Parenteral beta-lactamase inhibitor combinations for clinical use

Author: John P. Manzella
Date: May 15, 1995

Beta-lactamase enzymes are commonly produced by staphylococci, the Enterobacteriaceae, Pseudomonas aeruginosa and certain anaerobic organisms, such as Bacteroides. fragilis The production of beta lactamases is an important mechanism through which bacteria become resistant to antibiotics. The currently marketed betalactamase inhibitor combinations include ampicillin-sulbactam, ticarcillin-clavulanate potassium and, more recently, piperacillin-tazobactam. These extended spectrum antibiotic combinations share the ability to inhibit methicillin-susceptible staphylococci, nearly all anaerobic bacteria and many Enterobacteriaceae. Ticarcillin-clavulanate potassium and piperacillin-tazobactam also have activity against P. aeruginosa. The combination agents are useful in the treatment of moderate to severe infections, particularly when a polymicrobial etiology is suspected or documented.

The resistance of bacteria to beta lactam antibiotics has been an increasingly important problem over the past several decades. The problem is significant because bacteria possess virtually unlimited survival capability under adverse conditions. Several mechanisms of bacterial resistance to antibiotics have been described, with one of the major mechanisms being the production of beta-lactamase enzymes.

A solution to the growing problem of resistance is the development of beta-lactamase inhibitors. These agents irreversibly bind to the beta-lactamase enzyme, preventing enzymatic opening of the beta-lactam ring of antibiotics.[1] Clavulanate potassium, sulbactam and tazobactam are beta-lactamase inhibitors that have been combined with beta-lactam antibiotics (Table 1).

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Chemistry and Mechanism of Action

All of the currently marketed beta-lactamase inhibitors are combined with a betalactam antibiotic. The three currently available compounds are ampicilin-sulbactam (Unasyn), ticarcillin-clavulanate potassium (Timentin) and, most recently, piperacillin-tazobactam (Zosyn).[2-4] Clavulanic acid, a clavam, is a natural product isolated from Streptomyces clavuligerus. Sulbactam and tazobactam are penicillanic acid sulfones.

Each of the "parent" beta-lactam compounds (i.e., ampicillin) works by inhibiting cell-wall synthesis. Beta-lactamase inhibitors are, themselves, beta-lactam antibiotics. However, instead of being hydrolyzed by beta lactamases, they incapacitate beta lactamases by irreversibly binding to the enzymes. Beta-lactamase inhibitors are capable of rendering highly resistant bacteria susceptible to a wide range of beta-lactam agents. However, these inhibitors will work only if the beta-lactamase enzyme is present. They will not alter resistance patterns when other factors cause resistance - for example, the alteration in penicillin binding seen with methicillin-resistant staphylococci. Unfortunately, not all of the beta lactamases produced by gram-negative bacteria are inhibited by these compounds.

In Vitro Antibacterial Activity

AMPICILLIN-SULBACTAM

Ampicillin-sulbactam extends the spectrum of ampicillin to include methicillin-sensitive Staphylococcus aureus, group A and group B streptococci, pneumococci, enterococci, beta-lactamase-producing strains of Haemophilus influenzae, Moraxella catarrhalis and Neisseria gonorrhoeae, and many Klebsiella and Proteus organisms. Ampicillin-sulbactam does not improve the activity of ampicillin against Escherichia coli (70 to 80 percent of strains are susceptible). Most anaerobic organisms, including Bacteroides fragilis, are also sensitive to ampicillin-sulbactam.[2]

TICARCILLIN-CLAVULANATE POTASSIUM

Ticarcillin by itself is active in vitro against a broad spectrum of pathogenic bacteria, including group A and group B streptococci, pneumococi, strains of S. aureus, gonococci and H. influenzae that do not produce beta lactamase, many enteric gram-negative bacilli, Pseudomonas aeruginosa and many anaerobes. When clavulanate potassium is added to ticarcillin, a striking increase occurs in activity against beta-lactamase-producing strains of S. aureus, N. gonorhoeae, E. coli, Klebsiella organisms and B. fragilis. Strains of P. aeruginosa that are resistant to ticarcillin are usually also resistant to ticarcillin-clavulanate potassium. Enterococci are moderately resistant, and methicillin-resistant staphylococci are resistant to ticarcillin-clavulanate potassium.[3]

PIPERACILLIN-TAZOBACTAM

Piperacillin alone is active against most streptococci (including the viridans group, group A and group B streptococci, pneumococci and enterococci), most gram-negative organisms in the Enterobacteriaceae group and most strains of P. aeruginosa. Adding tazobactam to piperacillin extends its spectrum to include S. aureus and a variety of anaerobes and gram-negative bacteria, including some third-generation cephalosporin-resistant strains of Klebsiella pneumoniae. Methicillin-resistant staphylococci and highly penicillin-resistant enterococci are resistant to piperacillin-tazobactam.

The combination of piperacillin and tazobactam does not have any more activity against P. aeruginosa than piperacillin alone. Neither piperacillin nor piperacillin-tazobactam is active against gram-negative bacilli that have chromosomally mediated beta-lactamase enzymes, including some Pseudomonas strains and other gram-negative bacilli that are commonly associated with hospital-acquired infections.[4] This same limitation applies to all of the beta-lactam/ beta-lactamase combination agents. In a comparative in vitro study, routine gram-negative clinical isolates were generally found to be more susceptible to piperacillin-tazobactam than to ticarcillin-clavulanate potassium.[5]

Clinical Studies

The U.S. Food and Drug Administration has approved the use of ampicillin-sulbactam in skin, intra-abdominal and gynecologic infections,[2] and ticarcillin-clavulanate potassium in urinary tract infections, skin and soft tissue infections, lower respiratory tract infections and sepsis due to susceptible organisms.[3] Piperacillin-tazobactam has been approved for intravenous treatment of intra-abdominal, pelvic, skin and skin-structure infections, and for community-acquired pneumonia of moderate severity.[4] The infections for which all of these agents may be particularly useful are those in which a polymicrobial etiology is common, such as diabetic foot infections and intra-abdominal and pelvic infections.

In the treatment of pelvic and intra-abdominal infections, ampicillin-sulbactam has been compared with a variety of regimens, including cefoxitin (Mefoxin) alone and metronidazole (Flagyl) plus gentamicin (Garamycin).[6-8] Cure rates with ampicillin-sulbactam were comparable to cure rates achieved with the other regimens, with a trend toward a more favorable response in patients receiving ampicillin-sulbactam compared with patients receiving cefoxitin.

In the treatment of soft tissue infections, ampicillin-sulbactam has been compared with the combination of clindamycin (Cleocin) and tobramycin (Nebcin).[9] Patient groups were similar with regard to age, sex, associated medical problems and bacteriologic flora of wounds. Treatment with ampicillin-sulbactam led to a 93 percent cure rate or improvement, compared with a rate of 81 percent in the clindamycin-tobramycin group. Eradication of organisms was better in the ampicillin-sulbactam group (67 percent versus 35 percent).

In another study, ampicillin-sulbactam was compared with imipenem-cilastatin (Primaxin) in the treatment of limb-threatening foot infections in 92 diabetic patients.[10] At the end of definitive treatment, outcomes were similar in the two treatment groups, with a cure rate of 81 percent for patients treated with ampicillin-sulbactam and a rate of 85 percent for patients treated with imipenem-cilastatin.

In a review[11] of six controlled clinical trials of ticarcillin-clavulanate potassium for the treatment of 189 skin infections, the overall satisfactory clinical response was found to be 93 percent. Bacteriologic response included eradication of S. aureus (58 percent of cases), Enterococcus species (75 percent), Enterobacteriaceae (88 percent) and P. aeruginosa (77 percent).

Ticarcillin-clavulanate potassium has also been compared with cefoxitin or clindamycin-gentamicin in the treatment of postpartum endometritis.[12,13] In general, clinical outcomes were similar. In another study[14] that compared clindamycin and gentamicin with ticarcillin-clavulanate potassium in 99 consecutive patients with complicated appendicitis, clinical response rates and complications were found to be comparable.

The efficacy of piperacillin-tazobactam was compared with that of ticarcillin-clavulanate potassium in the treatment of complicated bacterial infections of the skin that required hospitalization.[15] Clinical response rates were comparable for the two regimens.

Piperacillin-tazobactam has been reported to be more effective than imipenemcilastatin in the treatment of intra-abdominal infection,[16,17] with significantly more relapses and failures occurring in the imipenem-cilastatin group than in the group receiving piperacillin-tazobactam. Although piperacillin-tazobactam has generally been shown to be effective in treating lower respiratory tract infections, it has not been effective when used alone in patients with nosocomial P. aeruginosa pneumonia.[4]

Dosage

The recommended adult dosage of ampicillin-sulbactam is 1.5 g (1 g of ampicillin plus 0.5 g of sulbactam) to 3 g (2 g of ampicillin plus 1 g of sulbactam) every six hours.[2] Ticarcillin-clavulanate potassium is available as 3 g of ticarcillin with either 0.1 or 0.2 g of clavulanic acid. The usual dosage is 3 g of ticarcillin and 0.1 g of clavulanic acid every four to six hours.[3]

The recommended adult dosage of piperacillin-tazobactam is 3 g of piperacillin plus 375 mg of tazobactam every six hours.[4] The dosage of piperacillin in this combination is lower than the dosage recommended when piperacillin is used alone in the treatment of serious infections (18 g per day), particularly those due to P. aeruginosa. The usual dosage for each of these antibiotics is reduced in patients with renal insufficiency. Dosage guidelines for patients with renal insufficiency, including those requiring hemodialysis, are included in the package inserts of these agents.

Adverse Reactions and Safety Profile

The toxicity of each of these compounds appears to be similar to that of other betalactam antibiotics.[2-4] The two most frequent adverse reactions with each of these antibiotics are diarrhea and skin rash. Patients who are allergic to penicillin should not receive any of these agents. Ticarcillin-clavulanate potassium contains more sodium per gram than either piperacillin-tazobactam or ampicillin-sulbactam. Both piperacillin-tazobactam and ticarcillin-clavulanate potassium have been associated with an increased incidence of hypokalemia. Like any of the other beta-lactam antibiotics, these agents have, on occasion, been associated with mild, reversible laboratory abnormalities, such as eosinophilia, increased transaminase levels, leukopenia, thrombocytopenia and anemia.

REFERENCES

[1.] Bush K. Beta-lactamase inhibitors from laboratory to clinic. Clin Microbiol Rev 1988;1:109-23. [2.] Ampicillin/sulbactam (Unasyn). Med Lett Drugs Ther 1987;29(747):79-81. [3.] Ticarcillin-clavulanic acid (Timentin). Med Lett Drugs Ther 1985;27(694):69-70. [4.] Piperacillin/tazobactam. Med Lett Drugs Ther 1994;36(914):7-9 [Published erratum appears in Med Lett Drugs Ther 1994;36(921):40]. [5.] Fass RJ, Prior RB. Comparative in vitro activities of piperacillin-tazobactam and ticarcillin-clavulanate. Antimicrob Agents Chemother 1989;33:1268-74. [6.] Crombleholme WR, Ohm-Smith M, Robbie MO, Dekay V, Sweet RL. Ampicillin/sulbactam versus metronidazole-gentamicin in the treatment of soft tissue pelvic infections. Am J Obstet Gynecol 1987; 156:507-12. [7.] Senft HH, Stiglmayer R, Eibach HW, Koerner H. Sulbactam/ampicillin versus cefoxitin in the treatment of obstetric and gynaecological infections. Drugs 1986;31(Suppl 2):18-21. [8.] Nichols RL. The treatment of intraabdominal infections in surgery. Diagn Microbiol Infect Dis 1989; 12(Suppl 4):195-9. [9.] Stromberg BV, Reines HD, Hunt P. Comparative clinical study of sulbactam and ampicillin and clindamycin and tobramycin in infections of soft tissues. Surg Gynecol Obstet 1986;162:575-8. [10.] Grayson ML, Gibbons GW, Habershaw GM, Freeman DV, Pomposelli FB, Rosenblum BI, et al. Use of ampicillin/sulbactam versus imipenem/ cilastatin in the treatment of limb-threatening foot infections in diabetic patients. Clin Infect Dis 1994;18:683-93. [11.] File TM Jr, Tan JS. Ticarcillin-clavulanate therapy for bacterial skin and soft tissue infections. Rev Infect Dis 1991;13(Suppl 9):733-6. [12.] Pastorek JG Jr, Aldridge KE, Cunningham GL, Faro S, Graffeo S, McNeeley GS, et al. Comparison of ticarcillin plus clavulanic acid with cefoxitin in the treatment of female pelvic infection. Am J Med 1985;79:161-3. [13.] Apuzzio JJ, Ganesh V, Kaminski Z, Bergen B, Holland B, Louria DB. Comparision of ticarcillin plus clavulanic acid with clindamycin and gentamicin in the treatment of postcesarean endomyometritis. Surg Gynecol Obstet 1988;166:413-7. [14.] Sirinek KR, Levine BA. A randomized trial of ticarcillin and clavulanate versus gentamicin and clindamycin in patients with complicated appendicitis. Surg Gynecol Obstet 1991;172(Suppl):30-5. [15.] Tan JS, Wishnow RM, Talan DA, Duncanson FP, Norden CW. Treatment of hospitalized patients with complicated skin and skin structure infections: double-blind, randomized, multicenter study of piperacillin-tazobactam versus ticarcillin-clavulanate. Antimicrob Agents Chemother 1993;37: 1580-6. [16.] Brismar B, Malmborg AS, Tunevall G, Wretlind B, Bergman L, Mentzing LO, et al. Piperacillin-tazobactam versus imipenem-cilastatin for treatment of intra-abdominal infections. Antimicrob Agents Chemother 1992;36:2766-73. [17.] Eklund AE, Nord CE. A randomized multicenter trial of piperacillin/tazobactam versus imipenem/cilastatin in the treatment of severe intra-abdominal infections. J Antimicrob Chemother 1993;31(Suppl A):79-85.

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