Penicillins, Monobactams, Agents and Carbapenems
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Update on Antimicrobial Penicillins, Monobactams, Agents and Carbapenems Gerald P. Bodey, MD T o help physicians choose among a bewildering array of antimicrobial agents, this article reviews 3 groups of ,-lactam antibiotics: 1) the pen- icillins, an extremely familiar drug group that includes a wide range of derivatives; 2) the monobactams, a newer class of antibiotics that provides only 1 commercially available drug, aztreonam; and 3) the carbapenems, which also pro- vide only 1 commercially available drug, imipenem. Because the basic structure of all penicillins, monobactams, and carbapenems (as well as cephalosporins) is a 4-membered P-lactam ring, these drugs are known as ,-lactam antibiotics (Fig. 1). The other moieties attached to the P-lactam ring de- termine these agents' penetrability through the outer membrane of gram-negative bacilli, their resistance to ,-lactamases, and, thus, their activity against various bacteria. Because the integrity of the 13-lactam ring is a determinant of activity, a major mechanism of bacterial resistance is disruption of the ring by ,-lactamases. Mechanisms of Action and Resistance 1-lactams are bactericidal antibiotics that inhibit the final stages of cell-wall syn- thesis; hence, they are effective only against organisms that are proliferating and actively producing cell-wall constituents. Laboratory studies indicate that these antibiotics do not kill nonproliferating organisms. During the past several decades, extensive studies of the J3-lactams' mechanisms of action have helped reveal the complexities of the structure and metabolism of pathogenic bacteria. For a 13-lactam to kill an organism, the drug must be able to penetrate the outer cell-wall structures and reach the site of cell-wall synthesis; it must also resist enzymatic destruction by 3-lactamases and bind to the enzymes associated with cell-wall synthesis (transpeptidases, carboxypeptidases, and endopeptidases), which are known as penicillin-binding proteins (PBPs). Organisms may become ,-lactam resistant by 1) altering their outer-membrane permeability, 2) producing 3-lactamases, or 3) altering their PBPs. Key words: Antibiotics; bacterial infections; carbapenems; drug Permeability resistance, microbial; drug The outer cell-wall structures of gram-positive and gram-negative bacteria differ in therapy, combination; monobactams; penicillins complexity. Most gram-positive bacteria have a relatively simple outer cell-wall structure, consisting of a cytoplasmic membrane (where the PBPs are located) covered by peptidoglycan strands. Hence, 3-lactams can penetrate gram-positive From: The Department of Medical Specialties, Section organisms with little difficulty. Among such organisms, altered membrane permea- of Infectious Diseases, The bility has not been recognized as a mechanism of resistance. University of Texas M.D. Gram-negative bacilli have a more complex outer cell-wall structure Anderson Cancer Center, (Fig. 2). The Houston, Texas outer membrane impedes the passage of ,-lactams; it does, however, contain channels known as porins, which allow the passage of large molecules including f3-lactams and nutrients. Three Series editor: characteristics of antibiotics can increase the drugs' Layne 0. Gentry, MD ability to pass through these porins: sufficiently small size, low hydrophobicity (that is, an affinity for water), and positive charge. For example, the antistaphylococcal penicillins (such as oxacillin, nafcillin, and are Address for reprints: others) ineffective against gram- Gerald P Bodey, MD, negative bacilli, because these drugs consist of molecules that are too large to pass M.D. Anderson Cancer through the porin channels. Center, Section of Infectious Gram-negative bacilli may develop resistance to ,B-lactams by Diseases, 1515 Holcombe altering their Blvd. fBox 47), Houston, TX membrane permeability. This mechanism of resistance has been detected in strains 77030 of Pseudomonas aeruginosa, Citrobacter and Enterobacter species, Serratia mar- Texas HeaiY Institidejournal Penicillins, Monobactams, and Carbapenems 315 R- C- NilCN 0 N // COOH COOH 0 Penicillin (Penam) Carbapenem R-C-NH- H_ 0 CH 2 OH " SO H N O// COOH Monobactam Clavulanic Acid / H3CH O0 COONa Sulbactam Fig. 2 Diagrammatic representation of the cell wall of a Fig. 1 Chemical structures of selected ,B-lactams. gram-negative bacillus. cescens, and Neissenia gonorrboeae. For example, may or may not provide resistance, and their effect some P. aeruginosa develop resistance to imipenem may vary with different antibiotics. during therapy by altering membrane permeability. Drug manufacturers can circumvent the effect of This mechanism of resistance can be overcome by P3-lactamases by producing antibiotics resistant to designing P-lactams with different permeability char- destruction. Examples are the antistaphylococcal acteristics. penicillins that kill penicillin-G-resistant S. aureus. Recently, investigators have discovered certain sub- P-lactamases stances that can specifically inhibit 3-lactamases. P-lactamases are bacterial enzymes that open the f- Two of these, clavulanic acid and sulbactam, will be lactam ring, thereby inactivating the antibiotic.1 f- diiscussed later. lactamases are prevalent in most bacteria, including gram-positive cocci and gram-negative bacilli, as well Penicillin-Binding Proteins as Mycobactetlum, Nocardia, and Legionella organ- The term penicillin-binding proteins (PBPs) is a isms. Essentially all pathogenic gram-negative bacte- misnomer, since the cell produces these enzymes to ria have strains that produce P-lactamases. Each P- complete the cross-binding of peptidoglycan strands, lactamase is specific for certain ,B-lactam antibiotics. the final stage of cell-wall synthesis, not to bind to The P-lactamases ofgram-positive cocci differ from penicillins. The variety of PBPs present depends up- those of gram-negative bacilli. Production of most on the organism. Seven PBPs have been identified in gram-positive coccal ,-lactamases is mediated by Escbericbia coli, 5 have been seen in Streptococcus plasmids and is inducible; that is, the organism pro- pneumoniae, and 6 in Clostridiumperfringens. Each duces the enzyme only in the presence of a f-lactam. enzyme performs a specific function, and not all are Generally, the enzyme is produced in large amounts essential to the organism's survival.' Different -lac- and dispersed extracellularly; this fact is important, tams bind to different PBPs. In E. coli, for example, because these organisms have no significant barriers many penicillins bind to PBP1A, whereas imipenem to antibiotic penetration. The ,-lactamases of gram- binds preferentially to PBP2, and aztreonam binds to positive cocci usually provide clear-cut resistance to PBP3. susceptible P-lactams. For example, 3-lactamase- Bacteria can develop f-lactam resistance by alter- producing strains of Staphylococcus aureus are re- ing their PBPs. To do this, the organisms can 1) de- sistant to penicillin G, aminopenicillins (ampicillin), crease their affinity to ,-lactams, 2) overproduce a carboxypenicillins (ticarcillin), and ureidopenicillins critical PBP, or 3) produce a new PBP. Penicillin re- (piperacillin), but are susceptible to methicillin and sistance in S. pnieuinoniae and methicillin resistance isoxazolyl penicillins (oxacillin). in S. auireus have been associated with the produc- Prodluction of the 3-lactamases of gram-negative tion of new PBPs. Other organisms that have devel- bacilli may be plasmid or chromosomally mediated oped resistance because of altered PBPs include and may be inducible or constitutive. Constitutive Streptococcusfaecalis, Streptococcusfaecium, Staph- enzymes are produced whether or not a r-lactam is Ylococcus epidermidis. E. coli, P. aeruginosa, N. present. Generally, ,-lactamases are produced in gonorrhoeae, and Bacteroides species. Although the small quantities and are located in the periplasmic physician may be able to overcome this by using space near the antibiotic s target. Multiple P-lacta- another ,-lactam that binds to other PBPs, it is usually mases may be present in the same organism; they necessary to rely on other types of antibiotic therapy. .16 Penicillins, Monobactams, and Carbapenems I Wume 1 7. Number 4, 1990 General Side Effects malaise, urticaria, joint pains, and lymphadenopathy. Erythema nodosum and exfoliative dermatitis occur Because the mechanism of action of 3-lactam anti- much less frequently. Hematologic side effects in- biotics is directed against the synthesis of the bacte- clude transient neutropenia, leukopenia, thrombo- rial cell wall, and because human cells have no such cytopenia, maturation arrest, and Coombs'-positive structure, these antibiotics are among the least toxic hemolytic anemia. All of these side effects are attrib- in our armamentarium. Many 3-lactam antibiotics uted to hypersensitivity reactions, but some occur share side effects in common, and these reactions will only at high doses. A coagulation disorder related to be discussed in this section. Side effects unique to a impaired platelet aggregation has been associated specific antibiotic will be discussed in the section with high-dose penicillin-G therapy (> 24 million concerning that antibiotic. Major categories of side units daily) but is more common with carbenicillin effects include hypersensitivity reactions, as well and ticarcillin. as gastrointestinal, hematologic, renal, hepatic, and Gastrointestinal side effects, which primarily fol- neurologic sequelae. ,-lactams interfere with some