Sulfa Drugs and Beta-Lactam Antibiotics Part 2 PDF

The more lipophilic the side chain of a penicillin, the more serum protein bound the antibiotic (Table 29.6). 70 Stability of the penicillins toward β-lactamase is influenced by the bulk in the acyl group attached to the primary amine. βLactamases are much less tolerant to the presence of steric hin...

The more lipophilic the side chain of a penicillin, the more serum protein bound the antibiotic (Table 29.6). 70 Stability of the penicillins toward β-lactamase is influenced by the bulk in the acyl group attached to the primary amine. βLactamases are much less tolerant to the presence of steric hindrance near the side chain amide bond than are the penicillin binding proteins. The stability of methicillin to β-lactamases is an example of this. When the aromatic ring is attached directly to the side chain carbonyl and both ortho positions are substituted by methoxy groups, β-lactamase stability results (Fig. below). β-lactamase–resistant/–sensitive structural features. 71 Movement of 1 of the methoxy groups to the para position or replacing one of them with a hydrogen results in an analogue sensitive to β-lactamases. Putting in a methylene between the aromatic ring and 6-aminopenicillic acid likewise produces a βlactamase–sensitive agent (Fig. below). These findings provide strong support for the hypothesis that its resistance to enzyme degradation is based on differential steric hindrance. Prime examples of this effect are seen in nafcillin and dicloxacillin (Table 29.4 slide 57). β-lactamase–resistant/–sensitive structural features. 72 Mechanism of Action. The molecular mode of action of the βlactam antibiotics is a selective and irreversible inhibition of the enzymes processing the developing peptidoglycan layer. Cell wall cross-linking and mechanism of action of β-lactams. Path A represents the normal cross-linking mechanism. Path B illustrates the reaction of β-lactam 73 antibiotics with the penicillin-binding protein (PBP). Path A. Just before cross-linking occurs, the peptide pendant from the lactate carboxyl of a muramic acid unit terminates in a d- alanyl-d-alanine unit. The terminal d-alanine unit is exchanged for a glycine unit on an adjacent strand in a reaction catalyzed by a cell wall transamidase. This enzyme is one of the penicillin binding proteins (carboxypeptidases, endopeptidases, and transpeptidases) that normally reside in the bacterial inner membrane and perform construction, repair, and housekeeping functions, maintaining cell wall integrity and playing a vital role in cell growth and division. They differ significantly between species and even individual strains, and this fact is used to rationalize different potency and morphologic outcomes following β-lactam attack on the different bacteria. 74 The cell wall transamidase uses a serine hydroxyl group to attack the penultimate d-alanyl unit forming a covalent ester bond, and the terminal d-alanine, which is released by this action, diffuses away. The enzyme-peptidoglycan ester bond is attacked by the free amino end of a pentaglycyl unit of an adjacent strand, regenerating the transpeptidase’s active site for further catalytic action and producing a new amide bond, which connects two adjacent strands together. Path B. The penicillins and the other β-lactam antibiotics have a structure that closely resembles that of acylated d-alanyl-dalanine. The enzyme mistakenly accepts the penicillin as though it were its normal substrate. 75 The highly strained β-lactam ring is much more reactive than a normal amide moiety, particularly when fused into the appropriate bicyclic system. The intermediate acyl-enzyme complex is rather different structurally from the normal intermediate in that the hydrolysis does not break penicillin into two pieces as it does with its normal substrate. In the penicillins, a heterocyclic residue is still covalently bonded and cannot diffuse away as the natural terminal d-alanine unit does. This presents a steric barrier to approach by the nearby pentaglycyl unit and thus keeps the enzyme’s active site from being regenerated and the cell wall precursors from being cross-linked. The result is a defective cell wall and an inactivated enzyme. 76 The relief of strain that is obtained on enzymatic β-lactam bond cleavage is so pronounced that there is virtually no tendency for the reaction to reverse. Water is also an insufficiently effective nucleophile and cannot hydrolyze the complex either. Thus, the cell wall transamidase is stoichiometrically inactivated. The gaps in the cell wall produced by this covalent interruption are not filled in because the enzyme is now inactivated. The resulting cell wall is structurally weak and subject to osmotic stress. Cell lysis can result, and the cell rapidly dies assisted by another class of bacterial enzymes, the autolysins. 77 Resistance. Resistance to β-lactam antibiotics is increasingly common and is rather alarming. It can be intrinsic and involve decreased cellular uptake of drug, or involve lower binding affinity to the protein binding proteins. This is particularly the case with methicillin-resistant Staphylococcus aureus (MRSA). MRSA produces a mutated PBP-2 (PBP-2a) that does not efficiently bind methicillin any longer. More common, is the production of β-lactamases. β-Lactamases are enzymes (usually serine proteases) elaborated by microorganisms that catalyze hydrolysis of the β-lactam bond and inactivate β-lactam antibiotics to penicilloic acids before they can reach the protein binding proteins (se next slide). 78 β-lactamase–catalyzed hydrolysis of penicillins. 79 β-Lactamases resemble the cell wall transamidase, which is the usual target. Hydrolytic regeneration of the active site is dramatically more facile with β-lactamases than is the case with cell wall transamidase, so that the enzyme can turn over many times and a comparatively small amount of enzyme can destroy a large amount of drug. With gram-positive bacteria, such as staphylococci, the βlactamases are usually shed continuously into the medium and meet the drug outside the cell wall (see Fig. slide 46). They are biosynthesized in significant quantities. 80 With gram-negative bacteria, the β-lactamases are secreted into the periplasmic space between the inner and outer membrane so, while still distal to the protein binding proteins, they do not readily escape into the medium and need not be resynthesized as often (see figure slide 51). Allergenicity. Most commonly, the allergy is expressed as a mild drug rash or itching and is of delayed onset. Occasionally, the reaction is immediate and profound. It may include cardiovascular collapse and shock and can result in death. 81 Benzylpenicillin Group. Benzylpenicillin (Penicillin G, Table 29.4 slide 57). With the exception of Neisseria gonorrhoeae and Haemophilus influenzae, and a few bacteria encountered less frequently, the useful antimicrobial spectrum of benzylpenicillin is primarily against gram-positive cocci. Because of its cheapness, efficacy, and lack of toxicity (except for acutely allergic patients), benzylpenicillin remains a remarkably useful agent for treatment of diseases caused by susceptible microorganisms. 82 Phenoxymethylpenicillin (Penicillin V, Table 29.4). Penicillin V is produced by fermentation where the medium is enriched in phenoxyacetic acid. It can also be prepared by semisynthesis. It is considerably more acid stable than benzylpenicillin as indicated by oral absorption (Table 29.5). This is rationalized as being due to the electronegative O atom in the C-7 amide side chain inhibiting participation in β-lactam bond hydrolysis. In any case, penicillin V was the first of the so-called oral penicillins giving higher and more prolonged blood levels than penicillin G itself. Its antimicrobial and clinical spectrum is roughly the same as that of benzylpenicillin, although it is somewhat less potent and is not used for acutely serious infections. Penicillin V has approximately the same sensitivity to β-lactamases and allergenicity as penicillin G. 83 Penicillinase-Resistant Penicillins. Nafcillin (Table 29.4). Nafcillin has a 2-ethoxynaphthyl side chain. This bulky group serves to inhibit destruction by β-lactamases analogous to methicillin. Increased steric bulk in the side chain leads to a β-lactamase– resistant drug. Nafcillin has a narrow antimicrobial spectrum so is used clinically for infections due to β-lactamase–producing S. aureus and a few other gram-positive organisms. 84 Dicloxacillin. Using a substituted isoxazolyl ring as a bioisosteric replacement for the benzene ring of penicillin G produces the isoxazolyl penicillins (oxacillin and dicloxacillin). These drugs are generally less potent than benzylpenicillin against gram-positive microorganisms (generally staphylococci and streptococci) that do not produce a β-lactamase but retain their potency against those that do. They are somewhat more acid stable; thus they may be taken orally. Because they are highly serum protein bound (Table 29.6). Like nafcillin, the isoxazolyl group of penicillins is primarily used against penicillinase-producing S. aureus. 85 Penicillinase-Sensitive, Broad-Spectrum, Oral Penicillins. Ampicillin (Table 29.4 slide 57). Many common gram-negative pathogens are sensitive to ampicillin. This is believed to be due to greater penetration of ampicillin into gram-negative bacteria. The acid stability is believed to be caused by the electron-withdrawing character of the protonated primary amine group reducing the side chain carbonyl participation in hydrolysis of the β-lactam bond as well as to the comparative difficulty of bringing H3O+ into the vicinity of the protonated amino group. The oral activity is also enhanced, in part, to active uptake by the dipeptide transporters. It lacks stability toward β-lactamases, and resistance is increasingly common. Several β-lactamase inhibitors for coadministration have been developed that restore many penicillinase-producing strains to the clinical spectrum of the aminopenicillins. 86 Amoxicillin (Table 29.4 slide 57). The p-phenolic hydroxyl group in the side chain phenyl moiety adjusts the isoelectric point of the drug to a more acidic value and is believed to be partially responsible, along with the intestine dipeptide transporter, for the enhanced blood levels obtained with amoxicillin compared with ampicillin itself (Table 29.5). Better oral absorption leads to less disturbance of the normal gastrointestinal flora and less drug-induced diarrhea. The antimicrobial spectrum and clinical uses of amoxicillin are approximately the same as those of ampicillin. 87 The addition of clavulanic acid (below) to amoxicillin gives a combination (Augmentin) in which the clavulanic acid serves to protect amoxicillin to a considerable extent against β-lactamases. This expands the spectrum of activity to include organisms and strains that produce β-lactamases. 88 Clavulanic Acid. It is a mold product that has only weak intrinsic antibacterial activity but is an excellent irreversible inhibitor of most β-lactamases. It is believed to acylate the active site serine by mimicking the normal substrate. While hydrolysis occurs with some β-lactamases, in many cases, subsequent reactions occur that inhibit the enzyme irreversibly. This leads to its classification as a mechanism-based inhibitor (or so-called suicide substrate). The precise chemistry is not well understood (slide next slide), but when clavulanic acid is added to amoxicillin and ticarcillin preparations, the potency against β-lactamase–producing strains is markedly enhanced. 89 Speculative mechanism for irreversible inactivation of β-lactamase by clavulanic acid and sulbactam. 90 Sulbactam. It is prepared by partial chemical synthesis from penicillins. The oxidation of the S atom to a sulfone (SO2) greatly enhances the potency of sulbactam. The combination of sulbactam and ampicillin (Unasyn) is also clinically popular. Not all βlactamases are sensitive to the presence of clavulanic acid or sulbactam. 91 Penicillinase-Sensitive, Broad-Spectrum, Parenteral Penicillins. Ticarcillin (Table 29.4 slide 57). It is a S-based bioisostere of benzylpenicillin in which one of the methylene hydrogens of the side chain has been substituted with a carboxylic acid moiety. Ticarcillin is classified as a carboxy penicillin. The addition of this functional group increases the water solubility of the drug and significantly enhances the potency against gram-negative organisms by increasing penetration through hydrophilic porins in these organisms. The drug is susceptible to β-lactamases and is acid unstable and thus must be given by injection. When potassium clavulanate is added to ticarcillin (Timentin), the combination has enhanced spectrum due to its enhanced stability to lactamases. 92 Piperacillin (Table 29.4 slide 57). This ampicillin analogue is referred to as an acylureidopenicillin and preserve the useful anti–grampositive activity of ampicillin but has a higher anti–gram-negative potency. Some strains of P. aeruginosa are sensitive to this agent. It is speculated that the added side chain moiety mimics a longer segment of the peptidoglycan chain than ampicillin does. This cell wall fragment is usually a tetrapeptide, so there is expected to be room for an extension in this direction. This would give more possible points of attachment to the penicillin-binding proteins, and perhaps these features are responsible for the enhanced antibacterial properties. This agent is used on gram-negative bacteria, especially K. pneumoniae and the anaerobe, B. fragilis. Resistance due to β-lactamases is a prominent feature of its use. 93 Piperacillin and Tazobactam Combination (Zosyn). Tazobactam is often coadministered with piperacillin because of tazobactam’s ability to inhibit β-lactamases. Tazobactam, like other β-lactamase inhibitors, has little or no antibacterial activity. This effect is analogous to that of clavulanic acid and sulbactam. This combination is the broadest spectrum penicillin currently available. 94 Cephalosporins. History. Abraham and Newton described the structure of the first cephalosporin, cephalosporin C. The compound was not very potent, it had activity against some penicillin-resistant cultures due to its stability to β-lactamases. Cephalosporin C is not potent enough to be a useful antibiotic, but removal, through chemical means, of the natural side chain produced 7-aminocephalosporanic acid, which, analogous to 6aminopenicillanic acid, could be fitted with unnatural side chains (see figure next slide). 95 5 4 6 7 3 1 2 10 Chemical preparation of 7-ACA and 7-ADCA. 96 Chemical Properties. The cephalosporins have their β-lactam ring fused to a six-membered dihydrothiazine ring, in contrast to the penicillins where the β-lactam ring is fused to a five-membered thiazolidine ring. As a consequence of the bigger ring, the cephalosporins should be less strained and less reactive/potent. However, much of the reactivity loss is made up by possession of an olefinic linkage at C-2,3 and a methyleneacetoxy or other leaving group at C-3. When the β-lactam ring is opened by hydrolysis, the leaving group can be ejected, carrying away the developing negative charge. This greatly reduces the energy required for the process (see figure next slide). 97 7 4 3 2 Thus the facility with which the β-lactam bond of the cephalosporins is broken is modulated both by the nature of the C-7 substituent (analogous to the penicillins) as well as the nature of the C-3 substituent and its ability to serve as a leaving group. Considerable support for this hypothesis comes from the finding that isomerization of the olefinic linkage to C-3,4 leads to great losses in antibiotic activity. Most cephalosporins are comparatively unstable in aqueous solutions. 98 Metabolism. The cephalosporins that have an acetyl group in the side chain are subject to enzymatic hydrolysis in the body. This results in a molecule with a hydroxymethyl moiety at C-3. A hydroxy moiety is a poor leaving group, so this change is considerably deactivating with respect to breakage of the β-lactam bond. In addition, the particular geometry of this part of the molecule leads to facile lactonization with the carboxyl group attached to C-2 (see figure next slide). 99 3 2 Metabolism of C-3-acetyl–substituted cephalosporins. 100 This results is an inactivation of the drugs. The penicillin binding proteins have an absolute requirement for a free carboxyl group to mimic that of the terminal carboxyl of the d-alanyl-d-alanine moiety in their normal substrate. Lactonization masks this docking functional group and, as a result, blocks affinity of the inhibitor for the enzyme. 101 Structure-Activity Relationship. The addition of an amino and a H to the α and α′ positions, respectively, results in a basic compound that is protonated under the acidic conditions of the stomach. The ammonium ion improves the stability of the β-lactam of the cephalosporin, leading to orally active drugs. The 7β amino group is essential for antimicrobial activity (X = H), whereas replacement of the hydrogen at C-7 (X = H) with an alkoxy (X = OR) results in improvement of the antibacterial activity of the cephalosporin. 102 Within specific cephalosporin derivatives, the addition of a 7α CH3O also improves the drugs stability toward β-lactamase. The derivatives where Y = S exhibit greater antibacterial activity than if Y = O, but the reverse is true when stability toward β-lactamase is considered. The 6α H is essential for biologic activity. And finally, antibacterial activity is improved when Z is a five-membered heterocycle versus a six-membered heterocycle. 103 The following changes improved β-lactamase resistance: (1) the l-isomer of an α amino α′ hydrogen derivative of a cephalosporin was 30-40 times more stable than the d-isomer; (2) the addition of a methoxyoxime to the α and α′ positions increased stability nearly 100-fold; and (3) the Z-oxime was as much as 20,000-fold more stable than the E-oxime (see figure below). These changes have been incorporated into a number of marketed and experimental cephalosporins (e.g., cefuroxime, ceftizoxime, ceftazidime, cefixime). Z and E oxime configuration. 104 Mechanism of Action. The cephalosporins are believed to act in a manner analogous to that of the penicillins by binding to the penicillin-binding proteins followed by cell lysis (figure slide 73). Cephalosporins are bactericidal in clinical terms. Resistance. Susceptible cephalosporins can be hydrolyzed by βlactamases before they reach the penicillin-binding proteins. Certain β-lactamases are constitutive (chromosomally encoded) in certain strains of gram-negative bacteria (Citrobacter, Enterobacter, Pseudomonas, and Serratia) and are normally repressed. These can be induced by certain β-lactam antibiotics (e.g., imipenem, cefotetan, and cefoxitin). Specific examples will be seen in the next slides wherein resistance to β-lactamase hydrolysis is conveyed by strategic steric bulk near the side chain amide linkage. Penetration barriers to the cephalosporins are also known. 105 Allergenicity. Allergenicity is less commonly experienced and is less severe with cephalosporins than with penicillins. Cephalosporins are frequently administered to patients who have had a mild or delayed penicillin reaction; however, cross allergenicity is possible. Nomenclature and Classification. Most cephalosporins have generic names beginning with cef- or ceph-. The cephalosporins are classified by a trivial nomenclature system loosely derived from the chronology of their introduction but more closely related to their antimicrobial spectrum. 106 The first-generation cephalosporins are primarily active in vitro against gram-positive cocci (penicillinase-positive and -negative S. aureus and S. epidermis), group A β-hemolytic streptococci (S. pyogenes), group B streptococci (S. agalactiae), and S. pneumoniae. They are not effective against methicillin-resistant Staphylococcus aureus. They are not significantly active against gram-negative bacteria, although some strains of E. coli, K. pneumoniae, P. mirabilis, and Shigella sp. may be sensitive. 107 The second-generation cephalosporins generally retain the anti– gram-positive activity of the first-generation agents but include H. influenzae as well and add to this better anti–gram-negative activity, so that some strains of Acinetobacter, Citrobacter, Enterobacter, E. coli, Klebsiella, Neisseria, Proteus, Providencia, and Serratia are also sensitive. Cefotetan and cefoxitin also have antianaerobic activity as well. 108 The third-generation cephalosporins are less active against staphylococci than the first-generation agents but are much more active against gram-negative bacteria than either the first- or the second-generation drugs. They are frequently particularly useful against nosocomial multidrug-resistant hospital-acquired strains. Morganella sp. and P. aeruginosa can also be added to the list of species that are often sensitive. Newer third-generation agents have been combined with β- lactamase inhibitors to further improve the spectrum against βlactamase–producing strains. 109 The fourth-generation cephalosporins have an antibacterial spectrum like enterobacteria the third-generation drugs that are to resistant the but add some third-generation cephalosporins. They are also more active against some grampositive organisms. Adverse Effects. Aside from mild or severe allergic reaction, the most commonly experienced cephalosporin toxicities are mild and temporary nausea, vomiting, and diarrhea. 110 First-Generation Cephalosporins 111 At C-3 a thio-linked thiadiazole ring is in cefazolin. This group is an activating leaving group, the moiety is not subject to the inactivating host hydrolysis reaction. Cephalexin does not have an activating side chain at C-3, and as a consequence is somewhat less potent. It does not undergo metabolic deactivation and thus maintains potency. 112 Second-Generation Cephalosporins 113 The N-methyl-5-thiotetrazole (MTT) group enhances potency and prevents metabolism by deacetylation. Cefuroxime has a Z-oriented methoxyimino moiety as part of its C-7 side chain. This conveys considerable resistance to attack by many β-lactamases but not by all. This is believed to result from the steric demands of this group. Resistance by P. aeruginosa is attributed to lack of penetration of the drug rather than to enzymatic hydrolysis. The carbamoyl moiety at C-3 is intermediate in metabolic stability between the classic acetyl moieties and the thiotetrazoles. 114 Cefuroxime axetil is a prodrug. The ester bond is cleaved metabolically, and the resulting intermediate form loses acetaldehyde spontaneously to produce cefuroxime itself. 115 Cefoxitin. The most novel chemical feature of cefoxitin is the possession of an α-oriented methoxyl group in place of the normal H-atom at C-7. This increased steric bulk conveys very significant stability against β-lactamases. Agents that contain this 7α methoxy group are commonly referred to as cephamycins. Cefoxitin has useful activity against gonorrhea and against some anaerobic infections (including B. fragilis) as compared with its secondgeneration relatives. On the negative side, cefoxitin has the capacity to induce certain broad-spectrum β-lactamases. 116 Cefotetan. It is a cephamycin. Like cefoxitin, cefotetan : - has better activity against anaerobes than the rest of this group, - is stable to a wide range of β-lactamases but is also an inducer in some bacteria. Cefaclor. It is quite acid stable and also quite stable to metabolism. It is less active against gram-negative bacteria than the other second-generation cephalosporins but is more active against gram- negative bacteria than the first-generation drugs. Cefprozil. The C=C bond is present in its 2 geometric isomeric forms, both of which exhibit antibacterial activity. The predominant trans form (Table 29.8) is much more active against gram-negative organisms. Cefprozil most closely resembles cefaclor in its properties but is a little more potent. 117 Third-Generation Cephalosporins 118 119 Cefotaxime. The Z-methoxyimino moiety at C-7 conveys significant β-lactamase resistance. It has excellent anti–gram-negative activity. It has a metabolically vulnerable acetoxy group attached to C-3 and loses about 90% of its activity when this is hydrolyzed. Cefotaxime should be protected from heat and light and may color slightly without significant loss of potency. Cefotaxime has less activity against staphylococci but has greater activity against gram-negative organisms. Ceftizoxime. The whole C-3 side chain has been omitted to prevent deactivation by hydrolysis. It rather resembles cefotaxime in its properties; however, not being subject to metabolism, its pharmacokinetic properties are much less complex. 120 Ceftriaxone. The C-3 side chain consists of a metabolically stable and activating thiotriazinedione in place of the normal acetyl group. The C-3 side chain is sufficiently acidic that at normal pH, it forms an enolic sodium salt, and thus the commercial product is a disodium salt. It is useful for many severe infections and notably in the treatment of some meningitis infections caused by gram-negative bacteria. It is quite stable to many β-lactamases but is sensitive to some inducible chromosomal β-lactamases. 121 Ceftazidime with avibactam. Ceftazidime has more pronounced βlactamase stability, greater P. aeruginosa activity, and increased activity against gram-positive organisms. The C-3 side chain is charged pyridinium moiety which enhances water solubility and also highly activates the β-lactam bond toward cleavage. It is attacked readily in sodium bicarbonate solutions. Resistance is mediated by chromosomally mediated β-lactamases and also by lack of penetration into target bacteria. It has a very broad antibacterial spectrum. It has been combined with avibactam (broad-spectrum βlactamase inhibitor) to treat urinary tract infections caused by β- lactamase–producing organisms. 122 Cefixime. It has anti–gram-negative activity intermediate between that of the second-generation and third-generation agents. It is poorly active against staphylococci because it does not bind satisfactorily to a specific penicillin binding protein (PBP-2). Ceftibuten. It has an enhanced β-lactamase stability and may contribute to oral activity as well. Ceftibuten has no C-3 side chain and thus is not measurably metabolized. It is highly (75%-90%) absorbed on oral administration, but this is decreased significantly by food. Being lipophilic and acidic, it is significantly serum protein bound (65%). Some isomerization of the geometry of the olefinic linkage appears to take place in vivo before excretion. It is mainly used for respiratory tract infections, otitis media, and pharyngitis, as well as urinary tract infections by susceptible microorganisms. 123 Cefpodoxime Proxetil. It is a prodrug. It is cleaved enzymically to isopropanol, CO2, acetaldehyde, and cefpodoxime in the gut wall. It has better anti–Staphylococcus aureus activity than cefixime and is used to treat pharyngitis, urinary tract infections, upper and lower respiratory tract infections, otitis media, skin and soft tissue infections, and gonorrhea. Cefdinir. It has an enhanced anti–gram-positive activity. It has reasonable resistance to β-lactamases. 124 Cefditoren Pivoxil. It is an orally active prodrug. The pivoxil ester is hydrolyzed following intestinal absorption to release the active drug, cefditoren, along with formaldehyde and pivalic acid. The bioavailability of cefditoren pivoxil is increased if taken with food. It is indicated for mild to moderate infections in adults and adolescents with chronic bronchitis, pharyngitis/tonsillitis, and uncomplicated skin infections associated with gram-negative bacteria. 125 Fourth-Generation Cephalosporins Cefepime. It is a semisynthetic agent containing a Z-methoxyimine moiety and an aminothiazolyl group at C-7, broadening its spectrum, increasing its β-lactamase stability, and increasing its antistaphylococcal activity. The quaternary N-methylpyrrolidine group at C-3 seems to help penetration into gram-negative bacteria. The fourth-generation cephalosporins are characterized by enhanced antistaphylococcal activity and broader anti–gramnegative activity than the third-generation group. It is used against urinary tract infections, skin and skin structure infections, pneumonia, and intra-abdominal infections. 126 Ceftaroline Fosamil. It is bactericidal against methicillin-resistant Staphylococcus aureus due to its affinity for PBP-2a and against S. pneumoniae due to its affinity for PBP-2x. It can be used to treat methicillin-resistant Staphylococcus aureus infections of skin and soft tissues. It is administered as a water-soluble prodrug that is readily hydrolyzed to the active ceftaroline (loss of the phosphate ester). 127 Carbapenems. Thienamycin, the first of the carbapenems, was isolated from Streptomyces cattleya. It differs structurally from the penicillins and cephalosporins. The S atom is not part of the five-membered ring but rather has been replaced by a methylene moiety at that position. 128 The carbapenem ring system is highly strained and very susceptible to reactions cleaving the β-lactam bond (including reaction between 2 molecules resulting in inactivation). Inactivation of thienamycin via intermolecular reaction. 129 Carbapenems bind differently to the penicillin-binding proteins (especially strongly to PBP-2), but the result is very potent broad- spectrum activity. However, none of the current carbapenems have activity against methicillin-resistant Staphylococcus aureus. Imipenem (structure next slide), like thienamycin, penetrates very well through porins and is very stable, even inhibitory, to many βlactamases. Imipenem is not orally active. Renal dehydropeptidase-l metabolizes imipenem through hydrolysis of the β-lactam and deactivates it. An inhibitor for this enzyme, cilastatin, is coadministered with imipenem to protect it. The combination of imipenem and cilastatin is useful for treatment of serious infections by aerobic gram-negative bacilli, anaerobes, and S. aureus. 130 Carbapenem antibiotics and coadministered compounds. 131 Meropenem is a synthetic carbapenem. It has a chiral methyl group at C-4 which conveys intrinsic resistance to hydrolysis by dehydropeptidase-1. Doripenem contains the 4-β-methyl group, which confers stability toward dehydropeptidase-1. It is similar in spectrum to imipenem and meropenem but is considered more potent against Pseudomonas species. Ertapenem is another synthetic carbapenem. The 4-β-methyl group confers stability toward dehydropeptidase-1. It is not active against Pseudomonas or Acinetobacter and thus should not be substituted for other carbapenems for these organisms. 132 Monobactams. They are a class of monocyclic β-lactam antibiotics. Aztreonam is a totally synthetic antibiotic whose antimicrobial spectrum is devoted almost exclusively to gramnegative microorganisms, and it is capable of inactivating some βlactamases. Its molecular mode of action is closely similar to that of the penicillins, cephalosporins, and carbapenems, the action being characterized by strong affinity for PBP-3, producing filamentous cells as a consequence. 133 The monobactams demonstrate that a fused ring is not essential for antibiotic activity. The α-oriented methyl group at C-2 is associated with the stability of aztreonam toward β-lactamases. The protein binding is moderate (∼50%), and the drug is nearly unchanged by metabolism. Aztreonam is primarily excreted in the urine. Aztreonam is used against severe infections caused by gramnegative microorganisms (mainly urinary tract, upper respiratory tract, bone, cartilage, abdominal, obstetric, and gynecologic infections and septicemias). 134