What are the common side effects of ticarcillin. How does ticarcillin affect liver function. What precautions should be taken when administering ticarcillin intravenously. When was ticarcillin withdrawn from the US market. How does ticarcillin compare to other penicillin antibiotics.

Overview of Ticarcillin: An Extended-Spectrum Antibiotic

Ticarcillin is a fourth-generation, extended-spectrum penicillin antibiotic that was previously used to treat moderate-to-severe infections caused by susceptible gram-positive and gram-negative bacteria. Its extended spectrum made it particularly effective against Pseudomonas aeruginosa, as well as some Enterobacter and Proteus species.

Ticarcillin’s resistance to many beta-lactamases made it a valuable tool in combating certain antibiotic-resistant infections. However, it’s important to note that ticarcillin was withdrawn from the United States market in 2004.

Key Features of Ticarcillin

• Extended-spectrum carboxypenicillin antibiotic
• Effective against Pseudomonas aeruginosa and other resistant bacteria
• Resistant to many beta-lactamases
• Withdrawn from the US market in 2004

Dosage and Administration of Ticarcillin

When ticarcillin was available, it was typically administered intravenously in doses of 200 to 300 mg/kg per day, divided into doses given every 4 to 6 hours. The drug was available in parenteral forms, both generically and under the brand name Ticar.

Can ticarcillin be administered orally? No, ticarcillin was only available in intravenous formulations due to its poor oral bioavailability and the need for high blood concentrations to treat severe infections.

Common Side Effects of Ticarcillin

Like all medications, ticarcillin can cause various side effects. The most common side effects reported with ticarcillin use include:

• Nausea
• Diarrhea
• Dizziness
• Headache
• Rash
• Hypersensitivity reactions

Are there any severe side effects associated with ticarcillin? Yes, while rare, potentially severe adverse events can occur, including:

• Severe hypersensitivity reactions
• Anaphylaxis
• Stevens-Johnson syndrome

Ticarcillin and Liver Function: Hepatotoxicity Concerns

Intravenous ticarcillin therapy has been associated with mild and transient elevations in serum aminotransferases. These elevations are generally self-limited and only slightly more common with ticarcillin than with comparative antibiotics.

More commonly reported are instances of anicteric hepatic injury from carbenicillin, a similar carboxypenicillin with extended coverage against Pseudomonas. High doses of intravenous carbenicillin have been known to cause serum aminotransferase elevations without jaundice in 15% to 30% of patients.

Ticarcillin vs. Carbenicillin: Liver Effects

Do liver enzyme elevations resolve after discontinuing ticarcillin? Yes, these elevations typically return to normal promptly after discontinuation or switching to another antibiotic. Interestingly, while recurrence is common with retreatment using carbenicillin, it is not typically seen with ticarcillin.

Rare instances of idiosyncratic, clinically apparent cholestatic liver injury have been reported in persons receiving ticarcillin in combination with clavulanate. These cases resemble the rare idiosyncratic reactions that can occur with many penicillins and are similar to the cholestatic liver injury associated with amoxicillin/clavulanate.

Mechanism of Liver Injury in Ticarcillin Use

The cause of idiosyncratic liver injury associated with ticarcillin use is likely related to hypersensitivity or allergy. However, it’s important to note that no cases of rechallenge or reexposure have been reported, making it challenging to confirm this mechanism definitively.

Is the liver injury caused by ticarcillin dose-dependent? No, the idiosyncratic nature of the liver injury suggests that it is not directly related to the dose of ticarcillin administered but rather to individual patient factors and potential allergic reactions.

Prognosis and Management of Ticarcillin-Induced Liver Injury

Due to the limited number of reported cases of ticarcillin-related liver injury, it’s challenging to assess the prognosis and outcome definitively. However, some general guidelines can be followed:

1. Patients who experience ticarcillin-induced hepatitis should avoid reexposure to other penicillins.
2. Cephalosporins should be used with caution in these patients due to potential cross-reactivity.
3. Close monitoring of liver function tests is recommended when initiating treatment with related antibiotics.

How long does it take for liver function to normalize after discontinuing ticarcillin? While individual cases may vary, liver function tests typically begin to improve within days to weeks after discontinuing the medication. Complete resolution may take several weeks to months in some cases.

Comparing Ticarcillin to Other Penicillin Antibiotics

Ticarcillin belongs to the fourth generation of penicillins, which are characterized by their extended spectrum of activity. Other drugs in this class include:

• Piperacillin
• Piperacillin-Tazobactam
• Ticarcillin-Clavulanate

These antibiotics share some similarities in their spectrum of activity and potential side effects, but there are also important differences to consider.

Ticarcillin vs. Piperacillin

Both ticarcillin and piperacillin are extended-spectrum penicillins with activity against Pseudomonas aeruginosa. However, piperacillin generally has a broader spectrum of activity and is more commonly used in current clinical practice.

Is piperacillin more effective than ticarcillin against Pseudomonas infections? While both antibiotics are effective against Pseudomonas, piperacillin is often considered to have slightly better activity and is more frequently used in combination with tazobactam for enhanced efficacy against beta-lactamase-producing organisms.

Ticarcillin-Clavulanate Combination

Ticarcillin is sometimes combined with clavulanate, a beta-lactamase inhibitor, to enhance its efficacy against beta-lactamase-producing bacteria. This combination, known as Timentin, provides a broader spectrum of activity compared to ticarcillin alone.

Does the addition of clavulanate increase the risk of liver injury? While the combination of ticarcillin and clavulanate may be more effective against certain bacteria, it may also slightly increase the risk of cholestatic liver injury, similar to what is observed with amoxicillin-clavulanate combinations.

Historical Context and Current Status of Ticarcillin

Ticarcillin played a significant role in the treatment of severe infections, particularly those caused by Pseudomonas aeruginosa, during its time on the market. However, the landscape of antibiotic therapy has evolved significantly since ticarcillin’s introduction.

Reasons for Withdrawal from the US Market

Ticarcillin was withdrawn from the United States market in 2004. While the exact reasons for its withdrawal are not explicitly stated in the provided information, several factors likely contributed to this decision:

• Development of newer, more effective antibiotics
• Changes in bacterial resistance patterns
• Availability of alternative treatments with better safety profiles
• Economic considerations for pharmaceutical companies

Are there any countries where ticarcillin is still available? While ticarcillin has been withdrawn from the US market, it may still be available in some other countries. However, its use has generally been superseded by newer antibiotics with similar or improved efficacy and safety profiles.

Future Perspectives and Research Directions

Although ticarcillin is no longer in clinical use in many countries, the lessons learned from its development, use, and associated side effects continue to inform antibiotic research and development.

Antibiotic Resistance and New Drug Development

The ongoing challenge of antibiotic resistance highlights the need for continued research into new antibiotics and alternative treatment strategies. Some areas of focus include:

• Development of new beta-lactamase inhibitors
• Exploration of novel antibiotic classes
• Investigation of combination therapies to combat resistance
• Research into non-antibiotic approaches to treating bacterial infections

Could ticarcillin or similar antibiotics make a comeback in the future? While it’s unlikely that ticarcillin itself will return to widespread use, the principles behind its development and the lessons learned from its clinical application continue to inform the creation of new antibiotics. Future drugs may build upon the strengths of ticarcillin while addressing its limitations and the evolving landscape of bacterial resistance.

Improving Safety Profiles of Antibiotics

The experience with ticarcillin and other penicillin antibiotics has led to increased awareness of potential liver-related side effects. This knowledge is being applied in the development of new antibiotics, with a focus on:

• Improved screening for hepatotoxicity during drug development
• Better understanding of the mechanisms underlying drug-induced liver injury
• Development of biomarkers to predict and monitor liver toxicity
• Exploration of strategies to mitigate liver-related side effects

How can the risk of antibiotic-induced liver injury be minimized in clinical practice? While completely eliminating the risk of liver injury is challenging, several strategies can help minimize this risk:

1. Careful patient selection and consideration of individual risk factors
2. Regular monitoring of liver function tests during antibiotic therapy
3. Prompt discontinuation of the antibiotic if liver abnormalities are detected
4. Education of healthcare providers and patients about potential signs and symptoms of liver injury
5. Continued research into the mechanisms of antibiotic-induced liver injury to inform prevention strategies

Conclusion and Key Takeaways

Ticarcillin, once a valuable tool in the treatment of severe bacterial infections, particularly those caused by Pseudomonas aeruginosa, has left a lasting impact on the field of antibiotic therapy. While no longer in clinical use in many countries, the lessons learned from its development, use, and associated side effects continue to inform current practice and future research.

Summary of Ticarcillin’s Legacy

• Extended-spectrum penicillin with efficacy against resistant bacteria
• Associated with rare but potentially serious liver-related side effects
• Withdrawn from the US market in 2004
• Contributed to our understanding of antibiotic-induced liver injury
• Informs ongoing research into new antibiotics and safety strategies

What is the most important lesson learned from the ticarcillin experience? Perhaps the most crucial takeaway is the need for ongoing vigilance and research in antibiotic development and use. While antibiotics like ticarcillin have saved countless lives, they also come with potential risks that must be carefully managed. The balance between efficacy and safety remains a central challenge in the fight against bacterial infections, driving continued innovation in the field of antimicrobial therapy.

Ticarcillin – LiverTox – NCBI Bookshelf

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Last Update: October 20, 2020.

OVERVIEW

Introduction

Ticarcillin is an extended-spectrum carboxypenicillin antibiotic and is used to treat moderate-to-severe infections due to susceptible organisms. Ticarcillin has been linked with idiosyncratic liver injury, but only rarely and as isolated case reports.

Background

Ticarcillin (tye” kar sil’ in) is a fourth generation, extended-spectrum penicillin antibiotic which was previously used for moderate-to-severe infections caused by susceptible gram positive and gram negative agents. The extended spectrum of ticarcillin made it an appropriate agent in therapy of Pseudomonas aeruginosa. Ticarcillin also has extended activity against some Enterobacter and Proteus species. Ticarcillin has activity against most of the agents that are sensitive to natural penicillins, but is often less active. Ticarcillin is resistant to inactivation by many, but not all beta-lactamases. Ticarcillin was withdrawn from the market in the United States in 2004. Previously it was available in parenteral forms generically and under the name Ticar and is usually given in doses of 200 to 300 mg/kg per day in divided doses intravenously every 4 to 6 hours. Common side effects included nausea, diarrhea, dizziness, headache, rash and hypersensitivity reactions. Rare but potentially severe adverse events included severe hypersensitivity reactions, anaphylaxis and Stevens Johnson syndrome.

Hepatotoxicity

Intravenous ticarcillin therapy has been associated with mild and transient serum aminotransferase elevations that were generally self-limited and only slightly more common with ticarcillin than with comparative antibiotics. Much more commonly reported were instances of anicteric hepatic injury from carbenicillin, a similar carboxypenicillin with extend coverage against Pseudomonas. Persons receiving high doses of intravenous carbenicillin not uncommonly (15% to 30%) developed serum aminotransferase elevations without jaundice, which promptly fell to normal with discontinuation or switching to another antibiotic. Recurrence is common with retreatment using carbenicillin, but not with ticarcillin. A similar phenomenon occurs with intravenous oxacillin. Rare instances of idiosyncratic, clinically apparent cholestatic liver injury have been reported in persons receiving ticarcillin in combination with clavulanate, some of which resemble the rare idiosyncratic reactions that can occur with many penicillins and which resemble the cholestatic liver injury that occurs after amoxicillin/clavulanate.

Likelihood score: D (possible rare cause of clinically apparent liver injury).

Mechanism of Injury

The cause of the idiosyncratic liver injury associated with ticarcillin use was probably hypersensitivity or allergy. No cases of rechallenge or reexposure have been reported.

Outcome and Management

There have been too few cases of ticarcillin related liver injury to assess the prognosis and outcome. Patients with ticarcillin induced hepatitis should avoid reexposure to other penicillins and should take cephalosporins with caution.

References to the safety and potential hepatotoxicity of ticarcillin are provided in the drug record on Ticarcillin-Clavulanate.

Drug Class: Antiinfective Agents, Penicillins (Fourth Generation)

Other Drugs in the Class: Piperacillin, Piperacillin-Tazobactam, Ticarcillin-Clavulanate

CHEMICAL FORMULAS AND STRUCTURES

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Ticarcillin-Clavulanate – LiverTox – NCBI Bookshelf

Last Update: October 20, 2020.

OVERVIEW

Introduction

The combination of ticarcillin and clavulanate provides an extended-spectrum penicillin with a beta-lactamase inhibitor and was previously used to treat serious bacterial infections due to susceptible organisms. Given parenterally, ticarcillin-clavulanate can cause mild transient aminotransferase elevations, and therapy has been linked to instances of acute cholestatic liver disease similar to that described commonly with amoxicillin-clavulanate (Augmentin).

Background

The combination of ticarcillin, a fourth generation penicillin, and clavulanate combines the extended-spectrum of ticarcillin with beta-lactamase inhibitory activity of clavulanic acid. Neither ticarcillin nor ticarcillin-clavulanate are commercially available in the United States, the combination having been withdrawn from the market in 2015. This combination was indicated for serious infections of the lower respiratory tract, urinary tract, bones and joints and skin. The extended-spectrum of ticarcillin made it an appropriate agent in therapy of Pseudomonas aeruginosa. Ticarcillin also has extended activity against some Enterobacter and Proteus. Ticarcillin is poorly absorbed by mouth and requires parenteral administration. The combination of ticarcillin and clavulanate was approved for use in the United States initially in 1985 under the trade name of Timentin. The combination was provided as 3 grams of ticarcillin with 100 mg of clavulanate which was typically given intravenously every 4 to 6 hours for 5 to 14 days. Common side effects of ticarcillin included nausea, epigastric discomfort, diarrhea, headache, dizziness, rash and hypersensitivity reactions. Rare but potentially serious adverse events included anaphylaxis, hypersensitivity syndrome, renal dysfunction and Stevens Johnson syndrome.

Hepatotoxicity

Intravenous therapy with ticarcillin and clavulanate has been associated with elevations in serum aminotransferase levels in up to 10% of patients; however, these abnormalities were usually subclinical and self-limited. More important were rare instances of acute cholestatic liver injury arising several days to several weeks after initiation of ticarcillin-clavulanate. This hepatic injury resembled that caused by amoxicillin-clavulanate and was probably caused by the beta-lactamase inhibitor rather than the ticarcillin. However, too few cases were described in the literature to define the clinical characteristics of the idiosyncratic liver injury.

Likelihood score: D (possible rare cause of clinically apparent liver injury).

Mechanism of Injury

The cause of the liver injury associated with the combination of ticarcillin and clavulanate was probably hypersensitivity to the clavulanic acid. However, the possibility exists that some instances of hepatotoxicity following this combination were due to ticarcillin.

Outcome and Management

In the few cases of cholestatic liver injury following therapy with ticarcillin-clavulanate that have been described, resolution occurred rapidly in one patient whereas the second died of an underlying disease before recovery was complete. Cases of fatalities and chronic cholestasis have been described after amoxicillin-clavulanate therapy which is a much more commonly prescribed combination.

Drug Class: Antiinfective Agents, Penicillins (Fourth Generation)

Other Drugs in the Class: Piperacillin, Piperacillin-Tazobactam, Ticarcillin

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 20 October 2020

• Zimmerman HJ. Penicillins. In, Hepatotoxicity: The Adverse Effects of Drugs and Other Chemicals on the Liver. 2nd Ed. Philadelphia: Lippincott, 1999. p. 595-6.

  (Expert review of penicillins and liver injury published in 1999; piperacillin and ticarcillin are listed as associated with elevations in aminotransferase levels, but without reports of clinically apparent liver injury except with ticarcillin-clavulanate).

• Moseley RH. Hepatotoxicity of antimicrobials and antifungal agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 463-82.

  (Expert review of penicillin induced liver injury mentions that there have been few reports of liver injury due to the extended-spectrum penicillins).

• MacDougall C. Penicillins, cephalosporins, and other β-lactam antibiotics. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1023-38.

  (Textbook of pharmacology and therapeutics).

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  (Early experience in 101 patients with severe infections given im ticarcillin; local pain was common; minimal and transient elevations in ALT occurred in 4 and Alk P in 5 patients).

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  (Among 98 children given ticarcillin iv or im, 3 had AST elevations to 50-81 U/L without jaundice and all values decreased during continued treatment).

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  (Three patients with cystic fibrosis had elevations of ALT levels [to 54, 320 and 445 U/L] during iv carbenicillin therapy, minimally or not at all during subsequent iv ticarcillin therapy).

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  (Analysis of 1148 patients given iv mezlocillin for 1-52 days; 3.7% had hypersensitivity reactions, 0.9% elevations in ALT, AST or Alk P, all were reversible and anicteric. In direct comparison, AST elevations occurred in 1.5% of mezlocillin vs 7.4% of ticarcillin recipients).

• Ramírez-Ronda CH, Gutiérrez J, Bermúdez RH. Comparative effectiveness, safety and tolerance of mezlocillin and ticarcillin: a prospective randomized trial. J Antimicrob Chemother. 1982;9 Suppl A:125–9. [PubMed: 6210660]

  (Randomized clinical trial comparing mezlocillin [n=21] and ticarcillin [n=20]; no ALT elevations mentioned).

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  (Randomized clinical trial of azlocillin vs ticarcillin in 35 patients with urinary tract infections, both were highly effective; no mention of ALT elevations or hepatic injury).

• Jansen W, Schwarz A. Comparative evaluation of netilmicin-ticarcillin and tobramycin-ticarcillin in the treatment of serious systemic infections in elderly patients. Clin Ther. 1984;7:112–20. [PubMed: 6394127]

  (Clinical trial in 60 patients with severe infections treated with ticarcillin combined with an aminoglycoside for 4-12 days; 92% efficacy, oto- and nephrotoxicity was attributed to tobramycin, no mention of hepatotoxicity or ALT elevations).

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  (20 patients with severe infections received iv ticarcillin-clavulanate for 3 to 41 days; ALT elevations occurred in 3, but all were mild and self-limited).

• Cone LA, Woodard DR, Stoltzman DS, Byrd RG. Ceftazidime versus tobramycin-ticarcillin in the treatment of pneumonia and bacteremia. Antimicrob Agents Chemother. 1985;28:33–6. [PMC free article: PMC176304] [PubMed: 3899005]

  (Randomized clinical trial of ceftazidime [n=128] vs tobramycin-ticarcillin [n=131] for severe infections; no mention of ALT elevations).

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  (Description of 43 patients treated with ticarcillin-clavulanate; no mention of ALT elevations or liver toxicity).

• Cox CE. Comparative study of ticarcillin plus clavulanate potassium versus piperacillin in the treatment of hospitalized patients with urinary tract infections. Am J Med. 1985;79:88–90. [PubMed: 4073101]

  (Randomized clinical trial in hospitalized patients; 29% of ticarcillin-clavulanate vs 18% piperacillin recipients had laboratory adverse events, mostly ALT elevations, but specific numbers not given).

• Gebhart RJ, Duma RJ, Patterson PM. Timentin in the treatment of symptomatic complicated urinary tract infections in adult patients. Am J Med. 1985;79:101–5. [PubMed: 3852637]

  (Use of iv ticarcillin-clavulanate in 34 patients with urinary tract infection; adverse events occurred in only one patient, no ALT elevations mentioned).

• Pankey GA, Katner HP, Valainis GT, Clarkson MJ, Cortez LM, Dalovisio JR. Overview of bacterial infections of the skin and soft tissue and clinical experience with ticarcillin plus clavulanate potassium in their treatment. Am J Med. 1985;79:106–15. [PubMed: 4073076]

  (Trial in patients with severe skin infections found ALT elevations in 3 of 19 [16%] patients on ticarcillin-clavulanate, but none of 12 on cefazolin).

• Roselle GA, Bode R, Hamilton B, Bibler M, Sullivan R, Douce R, Staneck JL. Clinical trial of the efficacy and safety of ticarcillin and clavulanic acid. Antimicrob Agents Chemother. 1985;27:291–6. [PMC free article: PMC176263] [PubMed: 3888101]

  (43 patients given ticarcillin-clavulanate; 88% cure, 25% adverse events, but no mention of ALT elevations or liver injury).

• Sanders CV, Marier RL, Aldridge KE, Derks FW, Martin DH. Safety and effectiveness of ticarcillin plus clavulanic acid in the treatment of community-acquired acute pyelonephritis in adult women. Am J Med. 1985;79:96–100. [PubMed: 3907345]

  (Use of ticarcillin-clavulanate had poor efficacy in pyelonephritis and 2 of 19 [10%] patients had AST elevations).

• Ryan J, Dudley FJ. Cholestasis with ticarcillin-potassium clavulanate (Timentin). Med J Aust. 1992;156:291. [PubMed: 1738336]

  (75 year old man developed jaundice 31 days after stopping a 9 day course of ticarcillin-clavulanate [bilirubin 8.1 mg/dL, ALT 448 U/L, Alk P 1330 U/L]; died of progressive lymphoma soon thereafter).

• Sweet JM, Jones MP. Intrahepatic cholestasis due to ticarcillin-clavulanate. Am J Gastroenterol. 1995;90:675–6. [PubMed: 7717345]

  (60 year old woman with neutropenic sepsis developed jaundice with 2 days of starting ticarcillin-clavulanate and gentamicin with bilirubin rising to 33 mg/dL, ALT 142 U/L, Alk P 355 U/L, improving on stopping antibiotics, but temporary worsening with restarting ticarcillin-clavulanate, then resolving in 1 month; the role of sepsis in causing the jaundice is suggested by the very short latency after starting ticarcillin-clavulanate).

• Yellin AE, Johnson J, Higareda I, Congeni BL, Arrieta AC, Fernsler D, West J, et al. Ertapenem or ticarcillin/clavulanate for the treatment of intra-abdominal infections or acute pelvic infections in pediatric patients. Am J Surg. 2007;194:367–74. [PubMed: 17693284]

  (Among 105 children in a controlled trial, ALT elevations occurred in 3% on ertapenem vs 4% on ticarcillin-clavulanate; no details given).

• Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J., Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008;135:1924–34. [PMC free article: PMC3654244] [PubMed: 18955056]

  (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, none were attributed to ticarcillin or piperacillin).

• Devarbhavi H, Dierkhising R, Kremers WK, Sandeep MS, Karanth D, Adarsh CK. Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. Am J Gastroenterol. 2010;105:2396–404. [PubMed: 20648003]

  (313 cases of drug induced liver injury were seen over a 12 year period at a large hospital in Bangalore, India; none were attributed to extended spectrum, 4th generation penicillins).

• Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, Sturkenboom MC. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol. 2010;70:721–8. [PMC free article: PMC2997312] [PubMed: 21039766]

  (Worldwide pharmacovigilance database contained 9036 hepatic adverse drug reactions in children, but ticarcillin and piperacillin were not listed in the top 41 causes).

• Reuben A, Koch DG, Lee WM., Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology. 2010;52:2065–76. [PMC free article: PMC3992250] [PubMed: 20949552]

  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, none of which were attributed to an extended spectrum penicillin).

• Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013;144:1419–25. [PubMed: 23419359]

  (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, including 15 due to amoxicillin-clavulanate, 1 to dicloxacillin [2nd generation] and 1 to phenoxymethylpenicillin [1st generation], the latter two cases being anicteric; none were attributed to a 4th generation penicillin).

• Sistanizad M, Peterson GM. Drug-induced liver injury in the Australian setting. J Clin Pharm Ther. 2013;38:115–20. [PubMed: 23350857]

  (Among 17 persons with suspected drug induced liver injury seen over at 12 month period at a referral hospital in Tasmania, 11 were attributed to antibiotics including 4 to flucloxacillin, 2 amoxicillin with clavulanate, 2 amoxicillin, and 1 each to rifampin, moxifloxacin and ciprofloxacin; none to 4th generation penicillins).

• Devarbhavi H, Andrade RJ. Drug-induced liver injury due to antimicrobials, central nervous system agents, and nonsteroidal anti-inflammatory drugs. Semin Liver Dis. 2014;34:145–61. [PubMed: 24879980]

  (Review of drug induced liver injury from various classes of agents, mentions that amoxicillin-clavulanate is the leading cause of drug induced liver injury, marked by a latency of several days to weeks, often after stopping the antibiotic, the injury varying from cholestatic to hepatocellular and the mortality rate being as high as 7%; no discussion of the 4th generation penicillins).

• Björnsson ES. Epidemiology and risk factors for idiosyncratic drug-induced liver injury. Semin Liver Dis. 2014;34:115–22. [PubMed: 24879977]

  (Estimates of the incidence of drug induced liver injury have ranged from 2 to 19 case per 100,000 inhabitants, probably because of variation in medication use, definitions used and rigor of capturing all patients in a population; in recent studies, amoxicillin-clavulanate has been the most frequently implicated drug).

• Kaye JA, Castellsague J, Bui CL, Calingaert B, McQuay LJ, Riera-Guardia N, Saltus CW, et al. Risk of acute liver injury associated with the use of moxifloxacin and other oral antimicrobials: a retrospective, population-based cohort study. Pharmacotherapy. 2014;34:336–49. [PMC free article: PMC4260122] [PubMed: 24865821]

  (In a US healthcare database with 1.3 million antimicrobial users, there were 607 cases of liver injury and 11 cases of liver failure, the highest relative risk for current single use being 3. 2 for levofloxacin, 2.5 for amoxicillin-clavulanate, 2.5 for doxycycline, 2.3 for moxifloxacin and 2.3 for amoxicillin; no analysis of cases of other penicillins).

• Fontana RJ. Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives. Gastroenterology. 2014;146:914–28. [PMC free article: PMC4031195] [PubMed: 24389305]

  (Review of clinical phenotypes and pathogenesis of different forms of drug induced liver injury including antibiotics and amoxicillin-clavulanate and flucloxacillin, but not of other penicillins).

• Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo Clin Proc. 2014;89:95–106. [PubMed: 24388027]

  (Review of drug induced liver injury mentions that antibiotics are the most common cause and amoxicillin-clavulanate the most common single cause in Europe and the US, accounting for 8-22% of cases; no mention of other penicillins).

• Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A, Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol. 2014;13:231–9. [PubMed: 24552865]

  (Systematic review of literature of drug induced liver injury from Latin American countries published between 1996 and 2012 identified 176 cases, of which 37 [19%] were attributed to antimicrobials, including one to benzathine penicillin and 3 to amoxicillin-clavulanate, but none to 4th generation penicillins such as piperacillin or ticarcillin).

• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology. 2015;148:1340–52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 323 [36%] were attributed to antibiotics of which 106 [12%] were due to penicillins including one to a 1st, three to a 2nd [all due to oxacillin], 97 to a 3rd [91 to amoxicillin-clavulanate, and 6 to amoxicillin alone], and five to a 4th generation penicillin [all 5 to piperacillin-tazobactam]).

• Guéant JL, Romano A, Cornejo-Garcia JA, Oussalah A, Chery C, Blanca-López N, Guéant-Rodriguez RM, et al. HLA-DRA variants predict penicillin allergy in genome-wide fine-mapping genotyping. J Allergy Clin Immunol. 2015;135:253–9. [PubMed: 25224099]

  (In a genome wide association study of 387 patients with immediate allergic reactions to beta-lactam antibiotics, several class 2 HLA associations [HLA-DRA regions] were found for penicillin responses).

• Björnsson ES. Drug-induced liver injury: an overview over the most critical compounds. Arch Toxicol. 2015;89:327–34. [PubMed: 25618544]

  (Review of the most common causes of drug induced liver injury in 3 recent surveys, all of which listed amoxicillin-clavulanate as the most frequent cause; none listed other penicillins).

• Björnsson ES. Hepatotoxicity by drugs: the most common implicated agents. Int J Mol Sci. 2016;17:224. [PMC free article: PMC4783956] [PubMed: 26861310]

  (Review of the most common causes of drug induced liver injury based upon categorization from LiverTox, amoxicillin-clavulanate but no other penicillin was in the top category of causes [likelihood scores of A, with more than 100 cases published in the literature]).

• Faulkner L, Gibson A, Sullivan A, Tailor A, Usui T, Alfirevic A, Pirmohamed M, et al. Detection of primary T cell responses to drugs and chemicals in HLA-typed volunteers: implications for the prediction of drug immunogenicity. Toxicol Sci. 2016;154:416–29. [PubMed: 27637899]

  (Demonstration of T cell priming to drugs linked with specific class I HLA-alleles).

• Nicoletti P, Aithal GP, Bjornsson ES, Andrade RJ, Sawle A, Arrese M, Barnhart HX, et al. International Drug-Induced Liver Injury Consortium, Drug-Induced Liver Injury Network Investigators, and International Serious Adverse Events Consortium. Association of liver injury from specific drugs, or groups of drugs, with polymorphisms in HLA and other genes in a genome-wide association study. Gastroenterology. 2017;152:1078–89. [PMC free article: PMC5367948] [PubMed: 28043905]

  (A genome wide association study done on 862 Caucasian patients with drug induced liver injury demonstrated a strong link with HLA-A*33:01 in those with cholestatic liver injury, particularly in cases attributed to terbinafine, fenofibrate and ticlopidine).

• Blumenthal KG, Youngster I, Rabideau DJ, Parker RA, Manning KS, Walensky RP, Nelson SB. Peripheral blood eosinophilia and hypersensitivity reactions among patients receiving outpatient parenteral antibiotics. J Allergy Clin Immunol. 2015;136:1288–94.e1. [PMC free article: PMC4640981] [PubMed: 25981739]

  (Among 824 patients who underwent outpatient parenteral antibiotic therapy for at least 2 weeks, 210 [25%] developed eosinophilia including 58 of 207 [28%] who received “penicillins” of whom 3 developed signs of “possible” DRESS syndrome; specific penicillins accounting for the cases were not provided).

• Tailor A, Faulkner L, Naisbitt DJ, Park BK. The chemical, genetic and immunological basis of idiosyncratic drug-induced liver injury. Hum Exp Toxicol. 2015;34:1310–7. [PubMed: 26614821]

  (Review of mechanisms of idiosyncratic drug induced liver injury focusing upon chemically reactive drug metabolites and genetic associations, particularly those with HLA alleles that implicate the adaptive immune response).

• Meng X, Earnshaw CJ, Tailor A, Jenkins RE, Waddington JC, Whitaker P, French NS, et al. Amoxicillin and clavulanate form chemically and immunologically distinct multiple haptenic structures in patients. Chem Res Toxicol. 2016;29:1762–72. [PubMed: 27603302]

  (Analysis of amoxicillin and clavulanate adducts produced in vitro and detected in vivo in patients with amoxicillin-clavulanate hepatotoxicity, the adducts were also present in culture median used to detect reactivity of specific T cell clones from patients).

• Takeuchi Y, Shinozaki T, Kumamaru H, Hiramatsu T, Matsuyama Y. Analyzing intent-to-treat and per-protocol effects on safety outcomes using a medical information database: an application to the risk assessment of antibiotic-induced liver injury. Expert Opin Drug Saf. 2018;17:1071–9. [PubMed: 30252549]

  (Cohort matching of cases with vs without antibiotic therapy in a large electronic medical record database from the University of Tokyo Hospital from 2011 to 2015 with adjustments found rates of liver test abnormalities within 30 days of starting penicillins [25. 2 per 1000] was higher than that of fluoroquinolones [11.4] and macrolide antibiotics [8.1] as well as controls [6.5 to 7.1]).

• Cirulli ET, Nicoletti P, Abramson K, Andrade RJ, Bjornsson ES, Chalasani N, Fontana RJ, et al. Drug-Induced Liver Injury Network (DILIN) investigators. International DILI consortium (iDILIC). A missense variant in PTPN22 is a risk factor for drug-induced liver injury. Gastroenterology. 2019;156:1707–16.e2. [PMC free article: PMC6511989] [PubMed: 30664875]

  (Genome wide association studies on 2048 patients with drug induced liver injury and 12,439 controls identified a variant in PTPN22 which was highly associated with liver injury, allele frequency being 0.12 among cases and 0.08 among controls with highest association in Northern Europeans and in cases of amoxicillin clavulanate, PTPN22 being a cellular kinase involved in modulation of immune reactions).

Ticarcillin instructions for use

Pharmacological action
Indications
Contraindications
Side effects
Methods of application and doses
Special instructions

International name

Ticarcillin (Ticarcillin)

Pharmacological action

An antibiotic from the group of carboxypenicillins. It is characterized by a wide spectrum of antimicrobial activity. Active against many gram-positive (non-penicillinase-producing staphylococci, Streptococcus spp., Listeria spp., Peptostreptococcus spp., Clostridium spp.) and gram-negative microorganisms (Pseudomonas aeruginosa, E. coli, Proteus mirabilis, Providencia, Serratia spp., Salmonella, Shigella, Haemophilus influenzae, Neisseriaceae, Bacteroides spp., Fusobacterium spp). There are reports that the activity of ticarcillin against Pseudomonas aeruginosa is 2-4 times higher than the activity of carbenicillin. Ticarcillin is resistant to the action of penicillinase. Like other penicillins, it acts bactericidal, disrupts the synthesis of the cell wall of microorganisms.

Readings

Infections caused by pathogens sensitive to ticarcillin, incl. respiratory tract infections, urinary tract infections, skin and soft tissue infections, abdominal infections, pelvic infections, sepsis.

Contraindications

Hypersensitivity to ticarcillin and other penicillins.

Side effects

Possible allergic reactions, nausea, vomiting, anemia, thrombocytopenia, leukopenia, neutropenia, eosinophilia, increased prothrombin time and bleeding time, hypokalemia. Pain in the injection area, rarely – phlebitis. In some cases, an increase in the level of hepatic transaminases. In patients with impaired renal function, especially when using large doses of ticarcillin, increased neuromuscular excitability and convulsions are possible.

Dosage and administration

Doses of ticarcillin are set individually, taking into account the severity of the course of the disease and the localization of the infection, the sensitivity of the pathogen. Ticarcillin is usually given intravenously. In the treatment of most infections, the average dose for adults and children is 200-300 mg / kg every 4-6 hours, in the treatment of urinary tract infections 50-200 mg / kg every 4-8 hours.

Special instructions

Use with caution in patients with severe liver failure, with bronchial asthma, severe cardiovascular diseases, colitis. When taking ticarcillin in patients with impaired renal function, it is necessary to reduce the dose depending on the CC values. During treatment with ticarcillin, regular monitoring of the state of the blood coagulation system, peripheral blood patterns, liver function, and electrolyte composition of the blood is necessary. During pregnancy, ticarcillin is used only under strict indications. When ticarcillin is used simultaneously with oral contraceptives, the effect of the latter decreases. Due to the fact that ticarcillin is unstable to the action of penicillinase, in medical practice it is usually used in conjunction with substances that inhibit this enzyme (with clavulanic acid).

See also in the pharmaceutical guide:
Surgam nokte (Thiaprofenic acid)
Timentin (Ticarcillin + Clavulanic acid)

Interaction

Absent.

Prepared by: Ravodin Roman Anatolyevich, dermatovenereologist, dermatooncologist, dermatocosmetologist. Doctor of Medical Sciences, Associate Professor

Consult your doctor about possible contraindications

instructions for use, analogues, articles0001 Main page

Ticarcillin + [Clavulanic acid]

List of trade names

Combination drug, the action of which is due to the components that make up its composition. Ticarcillin is an antibacterial agent from the group of penicillins with a wide spectrum of action. Clavulanic acid is a beta-lactamase inhibitor. Due to its presence, the drug is active against most gram-positive microorganisms that produce and do not produce beta-lactamase: Staphylococcus aureus, Staphylococcus epidermidis; Staphylococcus saprophyticus; Streptococcus pneumoniae; Streptococcus bovis; Streptococcus faecalis; Streptococcus pyogenes; Streptococcus viridans; gram-negative microorganisms producing and non-producing beta-lactamase: Pseudomonas aeruginosa, other species of Pseudomonas, Escherichia coli; Proteus mirabilis; Proteus vulgaris; Providencia rettgeri; Providencia stuartii; Morganella morganii; some types of Enterobacter; Acinetobacter; Serratia; Moraxella catarrhalis (Branhamella), Neisseria gonorrhoeae; Neisseria meningitidis; some strains of Salmonella; Klebsiella, including Klebsiella pneumoniae; Citrobacter spp.; haemophilus influenzae; anaerobic microorganisms: Bacteroides spp. , including Bacteroides fragilis; some species of Clostridium spp., incl. Clostridium perfringens, Clostridium difficile, Clostridium sporogenes; Eubacter spp.; Fusobacterium spp.; Peptostreptococcus spp.

Pharmacokinetics

After an intravenous infusion of 30 minutes at a dose of 3.1 g, Cmax of ticarcillin – 330 μg / ml, clavulanic acid – 8 μg / ml. Ticarcillin penetrates into bile, pleural effusion, traces are found in tissues and interstitial fluid. Communication with plasma proteins of ticarcillin – 45%, clavulanic acid – 9%. Mean concentrations of ticarcillin and clavulanic acid are 324 and 8 µg/ml, AUC is 485 and 8.2 µg/ml/h, respectively. Excreted by the kidneys unchanged: within 6 hours 60-70% ticarcillin and 35-45% clavulanic acid. 2 hours after intravenous administration of 3.1 g, the concentration of ticarcillin in the urine is 1.5 mg / ml, clavulanic acid is 40 μg / ml; after 4-6 hours – 190 and 2 µg/ml, respectively. In children, after administration at a dose of 50 mg / kg, T1 / 2 of ticarcillin is 4. 4 hours in newborns and 1 hour in other children, T1 / 2 of clavulanic acid is 1.9 and 0.9 hours, respectively.

Bronchitis;
pneumonia;
urinary tract infections;
abdominal infections;
Mixed infections,
empiric therapy until the pathogen is identified.

Hypersensitivity (including to beta-lactam antibiotics), premature babies with impaired renal function.
With care. Severe liver dysfunction, pregnancy, lactation.

In / in, adults weighing more than 60 kg – 3.1 g 4-6 times a day, weighing less than 60 kg – 200-300 mg / kg / day, divided into 4-6 doses.
For infections of the pelvic organs of moderate severity – 200 mg / kg 4 times a day; in severe cases – 300 mg / kg 6 times a day. In patients with impaired renal function, the first dose is 3.1 g. Further, the dosing regimen is set depending on the CC: with CC more than 60 ml / min – 3.1 g 6 times a day, 30-60 ml / min – 2 g 6 times a day day; 10-30 ml / min – 2 g 3 times a day; with CC less than 10 ml / min – 2 g 2 times a day; with CC less than 10 ml / min and concomitant liver dysfunction – 2 g 1 time per day. Patients on hemodialysis – 2 g 2 times a day, with the addition of 3.1 g after each hemodialysis procedure. Patients on peritoneal hemodialysis – 3.1 g 2 times a day. The course of treatment is 10-14 days; in severe cases, it can be increased. Therapy is stopped 2 days after the disappearance of the symptoms of the disease. For children older than 3 months weighing less than 60 kg, a single dose is 50 mg / kg. For infections of mild and moderate severity – 200 mg / day, divided into 4 doses, for severe infections – 300 mg / kg / day, divided into 6 doses. For children weighing more than 60 kg – 3.1 g every 6 hours, for severe infections – 3.1 g every 4 hours.
To prepare a solution: for intravenous jet administration, add 13 ml of sterile water for injection or 0.9% NaCl solution to a vial (3.1 g), shake vigorously until completely dissolved; for intravenous drip, a 5% dextrose solution or a 0.9% NaCl solution is added to the pre-dissolved drug to obtain a solution with a concentration of 10 to 100 mg / ml. The color of the finished solution varies from pale to dark yellow, depending on the concentration, storage time and temperature.

Headache, dizziness, irritability, convulsions, taste and smell disturbances, nausea, vomiting, diarrhea, flatulence, abdominal pain; increased activity of “liver” transaminases, hepatitis, cholestatic jaundice, rarely – pseudomembranous enterocolitis; hypernatremia, hypokalemia, hypercreatininemia and increased uric acid concentration in the blood, thrombocytopenia, leukopenia, neutropenia, eosinophilia, anemia, increased prothrombin time and bleeding time, arthralgia, myalgia, skin rash, itching, urticaria, anaphylactic reactions, pain, burning, swelling and induration at the injection site, thrombophlebitis, chills, fever.
Overdose. Symptoms: increased neuromuscular excitability, convulsions.
Treatment: drug withdrawal, symptomatic therapy, hemodialysis.

Drugs that block tubular secretion slow down the excretion of ticarcillin and increase its concentration in the blood.