Penicillins and Cephalosporins
The penicillins and cephalosporins are β-lactam–containing antibacterial drugs that react with and inactivate a particular bacterial transpeptidase that is essential for bacterial cell-wall synthesis (Table 16-20). Some bacteria are resistant to the action of penicillins and cephalosporins. The lipopolysaccharide outer coat of many gram-negative bacteria may prevent certain hydrophilic antibiotics from reaching their cytoplasmic membrane sites of action. Furthermore, some bacteria produce β-lactamases (penicillinase), enzymes capable of cleaving the critical amide bond within these antibiotics. The different penicillins and cephalosporins vary in susceptibility to the β-lactamases produced by different bacterial species.
The penicillins and cephalosporins penetrate the blood–ocular and blood–brain barriers poorly and are actively transported out of the eye by the organic-acid transport system of the ciliary body. However, their penetration into the eye increases with inflammation and with co-administration of probenecid.
Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions can occur in association with penicillin and cephalosporin therapy. A history of immediate allergic response (anaphylaxis or rapid onset of hives) to any penicillin is a strong contraindication to the use of any other penicillin. Approximately 10% of people who are allergic to a penicillin will have cross-reactivity to cephalosporins.
There are 5 classes of penicillins, which differ in their spectrum of antibiotic activity and in their resistance to penicillinase:
Penicillin G, penicillin V, and phenethicillin are highly effective against most gram-positive and gram-negative cocci; many anaerobes; and Listeria, Actinomyces, Leptospira, and Treponema organisms. However, most strains of Staphylococcus aureus and many strains of Staphylococcus epidermidis, anaerobes, and Neisseria gonorrhoeae are now resistant, often through production of penicillinase. Resistance by enterococci often arises from altered penicillin-binding proteins. Penicillin V and phenethicillin are absorbed well orally, whereas penicillin G is better absorbed when administered intravenously because it is inactivated by stomach acid. These penicillins are excreted rapidly by the kidneys and have short half-lives unless they are given in depot form (ie, procaine penicillin G) or administered with probenecid, which competitively inhibits excretion by the kidneys.
The penicillinase-resistant penicillins include methicillin sodium, nafcillin, oxacillin sodium, cloxacillin sodium, dicloxacillin sodium, and floxacillin. They are less potent than penicillin G against susceptible organisms but are the drugs of choice for infections that are caused by penicillinase-producing S aureus and that are not methicillin resistant. Methicillin and nafcillin are acid labile; therefore, they are given either parenterally or by subconjunctival injection. The other medications in this group have reasonable oral absorption. When they are given systemically, co-administration of probenecid reduces renal excretion and outward transport from the eye.
The broad-spectrum penicillins such as ampicillin, amoxicillin, and bacampicillin hydrochloride have antibacterial activity that extends to such gram-negative organisms as Haemophilus influenzae, Escherichia coli, Salmonella and Shigella species, and Proteus mirabilis. Resistant strains of H influenzae are becoming more common. These drugs are stable in acid and may be given orally. They are not resistant to penicillinase or to the broader-spectrum β-lactamases that are increasingly common among gram-negative bacteria.
Carbenicillin and ticarcillin have antimicrobial activity that extends to Pseudomonas and Enterobacter species and indole-positive strains of Proteus. These drugs are given parenterally or subconjunctivally, although the indanyl ester of carbenicillin may be given orally. They are not resistant to penicillinase and are less active against gram-positive bacteria and Listeria species.
Piperacillin sodium, mezlocillin sodium, and azlocillin are particularly potent against Pseudomonas and Klebsiella species and retain strong gram-positive coverage and activity against Listeria species. They are administered parenterally or subconjunctivally, and they are not resistant to penicillinase.
Table 16-20 Principal Antibiotics and Their Administrationa
Bacterial susceptibility patterns and resistance to β-lactamases dictate the classification of the cephalosporins as first, second, third, or fourth generation, although fifth-and sixth-generation drugs are under development.
First generation. Cephalothin, cefazolin, cephalexin, cefadroxil, and cephradine have strong antimicrobial activity against gram-positive organisms, especially Streptococcus species and S aureus. They retain moderate activity against gram-negative organisms. Of these drugs, cephalothin is the most resistant to staphylococcal β-lactamase and is used in severe staphylococcal infections. Because cephalothin is painful when given intramuscularly, it is used only intravenously. In contrast, cefazolin is more sensitive to β-lactamase but has somewhat greater activity against Klebsiella species and E coli. Cefazolin also has a longer half-life and is tolerated both intramuscularly and intravenously; thus, it is used more frequently than the other first-generation cephalosporins. Cephalexin, cefadroxil, and cephradine are stable in gastric acid and are available in oral forms.
Second generation. These medications were developed to expand activity against gram-negative organisms while retaining much of their gram-positive spectrum of activity. Compared with first-generation medications, cefamandole, cefoxitin, and cefuroxime display greater activity against H influenzae, Enterobacter aerogenes, and Neisseria species. Cefamandole has increased activity against Enterobacter and indole-positive Proteus species, H influenzae, and Bacteroides species. Cefoxitin is active against indole-positive Proteus and Serratia organisms, as well as against Bacteroides fragilis. Cefuroxime is valuable in the treatment of penicillinase-producing N gonorrhoeae and ampicillin-resistant H influenzae, and its penetration of the blood–brain barrier is adequate for initial treatment of suspected pneumococcal, meningococcal, or H influenzae meningitis.
Third generation. The third-generation cephalosporins have further enhanced activity against gram-negative bacilli, specifically the β-lactamase–producing members of the Enterobacteriaceae family, but they are inferior to first-generation cephalosporins with regard to their activity against gram-positive cocci. Commonly used drugs include cefotaxime, cefoperazone sodium, ceftriaxone sodium, ceftazidime, and ceftizoxime sodium. These drugs have a similar spectrum of activity against gram-positive and gram-negative organisms; anaerobes; Neisseria, Serratia, and Proteus species; and some Pseudomonas isolates. Cefoperazone and ceftazidime are particularly effective against Pseudomonas but lose more coverage of the gram-positive cocci. Cefotaxime penetrates the blood–brain barrier better than the other cephalosporins can, and it presumably also penetrates the blood– ocular barrier.
Fourth generation. Cefepime hydrochloride and cefpirome have a spectrum of gram-negative coverage similar to that of the third-generation cephalosporins, but these drugs are more resistant to some β-lactamases.
No cephalosporin provides coverage for enterococci, Listeria and Legionella species, or methicillin-resistant S aureus (MRSA).
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.