Carbenicillin, Carindacillin: Antimicrobial Activity, Susceptibility, Administration and Dosage, Clinical Uses etc.

Carbenicillin (disodium alpha-carboxybenzyl-penicillin) is a semisynthetic penicillin derived from the penicillin nucleus, 6-aminopenicillinic acid (6-APA), and can only be administered parenterally (Knudsen et al., 1967). Two carbenicillin esters, carbenicillin indanyl sodium (carindacillin) and a phenyl ester of carbenicillin (carfecillin), were also developed. These are absorbed after oral administration and rapidly hydrolyzed in the body to produce carbenicillin. The chemical formula of carbenicillin is C17H18N2O6S and its molecular weight 378.4. Its chemical structure is shown in Figure 7.1a. Carbenicillin is now rarely used.

Figure 7.1 Chemical structure of a) carbenicillin and b) ticarcillin.

ANTIMICROBIAL ACTIVITY

The in vitro activity of carbenicillin and ticarcillin in comparison with ampicillin against common pathogens is shown in Table 7.1. The key clinical target of activity for these drugs is P. aeruginosa, although they have activity against a variety of other Gram-negative and -positive pathogens.

b a. Routine susceptibility

Gram-negative aerobic bacteria Pseudomonas aeruginosa

Activity against this organism, although of a relatively low order (Blondeau et al., 1998), is the most important feature of carbenicillin. It can be administered parenterally in sufficient dosage to obtain serum concentrations exceeding 50–60 mg/ml, which inhibit most P. aeruginosa strains. However, some strains are not inhibited by concentrations as high as 200 mg/ml. Strains of P. aeruginosa with increased resistance can emerge in patients treated with carbenicillin (Darrell and Waterworth, 1969). 

Other Gram-negative aerobic bacteria

These exhibit similar susceptibility to carbenicillin and ticarcillin (Sutherland et al., 1971). Compared with ampicillin, carbenicillin and ticarcillin have a relatively high activity against Proteus vulgaris, Providencia rettgeri, and Morganella morganii (see Table 7.1).

Gram-negative anaerobic bacteria

Most strains of Prevotella (previously Bacteroides) melaninogenica and Fusobacterium spp. are sensitive to carbenicillin and ticarcillin, with MICs in the range of 0.1–8.0 mg/ml. Bacteroides fragilis is more resistant, but 80% of strains can be inhibited by 64 mg/ml and 95% by 128 mg/ml carbenicillin, both of which are clinically attainable concentrations (Sutter and Finegold 1975; Sutter and Finegold 1976).

Gram-positive bacteria

Carbenicillin and ticarcillin are active against S. aureus (nonpenicillinase producers), Streptococcus pyogenes, and S. pneumoniae. Enterococcus faecalis and Listeria monocytogenes are not so sensitive and usually need quite high carbenicillin and ticarcillin concentrations for inhibition (Sutherland et al., 1971; McCracken et al., 1973).

MECHANISM OF DRUG ACTION

Carbenicillin and ticarcillin, like penicillin G inhibit the synthesis of bacterial cell walls. Their increased activity against organisms such as P. aeruginosa and M. morganii is mainly due to their superior ability to penetrate the outer cell membrane of these Gram-negative bacilli. These drugs are also less susceptible than penicillin G and many other beta-lactam antibiotics to at least one of the beta-lactamase produced by P. aeruginosa.

MODE OF DRUG ADMINISTRATION AND DOSAGE

a. Adults

Both carbenicillin and ticarcillin are best given in six to eight divided doses. For instance, if a total daily dose of 30 g carbenicillin or 18 g of ticarcillin is to be administered, doses of 5 or 3 g, respectively, can be given every 4 hours; each dose can be dissolved in 50–100ml of i.v. fluid in a pediatric buretrol for infusion over 30–60 minutes (Neu and Garvey, 1975). Alternatively, the drugs may be already dispensed in a secondary i.v. bottle.

Carbenicillin

An adult dose of 24–40 g of carbenicillin per day, given i.v., is necessary for the treatment of severe infections due to P. aeruginosa. Some Gram-negative bacteria, such as Proteus spp., may be more susceptible to both carbenicillin and ticarcillin.

Intramuscular or i.v. carbenicillin or ticarcillin, in a dosage of 1–2 g given every 4–6 hours, may be adequate for the treatment of infections caused by these bacteria (Neu and Garvey, 1975).

b. Newborn infants and children Carbenicillin

High doses of carbenicillin (400–600 mg/kg body weight per day) are necessary for the treatment of severe infections due to P. aeruginosa in children. For urinary tract infections, a low dosage schedule for children (50–100 mg/kg/day) may be suitable (Turck et al., 1970; Parry and Neu, 1976b).

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

Carbenicillin and ticarcillin are not absorbed from the gastrointestinal tract and must be administered either i.m. or i.v. The dosage used can be varied widely depending on the nature of the infection and the susceptibility of the pathogen. Carindacillin and carfecillin are well absorbed from the gastrointestinal tract but they are not suitable for the treatment of systemic infections because therapeutic serum levels are not attained. They are useful for oral treatment of certain urinary tract infections because adequate urine concentrations of carbenicillin are achieved.

b. Drug distribution

Serum levels after both i.m. and i.v. administration of ticarcillin are similar to those of carbenicillin, and its serum half-life (70 minutes) is only slightly longer than that of carbenicillin (60 minutes) (Neu and Garvey, 1975; Meyers et al., 1980). After administration of 1 g of ticarcillin i.m. to adults, a mean peak serum level of 35 mg/ml is reached in 1 hour; thereafter, it falls, and at 6 hours it is only about 6 mg/ml (Rodriguez et al., 1973a).

c. Clinically important pharmacokinetic and pharmacodynamic features

There are few detailed pharmacokinetic and pharmacodynamic data regarding carbenicillin and ticarcillin; however, it is assumed that, similar to other beta-lactams, the key clinical efficacy parameter is the time the serum concentrations of these drugs are above the MIC of the infecting pathogen.

d. Excretion

Carbenicillin and ticarcillin are excreted in urine by glomerular filtration and tubular secretion. Probenecid reduces their rate of excretion by partially blocking renal tubular secretion. High urinary concentrations of active carbenicillin or ticarcillin are obtained after the administration of the usual i.m. or i.v. doses; urinary levels of 65–2475 mg/ml are reached during the first 3 hours after a single 3-g i.v. dose of ticarcillin (Knudsen et al., 1967; Neu and Garvey, 1975).

e. Drug interactions

The key interaction with these agents is with probenicid, which prolongs the serum half-life. Carbenicillin, ticarcillin, and other penicillins which are used in large doses can inactivate aminoglycosides, such as kanamycin, gentamicin, tobramycin, netilmicin, and amikacin, both in vitro and in vivo (Davies et al., 1975; Pickering and Gearhart, 1979; Pieper et al., 1980; Farchione, 1981; see later under 7. Clinical uses of the drug).

TOXICITY

a. Hypersensitivity reactions

Carbenicillin and ticarcillin may provoke any of the reactions which occur with penicillin G in penicillin-sensitive subjects. Anaphylaxis due to carbenicillin has been reported (Silverblatt and Turck, 1969). These drugs are contraindicated in patients with a history of penicillin hypersensitivity. Eosinophilia has been fairly frequently noted during ticarcillin therapy (Parry and Neu, 1976b; Lang et al., 1991), and occasionally this has been associated with a urticarial rash (Ervin and Bullock, 1976). Carbenicillin can also cause drug fever (Lang et al., 1991).

b. Neurotoxicity

High doses of i.v. carbenicillin and ticarcillin, similar to ‘‘massive’’ doses of penicillin G, may cause neurotoxicity. This is more likely to occur in patients with renal failure Hoffman and Bullock (1970) reported two patients with severe renal failure who developed convulsions whilst receiving a daily i.v. carbenicillin dose of only 4 g. In one of these the carbenicillin CSF level was 37 mg/ml during the seizures, and the serum level was only about 320 mg/ml. 

c. Bleeding disorders

These have been noted in association with carbenicillin and ticarcillin given i.v. Lurie et al. (1970) described three patients in whom carbenicillin appeared to act as an anticoagulant by interfering with the conversion of fibrinogen to fibrin; these patients had severe renal failure, and the dosage used (24 g daily) exceeded that recommended for such patients. Waisbren et al. (1971) reported another five patients (two with renal failure) who developed bleeding associated with the administration of moderately high carbenicillin doses; the nature of the bleeding disorder was not elucidated.

d. Neutropenia

Reyes et al. (1973) described reversible neutropenia in two patients, which appeared to be dose related. In one with normal renal function who was treated with 50 g of carbenicillin i.v. per day, neutropenia recurred twice on readministration of the drug; neutropenia appeared after about 16 days of therapy and on each occasion resolved within about 1 week of the drug being ceased. In both patients bone marrow showed depression of myeloid precursors.

e. Hepatotoxicity

Elevated SGOT levels have been observed during carbenicillin therapy. Knirsch and Gralla (1970) noted these elevations only in patients receiving i.m. carbenicillin and concluded that they were due to muscle irritation. Other authors have observed raised SGOT levels during i.v. carbenicillin administration, suggesting that the source of the enzyme is the liver, though the degree of hepatotoxicity is usually slight and rapidly reversible after cessation of the drug (Boxerbaum et al., 1970; Gump, 1970).

f. Electrolyte and acid–base disturbances

In 1 g of carbenicillin there is 4.7 mEq. of sodium. The sodium load could, therefore, be significant in patients receiving large doses of i.v. carbenicillin. This may cause hypernatremia and pulmonary edema, particularly in patients with cardiac failure or impaired renal function. Some patients receiving large doses of i.v. carbenicillin developed hypokalemia, which was associated with metabolic alkalosis (Cabizuca and Desser, 1976).

g. Other side-effects

Pseudomembranous colitis has rarely been associated with i.v. carbenicillin therapy (Saadah, 1980). One case report described carbenicillin-induced hemorrhagic cystitis (Møller, 1978), a complication more commonly noted with methicillin.

CLINICAL USES OF THE DRUG

a. Carbenicillin

Carbenicillin is rarely used today. The main use of carbenicillin was for the treatment of systemic P. aeruginosa infections, provided that the MIC of the strain was not higher than 120 mg/ml. It was effective for these infections, despite the fact that they were usually associated with serious underlying diseases. Carbenicillin, either used alone or combined with aminoglycosides, such as gentamicin, tobramycin, or amikacin, was useful for the treatment of P. aeruginosa septicemia (including septicemia in neutropenic patients), endocarditis, meningitis, pneumonia, endophthalmitis, or external otitis (Mombelli et al., 1982; Bodey et al., 1983; Reyes and Lerner, 1983). 

b. Oral carindacillin and carfecillin

These drugs are mainly indicated for therapy of P. aeruginosa urinary tract infections. They may be useful occasionally for the treatment of similar infections caused by Enterobacter spp., P. vulgaris, P. rettgeri, or M. morganii (Turck, 1973; Leigh and Simmons, 1976). Infections by these pathogens usually occur in patients with some underlying urinary tract pathology, and bacteriuria is often recurrent and difficult to eradicate. Furthermore, superinfection with carbenicillin-resistant organisms such as Klebsiella spp. may occur (Hodges and Perkins, 1973).

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