Penicillin, antistaphylococcal penicillins, and broad-spectrum 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 "Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects"). The cephalosporins and other beta-lactam drugs are also discussed separately. (See "Cephalosporins" and "Combination beta-lactamase inhibitors, carbapenems, and monobactams".)

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) and 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], some 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 spp (except penicillinase-producing Neisseria)

●Most anaerobes (with certain important exceptions, including Bacteroides)

●Spirochetes

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. (See "Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects", section on 'Mechanisms of bacterial resistance'.)

Parenteral penicillin is the treatment of choice for Treponema pallidum (syphilis); there have been no reports of resistance to penicillin despite its use over decades (see "Syphilis: Treatment and monitoring"). Penicillin is also active against Borrelia species, including Borrelia burgdorferi, which causes Lyme disease, and against Leptospira species. (See "Treatment of Lyme disease" and "Leptospirosis: Treatment and prevention".)

Antistaphylococcal penicillins — Antistaphylococcal penicillins (nafcillin, oxacillin, cloxacillin and dicloxacillin) inhibit penicillinase-producing staphylococci but are inactive against oxacillin-resistant staphylococci [7] (see "Methicillin-resistant Staphylococcus aureus (MRSA): Microbiology"). However, for strains of Staphylococcus aureus sensitive to oxacillin, antistaphylococcal penicillins or cefazolin are preferable to vancomycin because vancomycin is less active against S. aureus than beta-lactams in in vitro and clinical studies [8]. (See "Clinical approach to Staphylococcus aureus bacteremia in adults", section on 'Methicillin-sensitive S. aureus'.)

Antistaphylococcal penicillins have less intrinsic activity than penicillin G for bacteria susceptible to both, and antistaphylococcal penicillins are ineffective for enterococci, Listeria, and Neisseria spp.

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 are 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), a much lower percent of the non-type b isolates from adult patients with community-acquired pneumonia are beta-lactamase positive [9-13].

Amoxicillin can also be used for spirochetal disease including as an alternative therapy for syphilis (combined with probenecid), Lyme disease, relapsing fever syndromes due to Borrelia species, and selected patients with leptospirosis. (See "Syphilis: Treatment and monitoring" and "Treatment of Lyme disease" and "Leptospirosis: Treatment and prevention".)

Amoxicillin is also as part of combination therapy for Helicobacter pylori. (See "Treatment regimens for Helicobacter pylori in adults".)

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 "Shigella infection: Treatment and prevention in adults".)

Third generation — Carbenicillin and ticarcillin also can penetrate the porin channel of gram-negative bacteria in high doses but 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. Oral carbenicillin is not effective for therapy of infections outside of the urinary tract. Carbenicillin is not available in the United States and of limited availability globally.

Ticarcillin has the same spectrum of activity as carbenicillin but is two to four times more active on a weight basis against P. aeruginosa. 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. Ticarcillin (single-ingredient) and ticarcillin-clavulanate (combination with a beta-lactamase inhibitor) are not available in the United States and are of limited availability globally. (See "Combination beta-lactamase inhibitors, carbapenems, and monobactams", section on 'Beta-lactamase inhibitor combinations'.)

Fourth generation — Piperacillin is a derivative of ampicillin [14]. 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 Enterobacterales 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. Piperacillin is usually administered now in combination with a beta-lactamase inhibitor. (See "Combination beta-lactamase inhibitors, carbapenems, and monobactams", section on 'Beta-lactamase inhibitor combinations'.)

PHARMACOLOGY — The half-lives of the penicillins are similar and all achieve adequate levels in most bodily fluids, but dose adjustment with renal insufficiency depends upon the presence of nonrenal 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 meningeal doses of parenteral therapy (table 1).

Dose adjustment with kidney insufficiency — Nafcillin, oxacillin, cloxacillin, and dicloxacillin have major nonrenal routes of clearance and need no dosing modification even in the presence of severe kidney failure. Ampicillin and the structurally related antibiotic piperacillin require dose modification predominantly when the creatinine clearance (CrCl) is below 50 or 40 mL/min respectively.

The dosing of penicillin, antistaphylococcal penicillins, and broad-spectrum penicillins and adjustment of dose in the patient with kidney dysfunction are shown in the table (table 2).

SUMMARY

●Penicillin spectrum of activity – Penicillin G is highly active against most gram-positive cocci, gram-positive rods, gram-negative cocci, and anaerobes. Exceptions are bacteria from these classes that have acquired resistance to penicillin as well as certain anaerobes that produce a beta-lactamase such as Bacteroides. Penicillin is only bacteriostatic against enterococci. It is also active against spirochetes. (See 'Penicillin G' above.)

●Antistaphylococcal penicillins – For strains of S. aureus sensitive to oxacillin, antistaphylococcal penicillins or cefazolin are preferable to vancomycin because they are more active in vitro and in clinical studies. (See 'Antistaphylococcal penicillins' above.)

●Broad-spectrum penicillins – These include ampicillin and piperacillin and have increased activity over penicillin G against gram-negative bacilli but are variably inactivated by beta-lactamases. (See 'Broad-spectrum penicillins' above.)

●Pharmacokinetics – All penicillins have relatively short half-lives and require frequent administration when given parenterally. Cerebrospinal fluid (CSF) penetration is poor except in the presence of inflammation. Doses and dose adjustments for kidney impairment are listed in the table (table 2). (See 'Pharmacology' above.)