcus aureus ATCC 25923||-||29 - 37||-|
|ATCC = American Type Culture Collection
MIC = Minimum Inhibitory Concentration
TIMENTIN has been studied in 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 had 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. Efficacy rates were comparable to those obtained in controlled trials.
The adverse event profile in these 704 pediatric patients treated with TIMENTIN was comparable to that seen in adult patients.
1. Cockcroft, DW, et al. Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41, 1976.
2. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Ninth Edition. 2012. CLSI document M07-A9. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.
3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard - Eleventh Edition. 2012. CLSI document M02-A11. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.
4. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fourth Informational Supplement. 2014. CLSI document M100-S24. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.
5. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard - Eighth Edition. 2012. CLSI document M11-A8. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.
Last reviewed on RxList: 6/27/2014
This monograph has been modified to include the generic and brand name in many instances.
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