buffer, and a preservative have been added or suspensions in peanut oil or sesame oil that have been gelled by the addition of 2% aluminum monostearate. Some commercial products are mixtures of penicillin G potassium or sodium with penicillin G procaine; the water-soluble salt provides rapid development of a high plasma concentration of penicillin, and the insoluble salt prolongs the duration of effect.
Penicillin G Benzathine
Since penicillin G benzathine, N,N'-dibenzylethylenediamine dipenicillin G (Bicillin, Permapen), is the salt of a diamine, 2 moles of penicillin are available from each molecule. It is very insoluble in water, requiring about 3,000 mL to dissolve 1 g. This property gives the compound great stability and prolonged duration of effect. At the pH of gastric juice, it is quite stable, and food intake does not interfere with its absorption. It is available in tablet form and in several parenteral preparations. The activity of penicillin G benzathine is equivalent to 1,211 units/mg.
Several other amines have been used to make penicillin salts, and research is continuing on this subject. Other amines that have been used include 2-chloroprocaine; l-N-methyl-1,2-diphenyl-2-hydroxyethylamine (l-ephenamine); dibenzylamine; tripelennamine (Pyribenzamine); and N,N/-bis-(dehydroabietyl)ethylenediamine (hydrabamine).
In 1948, Behrens et al.46 reported penicillin V, phe-noxymethylpenicillin (Pen Vee, V-Cillin) as a biosynthetic product. It was not until 1953, however, that its clinical value was recognized by some European scientists. Since then, it has enjoyed wide use because of its resistance to hydrolysis by gastric juice and its ability to produce uniform concentrations in blood (when administered orally). The free acid requires about 1,200 mL of water to dissolve 1 g, and it has an activity of 1,695 units/mg. For parenteral solutions, the potassium salt is usually used. This salt is very soluble in water. Solutions of it are made from the dry salt at the time of administration. Oral dosage forms of the potassium salt are also available, providing rapid, effective plasma concentrations of this penicillin. The salt of phe-noxymethylpenicillin with -bis(dehydroabietyl)ethyl-enediamine (hydrabamine, Compocillin-V) provides a very long-acting form of this compound. Its high water insolubility makes it a desirable compound for aqueous suspensions used as liquid oral dosage forms.
During 1960, methicillin sodium, 2,6-dimethoxyphenylpeni-cillin sodium (Staphcillin), the second penicillin produced as a result of the research that developed synthetic analogs, was introduced for medicinal use.
Reacting 2,6-dimethoxybenzoyl chloride with 6-APA forms 6-(2,6-dimethoxybenzamido)penicillanic acid. The sodium salt is a white, crystalline solid that is extremely soluble in water, forming clear, neutral solutions. As with other penicillins, it is very sensitive to moisture, losing about half of its activity in 5 days at room temperature. Refrigeration at 5°C reduces the loss in activity to about 20% in the same period. Solutions prepared for parenteral use may be kept as long as 24 hours if refrigerated. It is extremely sensitive to acid (a pH of 2 causes 50% loss of activity in 20 minutes); thus, it cannot be used orally.
Methicillin sodium is particularly resistant to inactivation by the penicillinase found in staphylococci and somewhat more resistant than penicillin G to penicillinase from Bacillus cereus. Methicillin and many other penicillinase-resistant penicillins induce penicillinase formation, an observation that has implications concerning use of these agents in the treatment of penicillin G-sensitive infections. Clearly, the use of a penicillinase-resistant penicillin should not be followed by penicillin G.
The absence of the benzyl methylene group of penicillin G and the steric protection afforded by the 2- and 6-methoxy groups make this compound particularly resistant to enzymatic hydrolysis.
Methicillin sodium has been introduced for use in the treatment of staphylococcal infections caused by strains resistant to other penicillins. It is recommended that it not be used in general therapy, to avoid the possible widespread development of organisms resistant to it.
The incidence of interstitial nephritis, a probable hypersensitivity reaction, is reportedly higher with methicillin than with other penicillins.
Oxacillin sodium, (5-methyl3-phenyl-4-isoxazolyl)penicillin sodium monohydrate (Prostaphlin), is the salt of a semisynthetic penicillin that is highly resistant to inactivation by penicillinase. Apparently, the steric effects of the 3-phenyl and 5-methyl groups of the isoxazolyl ring prevent the binding of this penicillin to the ^-lactamase active site and, thereby, protect the lactam ring from degradation in much the same way as has been suggested for methicillin. It is also relatively resistant to acid hydrolysis and, therefore, may be administered orally with good effect.
Oxacillin sodium, which is available in capsule form, is reasonably well absorbed from the gastrointestinal (GI) tract, particularly in fasting patients. Effective plasma levels of oxacillin are obtained in about 1 hour, but despite extensive plasma protein binding, it is excreted rapidly through the kidneys. Oxacillin experiences some first-pass metabolism in the liver to the 5-hydroxy methyl derivative. This metabolite has antibacterial activity comparable to that of oxacillin but is less avidly protein bound and more rapidly excreted. The halogenated analogs cloxacillin, dicloxacillin, and floxacillin experience less 5-methyl hydroxylation.
The use of oxacillin and other isoxazolylpenicillins should be restricted to the treatment of infections caused by staphylococci resistant to penicillin G. Although their spectrum of activity is similar to that of penicillin G, the isoxazolylpenicillins are, in general, inferior to it and the phenoxymethylpenicillins for the treatment of infections caused by penicillin G-sensitive bacteria. Because isoxa-zolylpenicillins cause allergic reactions similar to those produced by other penicillins, they should be used with great caution in patients who are penicillin sensitive.
The chlorine atom ortho to the position of attachment of the phenyl ring to the isoxazole ring enhances the activity of cloxacillin sodium, [3-(tf-chlorophenyl)-5-methyl-4-isoxa-zolyl]penicillin sodium monohydrate (Tegopen), over that of oxacillin, not by increasing its intrinsic antibacterial activity but by enhancing its oral absorption, leading to higher plasma levels. In almost all other respects, it resembles oxacillin.
Chapter 8 # Antibacterial Antibiotics 271 Dicloxacillin Sodium
The substitution of chlorine atoms on both carbons ortho to the position of attachment of the phenyl ring to the isox-azole ring is presumed to enhance further the stability of the oxacillin congener dicloxacillin sodium, [3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolyl]penicillin sodium monohydrate (Dynapen, Pathocil, Veracillin) and to produce high plasma concentrations of it. Its medicinal properties and use are similar to those of cloxacillin sodium. Progressive halogen substitution, however, also increases the fraction bound to protein in the plasma, potentially reducing the concentration of free antibiotic in plasma and tissues. Its medicinal properties and use are the same as those of cloxacillin sodium.
Nafcillin sodium, 6-(2-ethoxy-1-naphthyl)penicillin sodium (Unipen), is another semisynthetic penicillin that resulted from the search for penicillinase-resistant compounds. Like methicillin, nafcillin has substituents in positions ortho to the point of attachment of the aromatic ring to the carbox-amide group of penicillin. No doubt, the ethoxy group and the second ring of the naphthalene group play steric roles in stabilizing nafcillin against penicillinase. Very similar structures have been reported to produce similar results in some substituted 2-biphenylpenicillins.33
Unlike methicillin, nafcillin is stable enough in acid to permit its use by oral administration. When it is given orally, its absorption is somewhat slow and incomplete, but satisfactory plasma levels may be achieved in about 1 hour. Relatively small amounts are excreted through the kidneys; most is excreted in the bile. Even though some cyclic reabsorption from the gut may occur, nafcillin given orally should be readministered every 4 to 6 hours. This salt is readily soluble in water and may be administered intramuscularly or intravenously to obtain high plasma concentrations quickly for the treatment of serious infections.
Nafcillin sodium may be used in infections caused solely by penicillin G-resistant staphylococci or when streptococci are present also. Although it is recommended that it be used exclusively for such resistant infections, nafcillin is also effective against pneumococci and group A S-hemolytic streptococci. Because, like other penicillins, it may cause allergic side effects, it should be administered with care.
Ampicillin, 6-[d-a-aminophenylacetamido]penicillanic acid, d-a-aminobenzylpenicillin (Penbritn, Polycillin, Omnipen, Amcill, Principen), meets another goal of the research on semisynthetic penicillins—an antibacterial spectrum broader than that of penicillin G. This product is active against the same Gram-positive organisms that are susceptible to other penicillins, and it is more active against some Gram-negative bacteria and enterococci than are other penicillins. Obviously, the a-amino group plays an important role in the broader activity, but the mechanism for its action is unknown. It has been suggested that the amino group confers an ability to cross cell wall barriers that are impenetrable to other penicillins. d-(—)-Ampicillin, prepared from d-(—)-a-aminophenylacetic acid, is significantly more active than l-(+)-ampicillin.
Ampicillin is not resistant to penicillinase, and it produces the allergic reactions and other untoward effects found in penicillin-sensitive patients. Because such reactions are relatively rare, however, it may be used to treat infections caused by Gram-negative bacilli for which a broad-spectrum antibiotic, such as a tetracycline or chlor-amphenicol, may be indicated but not preferred because of undesirable reactions or lack of bactericidal effect. Ampicillin is not so widely active, however, that it should be used as a broad-spectrum antibiotic in the same manner as the tetracyclines. It is particularly useful for the treatment of acute urinary tract infections caused by E. coli or Proteus mirabilis and is the agent of choice against Haemophilus influenzae infections. Ampicillin, together with probenecid, to inhibit its active tubular excretion, has become a treatment of choice for gonorrhea in recent years. S-Lactamase-producing strains of Gram-negative bacteria that are highly resistant to ampicillin, however, appear to be increasing in the world population. The threat from such resistant strains is particularly great with H. influenzae and N. gonorrhoeae, because there are few alternative therapies for infections caused by these organisms. Incomplete absorption and excretion of effective concentrations in the bile may contribute to the effectiveness of ampicillin in the treatment of salmonellosis and shigellosis.
Ampicillin is water soluble and stable in acid. The protonated a-amino group of ampicillin has a pKa of 7.3,46 and thus it is protonated extensively in acidic media, which explains ampicillin's stability to acid hydrolysis and instability to alkaline hydrolysis. It is administered orally and is absorbed from the intestinal tract to produce peak plasma concentrations in about 2 hours. Oral doses must be repeated about every 6 hours because it is excreted rapidly and unchanged through the kidneys. It is available as a white, crystalline, anhydrous powder that is sparingly soluble in water or as the colorless or slightly buff-colored crystalline trihydrate that is soluble in water. Either form may be used for oral administration, in capsules or as a suspension. Earlier claims of higher plasma levels for the anhydrous form than for the trihydrate following oral administration have been disputed.47,48 The white, crystalline sodium salt is very soluble in water, and solutions for injections should be administered within 1 hour after being made.
Bacampicillin hydrochloride (Spectrobid) is the hydrochloride salt of the 1-ethoxycarbonyloxyethyl ester of ampicillin. It is a prodrug of ampicillin with no antibacterial activity. After oral absorption, bacampicillin is hydrolyzed rapidly by esterases in the plasma to form ampicillin.
Oral absorption of bacampicillin is more rapid and complete than that of ampicillin and less affected by food. Plasma levels of ampicillin from oral bacampicillin exceed those of oral ampicillin or amoxicillin for the first 2.5 hours but thereafter are the same as for ampicillin and amoxi-cillin.49 Effective plasma levels are sustained for 12 hours, allowing twice-a-day dosing.
Amoxicillin, 6-[d-(—)-a-amino-p- hydroxyphenylacetamido] penicillanic acid (Amoxil, Larotid, Polymox), a semisynthetic penicillin introduced in 1974, is simply the p-hydroxy analog of ampicillin, prepared by acylation of 6-APA with p-hydroxyphenylglycine.
Its antibacterial spectrum is nearly identical with that of ampicillin, and like ampicillin, it is resistant to acid, susceptible to alkaline and ß-lactamase hydrolysis, and weakly protein bound. Early clinical reports indicated that orally administered amoxicillin possesses significant advantages over ampicillin, including more complete GI absorption to give higher plasma and urine levels, less diarrhea, and little or no effect of food on absorption.50 Thus, amoxicillin has largely replaced ampicillin for the treatment of certain systemic and urinary tract infections for which oral administration is desirable. Amoxicillin is reportedly less effective than ampicillin in the treatment of bacillary dysentery, presumably because of its greater GI absorption. Considerable evidence suggests that oral absorption of a-aminobenzyl-substituted penicillins (e.g., ampicillin and amoxicillin) and cephalosporins is, at least in part, carrier mediated,51 thus explaining their generally superior oral activity.
Amoxicillin is a fine, white to off-white, crystalline powder that is sparingly soluble in water. It is available in various oral dosage forms. Aqueous suspensions are stable for 1 week at room temperature.
Carbenicillin Disodium, Sterile
Carbenicillin disodium, disodium a-carboxybenzylpeni-cillin (Geopen, Pyopen), is a semisynthetic penicillin released in the United States in 1970, which was introduced in England and first reported by Ancred et al.52 in 1967. Examination of its structure shows that it differs from ampicillin in having an ionizable carboxyl group rather than an amino group substituted on the a-carbon atom of the benzyl side chain. Carbenicillin has a broad range of antimicrobial activity, broader than any other known penicillin, a property attributed to the unique carboxyl group. It has been proposed that the carboxyl group improves penetration of the molecule through cell wall barriers of Gram-negative bacilli, compared with other penicillins.
Carbenicillin is not stable in acids and is inactivated by penicillinase. It is a malonic acid derivative and, as such, de-carboxylates readily to penicillin G, which is acid labile. Solutions of the disodium salt should be freshly prepared but, when refrigerated, may be kept for 2 weeks. It must be administered by injection and is usually given intravenously.
Carbenicillin has been effective in the treatment of systemic and urinary tract infections caused by P. aeruginosa, indole-producing Proteus spp., and Providencia spp., all of which are resistant to ampicillin. The low toxicity of carbeni-cillin, with the exception of allergic sensitivity, permits the use of large dosages in serious infections. Most clinicians prefer to use a combination of carbenicillin and gentamicin for serious pseudomonal and mixed coliform infections. The two antibiotics are chemically incompatible, however, and should never be combined in an intravenous solution.
Efforts to obtain orally active forms of carbenicillin led to the eventual release of the 5-indanyl ester carbenicillin indanyl, 6-[2-phenyl-2-(5-indanyloxycarbonyl)acetamido]penicil-lanic acid (Geocillin), in 1972. Approximately 40% of the usual oral dose of indanyl carbenicillin is absorbed. After absorption, the ester is hydrolyzed rapidly by plasma and tissue esterases to yield carbenicillin. Thus, although the highly lipophilic and highly protein-bound ester has in vitro activity comparable with that of carbenicillin, its activity in vivo is due to carbenicillin. Indanyl carbenicillin thus provides an orally active alternative for the treatment of carbenicillin-sensitive systemic and urinary tract infections caused by Pseudomonas spp., indole-positive Proteus spp., and selected species of Gram-negative bacilli.
Clinical trials with indanyl carbenicillin revealed a relatively high frequency of GI symptoms (nausea, occasional vomiting, and diarrhea). It seems doubtful that the high doses required for the treatment of serious systemic infections could be tolerated by most patients. Indanyl carbeni-cillin occurs as the sodium salt, an off-white, bitter powder that is freely soluble in water. It is stable in acid. It should be protected from moisture to prevent hydrolysis of the ester.
Ticarcillin Disodium, Sterile
Ticarcillin disodium, a-carboxy-3-thienylpenicillin (Ticar), is an isostere of carbenicillin in which the phenyl group is replaced by a thienyl group. This semisynthetic penicillin derivative, like carbenicillin, is unstable in acid and, therefore, must be administered parenterally. It is similar to carbenicillin in antibacterial spectrum and pharmacokinetic properties. Two advantages for ticarcillin are claimed:
(a) slightly better pharmacokinetic properties, including higher serum levels and a longer duration of action; and
(b) greater in vitro potency against several species of Gramnegative bacilli, most notably P. aeruginosa and Bacteroides fragilis. These advantages can be crucial in the treatment of serious infections requiring high-dose therapy.
Mezlocillin Sodium, Sterile
Mezlocillin (Mezlin) is an acylureidopenicühn with an antibacterial spectrum similar to that of carbenicillin and ticarcillin; however, there are some major differences. It is much more active against most Klebsiella spp., P. aeruginosa, anaerobic bacteria (e.g., Streptococcus faecalis and B. fragilis), and H. influenzae. It is recommended for the treatment of serious infections caused by these organisms.
Mezlocillin is not generally effective against ¡-lactamase-producing bacteria, nor is it active orally. It is available as a white, crystalline, water-soluble sodium salt for injection. Solutions should be prepared freshly and, if not used within 24 hours, refrigerated. Mezlocillin and other acylureidopenicillins, unlike carbenicillin, exhibit nonlinear pharmacokinetics. Peak plasma levels, half-life, and area under the time curve increase with increased dosage. Mezlocillin has less effect on bleeding time than carbenicillin, and it is less likely to cause hypokalemia.
Piperacillin Sodium, Sterile
Piperacillin (Pipracil) is the most generally useful of the extended-spectrum acylureidopenicillins. It is more active than mezlocillin against susceptible strains of Gram-negative aerobic bacilli, such as Serratia marcescens, Proteus, Enterobacter, Citrobacter spp., and P. aeruginosa. Mezlocillin, however, appears to be more active against Providencia spp. and K. pneumoniae. Piperacillin is also active against anaerobic bacteria, especially B. fragilis and S. faecalis (enterococcus). ¡-Lactamase-producing strains of these organisms are, however, resistant to piperacillin, which is hydrolyzed by S. aureus ¡-lactamase. The ¡-lactamase susceptibility of piperacillin is not absolute because ¡-lactamase-producing, ampicillin-resistant strains of N. gonorrhoeae and H. influenzae are susceptible to piperacillin.
Piperacillin is destroyed rapidly by stomach acid; therefore, it is active only by intramuscular or intravenous administration. The injectable form is provided as the white, crystalline, water-soluble sodium salt. Its pharmacokinetic properties are very similar to those of the other acylurei-dopenicillins.
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