Ticarcillin–Clavulanic Acid: Clinical Uses and Toxicity

Since its introduction for clinical use, ticarcillin–clavulanate has been used for a variety of clinical infections because of its broad spectrum of antibiotic activity (Kosmidis, 1986).

CLINICAL USES OF THE DRUG

7a. Respiratory tract infections

Ticarcillin–clavulanate has proven efficacy in treating respiratory tract infections, particularly nosocomial pneumonia (Brittain et al., 1985; Finegold and Johnson, 1985; Link, 1985; Mostow and O’Brien, 1985; Schwigon et al., 1986; Ramirez, 1994). It covers most Gram-positive, Gram-negative, and anaerobic bacteria that commonly cause this condition. It cannot, however, be relied upon where Pseudomonas or methicillin-resistant S. aureus are the suspected pathogens. The local incidence of Gram-negative bacteria with chromosomal class C betalactamases should also be considered as these bacteria may not be adequately treated by this drug. In an environment with a high prevalence of ESBL-producing bacteria, ticarcillin–clavulanate may also not be adequate as empiric therapy. Surveillance studies in Canada showed that ticarcillin–clavulanate had activity against W92% of 1982 respiratory isolates (Blondeau et al., 1999).
For community-acquired respiratory tract infections, ticarcillin– clavulanate has been compared with piperacillin–tazobactam in a randomized trial of 299 patients. Outcomes favored piperacillin– tazobactam, with a clinical response in 84% of the piperacillin– tazobactam group compared with 64% in the ticarcillin–clavulanate group (p = 0.02). The inferior activity of ticarcillin–clavulanate against some pneumococcal strains may be a factor in these results. Adverse events, however, were more common in the piperacillin–tazobactam group (31.6% vs 20.5%); predominantly gastrointestinal disturbances (Shlaes et al., 1994).

b. Intra-abdominal infections

Ticarcillin–clavulanate is appropriate therapy for peritonitis due to most surgical problems, such as perforated viscus, intra-abdominal abscesses, and penetrating abdominal wounds (Fabian and Boldreghini, 1985; Fink et al., 1989; Inthorn et al., 1989; Fink, 1991; Wilson and Nord, 1995). These infections are often polymicrobial and involve Gram-negative Enterobacteriaceae and anaerobes. Ticarcillin–clavulanate may be preferable to combination drug regimens (e.g. ampicillin plus gentamicin plus metronidazole) where there are concerns about potential aminoglycoside toxicity over long periods of therapy. 

c. Skin and soft tissue infection

Ticarcillin–clavulanate has a role in treating skin and soft tissue infection where polymicrobial infection is likely, for example in the chronic infections associated with pressure ulcers or ulcers in diabetic patients (LeFrock et al., 1985; Pankey et al., 1985; Rao et al., 1985; File and Tan, 1991a; File and Tan, 1991b; Pankey, 1991). Caution is required if P. aeruginosa or methicillin-resistant S. aureus is identified in the ulcer, as the drug’s activity against these bacteria is unreliable. Ticarcillin–clavulanate has been compared with piperacillin–tazobactam for skin and soft tissue infections in a randomized double-blinded controlled trial involving 20 hospitals – 153 patients were given piperacillin-tazobactam, whereas 98 received ticarcillin–clavulanate. 

d. Urinary tract infections

Ticarcillin–clavulanate demonstrated efficacy against W90% of 1921 isolates from urinary tract infections in Canada in the 1990s (Blondeau et al., 1999). It has shown efficacy in clinical use for complicated urinary tract infections in several small early studies (Cox, 1985; File et al., 1985; Sanders et al., 1985; Cox, 1986; Stapleton, 2002). A recent study from the USA described the antibiotic sensitivity profiles of 705 bacterial pathogens isolated from urinary tract infections in children and found that 94.2% were susceptible to ticarcillin–clavulanate (Bonsu et al., 2006); however, resistance rates vary in different regions.

e. Gynecologic infections

Ticarcillin–clavulanate has been used widely in the management of post-partum endometritis and other pelvic infections associated with gynecologic disorders (Apuzzio et al., 1985; Pastorek et al., 1985; Faro, 1988; Faro et al., 1988; Holloway, 1988; Sanders et al., 1988b; Faro, 1990; Lucas et al., 1990; Pastorek, 1990; Faro et al., 1991). It has been used to manage preterm rupture of membranes in a trial of 1695 women, when ticarcillin–clavulanate followed by amoxicillin– clavulanate was compared with no antibiotics, or ampicillin followed by amoxicillin.

f. Febrile neutropenia

Ticarcillin–clavulanate has been a recommended option for empiric treatment of febrile neutropenic patients in many guidelines, often accompanied by an aminoglycoside (Klastersky et al., 1975; Love et al., 1979; Klastersky et al., 1986; Klastersky et al., 1988; Sage et al., 1988). Examples of early reports of the use of ticarcillin–clavulnate accompanied by an aminoglycoside in febrile neutropenia described an 87% success rate in 33 children (Schaison et al., 1986) and 87% success rate of ticarcillin–clavulanate (at 5.2 g 8-hourly) plus tobramycin in 51 adults (Krieger et al., 1986). An 88% cure rate for ticarcillin–clavulanate plus gentamicin was reported in 95 episodes of febrile neutropenia in children (Yu et al., 1994), but a poorer response was reported by a separate group using the same combination in 75 episodes of febrile neutropenia in children (65% clinical success) (Bolton-Maggs et al., 1991).

g. Meningitis

Beta-lactam/beta-lactamase inhibitor combinations are generally not recommended for treating infections of the central nervous system. In vitro data regarding poor efficacy of ticarcillin–clavulanate against penicillin-resistant pneumococci mean that its use is not supported for empiric therapy for bacterial meningitis. For treatment of specific pathogens in CNS infection, ticarcillin–clavulanate is generally not recommended as penetration of these drugs into the cerebrospinal fluid is limited.

h. Endocarditis

Overall, there are only limited data regarding the use of ticarcillin– clavulanate for endocarditis. The efficacy of ticarcillin–clavulanate for treatment of S. aureus endocarditis has been evaluated and compared against flucloxacillin, oxacillin, naficillin, and vancomycin in an experimental rat model. Interestingly, ticarcillin–clavulanate was found to be as effective as the more traditional antistaphylococcal drugs, and was more effective than vancomycin in this model (Catherall et al., 1992).

i. Bone and joint

A study assessing the efficacy of ticarcillin–clavulanate for a wide range of bone, joint, and soft tissue infections, many of which were in patients with diabetes and/or peripheral vascular disease, reported a clinical success rate of 92% and microbiologic eradication rate of 93% in the 66 evaluable patients (Johnson et al., 1985). Other case series have reported the successful use of ticarcillin–clavulanate for bone and joint infections (Siebert and Kopp, 1985).

j. Burns

Reports of small case series of burns patients with septicemia reported satisfactory outcomes using a high dose of ticarcillin–clavulanate (5.2 g three times daily) with only three clinical failures in which either methicillin-resistant S. aureus or P. aeruginosa were identified (Diem and Graninger, 1986).

k. Ear, nose, and throat infections

Ticarcillin–clavulante has been described as a therapeutic option for patients with ear, nose, and throat infections due to its broad spectrum of activity and particular efficacy against anaerobes (Federspil et al., 1989).

l. Surgical antibiotic prophylaxis

Ticarcillin–clavulanate has been suggested as an option for prophylaxis in the perioperative period for a variety of surgical procedures, as it carries the advantage of providing broad-spectrum antimicrobial cover with single-drug therapy. It has been evaluated for intra-abdominal surgery, particularly elective colorectal surgery.

Ticarcillin–clavulanate has been used for prophylaxis for clean thoracic and vascular surgery, with similar efficacy to cefamandole (Kitzis et al., 1986). It has been described as a suitable agent for antibiotic prophylaxis for tonsillectomy, proving better than placebo in terms of postoperative symptoms (Grandis et al., 1992) and has been used for prophylaxis for gynecologic surgery, in which it was associated with similar outcomes in terms of postoperative wound infection rates as cefoxitin (Saltzman et al., 1985).

TOXICITY

a. Hypersensitivity and rashes

Ticarcillin is contraindicated in patients with a history of hypersensitivity to penicillins. It can cause anaphylaxis, rash, eosinophilia, and drug fevers. Interstitial nephritis leading to renal failure has also been reported (Ervin and Bullock, 1976; Parry and Neu, 1976; Lang et al., 1991). Desensitization protocols for ticarcillin–clavulanate have been described (Brown et al., 1982; McIntire and Castano, 1994).

As a presentation of hypersensitivity, ticarcillin can cause skin problems such as erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, urticaria, and itch.

b. Neurotoxicity

Very high doses of ticarcillin can cause neurotoxicity, similar to that seen with high-dose penicillin (Kallay et al., 1979; Neu, 1979). This may manifest as drowsiness, confusion, or seizures. It has been suggested that this phenomenon may be more likely in patients who are uremic or have underlying central nervous system disease.

c. Electrolyte disturbances

Every 3.1-g dose of ticarcillin–clavulanate contains 14 mEq of sodium (Hart and Bailey, 1996). A typical daily dose, therefore, provides around 2 g of sodium. This has the potential to lead to clinical problems with hypernatremia and subsequent fluid retention and pulmonary edema. Some patients may also develop hypokalemia and metabolic alkalosis as a consequence of the sodium load administration (Moody and Pawlicki, 1987). These problems are most likely to be clinically evident in patients with cardiac failure and/or renal impairment (Schimpff et al., 1976; Parry et al., 1977).

d. Gastrointestinal side-effects

Nausea, vomiting, and/or diarrhea can occur with administration of ticarcillin–clavulanate. Changes to gastrointestinal flora, particularly overgrowth of yeast colonizers, have also been reported (Samonis et al., 1993).

e. Hematologic toxicity and bleeding disorders

Bleeding disorders are a significant concern with ticarcillin use. All penicillins can affect platelet function, but ticarcillin has the most severe effect. This potential toxicity was reported soon after the introduction of ticarcillin–clavulnate for clinical use (Tasker et al., 1986). This effect is thought to be due to changes to the ADP receptors in the platelet membrane that leaves them unavailable for agonists to induce aggregation (Ferres and Nunn, 1983).

f. Hepatotoxicity

Cholestasis has been reported with ticarcillin–clavulanate use (Ryan and Dudley, 1992; Sweet and Jones, 1995), although the degree of hepatotoxicity with ticarcillin is thought to be lower than that associated with carbenicillin (Graft and Chesney, 1982).

g. Possible role in selection of vancomycin-resistant enterococci

In a mouse model, vancomycin-resistant enterococci (VRE) were more likely to be isolated after treatment with ticarcillin–clavulanate than with piperacillin-tazobactam or with a cephalopsorin (Donskey et al., 2000). Some authors have also reported a reduction in VRE acquisition after a change in hospital policy directing clinicians away from ticarcillin use and replacing it with piperacillin (Winston et al., 2004), but this observation and attribution have been challenged (Stiefel et al., 2004).

h. Use in pregnancy

Ticarcillin–clavulanate is in category B for use in pregnant women. No human studies are available regarding safety in pregnancy, but there is no evidence of teratogenicity in animal studies. Transfer across the placenta is thought to be low (Fortunato et al., 1992). Both ticarcillin and clavulanic acid enter breast milk.

References

Fleming DR, Ziegler C, Baize T et al. (2003). Cefepime versus ticarcillin and clavulanate potassium and aztreonam for febrile neutropenia therapy in high-dose chemotherapy patients. Am J Clin Oncol 26: 285.
Fortunato SJ, Bawdon RE, Swan KF et al. (1992). Transfer of Timentin (ticarcillin and clavulanic acid) across the in vitro perfused human placenta: Comparison with other agents. Am J Obstet Gynecol 167: 1595.
Franz P, von Rosen F, Garner C et al. (1989). Cerebrospinal fluid penetration after single or multiple dosage with ticarcillin/clavulanate. J Antimicrob Chemother 24 (Suppl. B): 107.
Fricke G, Doerck M, Hafner D et al. (1989). The pharmacokinetics of ticarcillin/ clavulanate acid in neonates. J Antimicrob Chemother 24 (Suppl. B): 111.
Fuchs PC, Barry AL, Thornsberry C, Jones RN (1984). In vitro activity of ticarcillin plus clavulanic acid against 632 clinical isolates. Antimicrob Agents Chemother 25: 392.
Garratty G, Arndt PA (1998). Positive direct antiglobulin tests and haemolytic anaemia following therapy with beta-lactamase inhibitor containing drugs may be associated with nonimmunologic adsorption of protein onto red blood cells. Br J Haematol 100: 777.
Gastineau D, Spector R, Philips D (1981). Severe neutropenia associated with ticarcillin therapy. Ann Intern Med 94: 711.
Gilbert DN, Lee BL, Dworkin RJ et al. (1998). A randomized comparison of the safety and efficacy of once-daily gentamicin or thrice-daily gentamicin in combination with ticarcillin-clavulanate. Am J Med 105: 182.
Graft DF, Chesney PJ (1982). Use of ticarcillin following carbenicillin-associated hepatotoxicity. J Pediatr 100: 497.
Graham DR, Talan DA, Nichols RL et al. (2002). Once-daily, high-dose levofloxacin versus ticarcillin-clavulanate alone or followed by amoxicillinclavulanate for complicated skin and skin-structure infections: A randomized, open-label trial. Clin Infect Dis 35: 381.
Hoffken G, Tetzel H, Koeppe P, Lode H (1985). Pharmacokinetics and serum bactericidal activity of ticarcillin and clavulanic acid. J Antimicrob Chemother 16: 763. Holland DJ, Chen SC, Chew WW, Gilbert GL (1994). Mycobacterium neoaurum infection of a Hickman catheter in an immunosuppressed patient. Clin Infect Dis 18: 1002.
Holloway WJ (1988). Infection in women. Clinical experience with betalactamase inhibitors. J Reprod Med 33: 595. Inthorn D, Muhlbayer D, Hartl WH (1989). Ticarcillin/clavulanate in the treatment of severe peritonitis. J Antimicrob Chemother 24 (Suppl. B): 141.
Jackson MA, Kusmiesz H, Shelton S et al. (1986). Comparison of piperacillin vs. ticarcillin plus tobramycin in the treatment of acute pulmonary exacerbations of cystic fibrosis. Pediatr Infect Dis 5: 440.
Jacobs MR, Aronoff SC, Johenning S et al. (1986a). Comparative activities of the beta-lactamase inhibitors YTR 830, clavulanate, and sulbactam combined with ampicillin and broad-spectrum penicillins against defined beta-lactamase-producing aerobic gram-negative bacilli. Antimicrob Agents Chemother 29: 980.
Kosmidis J (1986). Ticarcillin and clavulanic acid in serious infections. J Antimicrob Chemother 17 (Suppl. C): 169.
Krieger O, Bernhart M, Plohowich R et al. (1986). Timentin in combination with tobramycin as empirical therapy in febrile neutropenic patients with haematological malignancies. J Antimicrob Chemother 17 (Suppl. C): 211.
Lang R, Lishner M, Ravid M (1991). Adverse reactions to prolonged treatment with high doses of carbenicillin and ureidopenicillins. Rev Infect Dis 13: 68.
Leclercq R, Duval J (1995). [Bactericidal activity of combinations of ticarcillinclavulanic acid or other beta-lactams (amoxicillin, piperacillin-tazobactam, ticarcillin) with gentamicin against Enterococcus faecalis and E faecium]. Pathol Biol (Paris) 43: 245.
LeFrock JL, Johnson ES, Smith LG, Rosenberg E (1985). Noncomparative trial of ticarcillin plus clavulanic acid in skin and soft tissue infections. Am J Med 79: 122.