Penicillins

INTRODUCTION — Beta-lactam antibiotics are among the most commonly prescribed drugs, grouped together based upon a shared structural feature, the beta-lactam ring. The classification, spectrum of activity and pharmacology of one group of beta-lactam antibiotics, the penicillins, will be reviewed here. The mechanisms of action and resistance and major adverse reactions of the beta-lactam antibiotics are discussed separately. (See "Overview of the beta-lactam antibiotics"). The cephalosporins and novel beta-lactam drugs which constitute the other beta-lactams are also discussed separately. (See related topics).

CLASSIFICATION — Penicillins can be classified into the following categories: Penicillin G Antistaphylococcal penicillins (nafcillin, oxacillin, cloxacillin and dicloxacillin) Broad spectrum penicillins

Second generation (ampicillin, amoxicillin and related agents)
Third generation (carbenicillin and ticarcillin)
Fourth generation (piperacillin)


SPECTRUM OF ACTIVITY — One of the major differences among the penicillins is the range of bacteria against which they are active.

Penicillin G — Penicillin G is highly active against: Gram-positive cocci (except penicillinase-producing staphylococci, penicillin-resistant pneumococci [1-5] , enterococci, and oxacillin-resistant staphylococci) (See "Resistance of Streptococcus pneumoniae to beta-lactam antibiotics"). Gram-positive rods such as Listeria Gram-negative cocci such as Neisseria sp (except penicillinase-producing Neisseria gonorrhoeae) Most anaerobes (with certain exceptions, such as Bacteroides)

Penicillin G is only bacteriostatic for enterococci; reports document strains with increasing intrinsic resistance to penicillin and, rarely, with high level resistance due to penicillinase production [6] . (See "Mechanisms of antibiotic resistance in enterococci"). Serious infections with enterococci are generally treated with combination therapy of a cell wall active antibiotic such as penicillin, ampicillin, or vancomycin plus gentamicin or streptomycin (unless high level resistance to these aminoglycosides is present). Penicillin G is not active against gram-negative bacilli because of poor penetration through the porin channel.

Antistaphylococcal penicillins — Antistaphylococcal penicillins (nafcillin, oxacillin, cloxacillin and dicloxacillin) inhibit penicillinase-producing staphylococci but are inactive against oxacillin-resistant staphylococci [7] . (See "Microbiology and pathogenesis of methicillin-resistant Staphylococcus aureus"). However, for strains of S. aureus sensitive to oxacillin, antistaphylococcal penicillins are preferable to vancomycin because vancomycin appears less active against S. aureus than beta-lactams from in vitro and clinical studies [8] . Antistaphylococcal penicillins have less intrinsic activity than penicillin G for most bacteria and are ineffective for enterococci, Listeria, and Neisseria sp.

Broad spectrum penicillins — The broad spectrum penicillins are distinguished by their activity against gram-negative bacilli. These agents have been stratified into the second-generation penicillins (ampicillin, amoxicillin and related agents), the third-generation penicillins (carbenicillin and ticarcillin), and the fourth-generation penicillin piperacillin. None of the broad spectrum penicillins is effective against penicillinase-producing staphylococci.

Second generation — Ampicillin, amoxicillin, and closely related antibiotics are able to penetrate the porin channel of gram-negative bacteria but are not stable to beta-lactamases. These antibiotics are active against the majority of strains of Escherichia coli, Proteus mirabilis, Salmonella, Shigella, and Haemophilus influenzae. While a large percentage of encapsulated H. influenzae type b from the blood and cerebrospinal fluid (CSF) of children are beta-lactamase positive (and ampicillin resistant), only 15 percent of the non-type b isolates from adult patients with community-acquired pneumonia are beta-lactamase positive [9] .

Amoxicillin and ampicillin have an identical spectrum of activity, but amoxicillin is better absorbed from the intestine when administered orally and yields higher blood and urine levels. Amoxicillin is available generically and is preferable to ampicillin for oral use except in the therapy of Shigella infections sensitive to ampicillin. (See "Management of Shigella gastroenteritis in adults").

Third generation — Carbenicillin and ticarcillin also can penetrate the porin channel of gram-negative bacteria in high doses, but they are less active than ampicillin on a weight basis. However, the carboxy group on the side chain of these antibiotics expands the spectrum of activity by rendering them more resistant to the chromosomal beta-lactamases of certain organisms, such as indole-positive Proteus species, Enterobacter species, and Pseudomonas aeruginosa. Third and fourth generation penicillins are most useful in infections caused by these organisms.

Carbenicillin indanyl sodium is an orally absorbed form of carbenicillin which may be indicated for oral therapy of resistant urinary tract infections; the usual dose is one or two tablets (382 mg each) four times a day. Oral carbenicillin is not effective for therapy of infections outside of the urinary tract.

Ticarcillin has the same spectrum of activity as carbenicillin but is two to four times more active on a weight basis against P. aeruginosa; the normal maximum parenteral dose is 18 g/day. Ticarcillin is a disodium salt (which may cause a problem in patients with volume overload) and may cause a bleeding diathesis by inhibition of platelet function and prolongation of the bleeding time.

Fourth generation — Piperacillin is a derivative of ampicillin [10] . It covers much the same spectrum as carbenicillin and ticarcillin but is more active in vitro on a weight basis. In addition, it has some activity against strains of Klebsiella, although cephalosporins remain the preferred agents. It is more active than carbenicillin or ticarcillin against enterococci and Bacteroides fragilis, but other agents are preferred for the treatment of these organisms as well.

Piperacillin is somewhat more active against Enterobacteriaceae than carbenicillin or ticarcillin and more active than ticarcillin against P. aeruginosa. As with ticarcillin, clinical failures have occurred when piperacillin is used as a single agent to treat serious Pseudomonas infections.

The third and fourth-generation penicillins are generally considered together as anti-Pseudomonal penicillins [11] and only a single representative employed as standard therapy at a given hospital. Several factors enter the decision over which of these agents to choose: Piperacillin is more active in vitro on a weight basis in inhibiting bacterial growth but not in bacterial killing; for P. aeruginosa, ticarcillin is more rapidly bactericidal Piperacillin has little enhanced stability to beta-lactamases compared with the third-generation agents Piperacillin has less effect than ticarcillin on platelet function

None of these factors clearly favor one of these drugs over the others; thus, the choice of one for standard therapy in an institution may primarily be made based upon cost considerations.

PHARMACOLOGY — The half-lives of the penicillins and achievable levels in different bodily fluids generally are the same, but dose adjustment with renal insufficiency depends upon the presence of non-renal routes of excretion and differs among these drugs.

Half-life — All of the available penicillins have relatively short half-lives (generally one hour or less); all of the parenteral agents are usually administered on an every four hour basis when treating serious systemic infections in patients with normal renal function. Piperacillin has dose-dependent pharmacokinetics and a longer half-life when higher doses are administered.

Levels in different bodily fluids — All of the penicillins achieve therapeutic levels in pleural, pericardial, peritoneal and synovial fluids, as well as urine. All achieve levels in bile higher than corresponding serum levels (assuming the absence of obstruction); nafcillin, ampicillin, and piperacillin achieve very high levels in bile.

The penicillins penetrate the CSF poorly in the absence of inflammation but achieve therapeutic levels in patients with meningitis who are given high dose parenteral therapy (show table 1).

Dose adjustment with renal insufficiency — Nafcillin, oxacillin, cloxacillin, and dicloxacillin have major non-renal routes of clearance and need no dose modification even in the presence of severe renal failure. Ampicillin and the structurally related antibiotic piperacillin, require dose modification predominantly when the GFR is below 10 mL/min. Ticarcillin requires dose modification when the GFR is below 50 mL/min.

The pharmacology (show table 2), dosing (show table 3), and adjustment of dose in the patient with renal dysfunction (show table 4) of the newer penicillins are shown in the Tables