A. THE ACTIVE NUCLEUS of the penicillin molecule is a 4-membered ring, called the ββ–lactam ring (Figure 9-1).
II
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ClassSite of Action1Activity2Administration3Clearance4Distribution to CSF5Toxicity6Spectrum7Acquired Resistance8 Penicillin GWCO,PKsH,G,NE,A,R Penicillins, extendedWCO,PKsH,G,N,~E,A,R Cephalosporins, 1stWCo,PKsH,~,NE,A,R Cephalosporins, 3rdWCo,PKGH,S,–,NE,A,R AztreonamWCPKsGE Imipenem/CilastatinWCPKiG,H,C,,NR Aminoglycosides30SCPKiO,KE,R Tetracyclines30SSO,pK,LsB,P,S,,NR Erythromycin50SSO,pLiG,L,NA,R Chloramphenicol50SSO,PLGA,,NE Clindamycin50SSO,PLiG,S,NA,R VancomycinWCPKsN,O,KA QuinolonesGCO,PK,LGG,E,A,R SulfonamidesFASOL,KGA,H,U,,NA,R TrimethoprimFASOKGA,,NA MetronidazoleDCO,PLGDN *There are many exceptions to the general properties listed in this table. 1Site of Action: W cell wall; 30S ribosome; 50S ribosome; G gyrase; FA folic acid metabolism; D DNA. 2Activity: C bactericidal; S bacteriostatic. 3Administration: O oral; o occasionally oral; P parenteral; p occasionally parenteral. 4Clearance: K kidney; L liver 5Distribution to CSF: G good; s some; i inadequate 6Toxicity: A anemias; B binds calcium; C convulsions; D disulfiram-like; E erosion of cartilage; G gastrointestinal;H hypersensitivity; K kidney toxicity; L liver toxicity; N nonallergic rash; O ototoxic; P photosensitivity; S superinfection; U crystalluria. 7Spectrum: , Gram(); , Gram(); ~, some Gram(); N anaerobes. 8Acquired resistance: A active site change; E enzymatic break-down; R reduced accumulation.
OVERVIEW OF ANTIBACTERIAL DRUGS*TABLE9-1
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B. PENICILLIN BINDS TO PENICILLIN BINDING PROTEINS and induces many effects that inhibit cell wall synthesis (e.g., inhibition of transpeptidases).
1. Cross-linking of the bacterial cell wall is reduced.
2. The cell wall is weakened and the bacteria rupture due to the high internal osmotic pressure; thus, the penicillins are bactericidal.
3. Autolytic enzymes are activated.
C. THE PHARMACOKINETIC PROPERTIES of penicillin G affect how it is used.
1. It is relatively unstable in acid; thus, the bioavailability is low. It can be adminis-tered orally; however, serum penicillin concentrations are variable after this route of administration.
2. There is poor penetration into the cerebrospinal fluid (CSF), unless inflamma-tion is present.
3. Active renal tubular secretion results in a short half-life. Probenecid, which blocks active secretion, will reduce the renal clearance of penicillin G.
4. Depot preparations (penicillin G procaine or penicillin G benzathine intramuscularly) have long durations of action due to slow absorption from the site of injection.
D. Although the penicillins are very safe antibiotics, they have some important adverse effects.
1. Hypersensitivity reactions can develop.
a. Immediate hypersensitivity reactions, characterized by anaphylaxis, occur within 20 minutes.
i. Penicillin interacts with proteins to form minor determinants that act as haptens for inducing the immediate hypersensitivity reaction.
ii. The reaction is mediated by IgE antibodies.
iii. Anaphylactic reactions should be treated with epinephrine.
b. Accelerated (occurring within 1 day) and delayed (occurring within 1 week) reactions are less severe, often leading to skin rashes.
i. Penicilloic acid, which is a product of the breakdown of penicillins, inter-acts with proteins to form major determinants, which act as haptens for inducing the reactions.
ii. These reactions are mediated by IgG or IgM antibodies.
β-lactam ring (active nucleus) Binding site with hapten
Causes rapid elimination R-group determines:
Spectrum Kinetics Acid sensitivity
β-lactamase sensitivity
Thiazolidine ring CH3
CH3
CO2H S
O O RCNH
N
G Figure 9-1 General structure of the penicillins.
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c. Patients may display hypersensitivity to the first dose. This hypersensitivity is probably due to the environmental levels (e.g., in food) of penicillins.
d. Cross-sensitivity between the penicillins is very high.
e. Skin tests are available to check for hypersensitivity.
i. Penicillin G is useful but somewhat unreliable.
ii. Penicilloyl-polylysine is a major determinant.
iii. Minor determinants are not widely available.
2. Superinfections can develop, especially with the broad-spectrum penicillins such as ampicillin.
3. Sodium loading from the penicillins is most common with carbenicillin and ticarcillin, which are disodium salts.
4. Convulsions, caused by γ-aminobutyric acid (GABA) receptor blockade, can be induced at high dosages of penicillins.
5. Nonallergic skin rashes can occur with ampicillin, especially in patients with infectious mononucleosis.
6. Nephritis can occur, especially with patients given methicillin.
E. THE SPECTRUM of penicillin G includes:
1. Gram-positive bacteria
2. Gram-negative cocci, but not most other Gram-negative bacteria 3. Some anaerobes
F. Penicillin G is especially effective for treating infectious diseases due to 1. Neisseria meningitidis
2. Streptococci, including pneumococci (although there is now significant resistance), β-hemolytic streptococci, and some viridans streptococci
3. Clostridium perfringens 4. Fusobacterium
5. Treponema pallidum (syphilis)
G. Acquired resistance to penicillin G is usually due to penicillinases orββ-lactamases, which split the active part of the molecule, the β lactam ring.
H. AMIDASES are used to alter the side chain of penicillin G (Table 9-2), resulting in groups of:
1. Natural penicillins. Penicillin V is more effective after oral administration than penicillin G.
2. Penicillinase-resistant penicillins. These penicillins are useful for the treatment of infections involving penicillinase-producing bacteria, such as Staphylococcus aureus or S. epidermidis.
3. Extended-spectrum penicillins. These penicillins have more Gram-negative activ-ity than penicillin G.
a. Ampicillin or amoxicillin are useful for infectious diseases due to:
i. Enterococcus faecalis ii. Proteus mirabilis iii. Listeria monocytogenes
b. The antipseudomonal penicillins have higher activity versus Pseudomonas aeruginosa.
c. All extended-spectrum penicillins are penicillinase sensitive.
i. Either clavulanic acid, tazobactam, or sulbactam, which are ββ-lactamase inhibitors, can be combined with the extended-spectrum penicillins.
ii. Resistant organisms will be more sensitive to this combination.
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iii. These β-lactamase inhibitors contain a β-lactam ring, but they are not bacte-ricidal themselves. Instead, they bind to and inactivate β-lactamase enzymes so that the coadministered β-lactam antibiotic will remain active (i.e., not be cleaved).