Cell Envelope Disruptors: β-Lactam, Glycopeptide, and Lipopeptide Antibacterials PDF

58 Chapter Cell Envelope Disruptors: β-Lactam, Glycopeptide, and Lipopeptide Antibacterials Conan MacDougall...

58 Chapter Cell Envelope Disruptors: β-Lactam, Glycopeptide, and Lipopeptide Antibacterials Conan MacDougall β-LACTAMS: MECHANISMS OF ACTION THE CEPHALOSPORINS Mechanism of Action β-LACTAMS: MECHANISMS OF BACTERIAL Mechanism of Bacterial Resistance RESISTANCE Classification and General Pharmacology ADME and Agent-Specific Antibacterial Activity β-LACTAMASE INHIBITORS Adverse Reactions Therapeutic Uses THE PENICILLINS OTHER β-LACTAM ANTIBIOTICS Classification of the Penicillins and Summary of Their Pharmacological Carbapenems Properties Monobactams Penicillin G and Penicillin V The Penicillinase-Resistant Penicillins OTHER CELL ENVELOPE DISRUPTORS The Aminopenicillins: Ampicillin and Amoxicillin Glycopeptides Antipseudomonal Penicillins: The Carboxypenicillins and the Lipopeptides Ureidopenicillins Bacitracins The bacterial cellular envelope typically consists of the inner membrane, polymer. The cross-link is completed by a transpeptidation reaction that the cell wall, and, in gram-negative organisms, the outer membrane. occurs outside the plasma membrane (Figure 58–1B). The cell envelope is a key target for antibacterial agents, including the The β-lactam antibiotics inhibit this last step in peptidoglycan synthe- β-lactam antibiotics, glycopeptides, and lipopeptides, as well as other sis (Figure 58–2) by acylating the transpeptidase via cleavage of the –CO–N– minor classes (including bacitracin, discussed below, and polymyxins, bond of the β-lactam ring. The transpeptidase targets for the actions of discussed in Chapter 59). β-Lactam antibiotics—penicillins, cephalo- β-lactam antibiotics are collectively termed penicillin-binding proteins sporins, carbapenems, and monobactams—share a common structure (PBPs). Notably, bacteria may produce multiple functionally related but (β-lactam ring) and mechanism of action (i.e., inhibition of the synthesis distinct PBPs, and each PBPs can have varying affinities for individual of the bacterial peptidoglycan cell wall). β-Lactams are the single most β-lactams. The lethality of penicillins for bacteria appears to involve both important antibacterial class given their broad and varied spectrum of lytic and nonlytic mechanisms (Bayles, 2000), and inhibition of some activity, their potent antibacterial killing, and their generally favorable PBPs may be more consequential than others for bacterial killing. tolerability. Unfortunately, resistance to β-lactams has steadily increased, requiring development of new agents, which can evade (e.g., ceftaroline) or neutralize (e.g., β-lactamase inhibitors) these mechanisms. The β-Lactams: Mechanisms of Bacterial Resistance glycopeptides, including vancomycin, and lipopeptides (daptomycin) Bacterial resistance to β-lactam antibiotics typically occurs through one provide important treatment alternatives for infections due to gram- of three mechanisms: alterations in the PBP target, reduction of concen- positive organisms. tration at the target site, and/or enzymatic degradation of the β-lactam itself. A sensitive strain may acquire resistance via mutations that decrease the affinity of PBPs for the antibiotic or by acquiring the abil- β-Lactams: Mechanisms of Action ity to express new, low-affinity PBPs (e.g., via plasmid transfer). Altered The bacterial cell wall is comprised of heteropolymeric peptidoglycan PBPs with decreased affinity for β-lactam antibiotics can also be acquired that provides rigid mechanical stability. The β-lactam antibiotics inhibit by homologous recombination between PBP genes of different bacterial the last step in peptidoglycan synthesis. In gram-positive microorgan- species (Zapun et al., 2008). Four of the five high-molecular-weight PBPs isms, the cell wall is 50 to 100 molecules thick; in gram-negative bacteria, of the most highly penicillin-resistant Streptococcus pneumoniae isolates it is only one or two molecules thick (Figure 58–1A). The peptidoglycan have decreased affinity for β-lactam antibiotics as a result of interspecies is composed of glycan chains, which are linear strands of two alternat- homologous recombination events. In contrast, isolates with high-level ing amino sugars (N-acetylglucosamine and N-acetylmuramic acid), that resistance to third-generation cephalosporins contain alterations of only are cross-linked by peptide chains. Peptidoglycan precursor formation two of the five high-molecular-weight PBPs because the other PBPs have takes place in the cytoplasm. The synthesis of UDP–acetylmuramyl- inherently low affinity for the third-generation cephalosporins. Methicillin- pentapeptide is completed with the addition of a dipeptide, d-alanyl- resistant Staphylococcus aureus (MRSA) is resistant via acquisition of an d-alanine, which is formed by racemization and condensation of additional high-molecular-weight PBP (via a transposon) with a very low l-alanine. UDP-acetylmuramyl-pentapeptide and UDP-acetylglucosamine affinity for all β-lactam antibiotics; this mechanism is also responsible for are linked with the release of the uridine nucleotides to form a long methicillin resistance in the coagulase-negative staphylococci. In general, https://ebooksmedicine.net/  1148 Abbreviations serve as another mechanism of resistance, removing the antibiotic from its site of action before it can act (Figure 58–3) (Fernández and Hancock, 2012). ESBL: extended-spectrum β-lactamase Bacteria also can inactivate β-lactam antibiotics enzymatically via GI: gastrointestinal the action of β-lactamases (see Figure 58–1A). Thousands of different β-lactamases have been variously characterized by according to their CHAPTER 58 CELL ENVELOPE DISRUPTORS: β-LACTAM, GLYCOPEPTIDE, AND LIPOPEPTIDE ANTIBACTERIALS KPC: Klebsiella pneumoniae carbapenemase MIC: minimum inhibitory concentration molecular class or functional characteristics (Bush and Jacoby, 2010). MRSA: methicillin-resistant Staphylococcus aureus Their substrate specificities can be relatively narrow or can extend MRSE: methicillin-resistant Staphylococcus epidermidis to almost all β-lactams. In general, gram-positive bacteria produce PBP: penicillin-binding protein and secrete a large amount of β-lactamase, typically narrow-spectrum penicillinases. The sequence for staphylococcal penicillinase is encoded in a plasmid; this may be transferred by bacteriophage to other bacteria and their expression is inducible by substrate antibiot- ics. In gram-negative bacteria, β-lactamases are found in lower quan- resistance via alterations to the β-lactam target is more common among tities, but their location in the periplasmic space between the inner gram-positive versus gram-negative bacterial pathogens. and outer membranes (see Figure 58–1A) provides maximal pro- Bacterial resistance to β-lactam antibiotics also results from the inabil- tection of the microbe. β-Lactamases of gram-negative bacteria are ity of the agent to achieve sufficient concentrations at its site of action encoded either chromosomally or via transferable elements such as (Fernández and Hancock, 2012). In gram-positive bacteria, the pepti- plasmids; their expression may be constitutive or inducible. Of par- doglycan polymer is very near the cell surface (see Figure 58–1A), and ticular concern are carbapenemases: β-lactamases that are capable small β-lactam antibiotic molecules can penetrate easily to the outer layer of hydrolyzing carbapenems, as well as penicillins and cephalospo- of the cytoplasmic membrane and the PBPs. In gram-negative bacteria, rins. Microorganisms expressing such β-lactamases (along with other the inner membrane is internal to the outer membrane and capsule (see resistance mechanisms) may be resistant to all or almost all antibacte- Figure 58–1A); the outer membrane functions as an impenetrable barrier rials in clinical use (Queenan and Bush, 2007). for some antibiotics. Some small hydrophilic antibiotics, however, diffuse More than one of the aforementioned resistance mechanisms may through aqueous channels in the outer membrane that are formed by pro- be present in a pathogen, and they can work in concert to confer teins called porins. The number and size of pores in the outer membrane resistance. The local environment can also contribute to resistance vary among different gram-negative bacteria, thereby providing greater to β-lactam antibiotics. Microorganisms adhering to implanted or lesser access for antibiotics to the site of action. Active efflux pumps prosthetic devices (e.g., catheters, artificial joints, prosthetic heart A Gram-positive Gram-negative O-Poly-saccharide Porin channel Lipid A β-Lactamase Lipopoly- saccharide Lipoteichoic (LPS) acid Outer Lipoprotein membrane Peptidoglycan layers Periplasmic space β-Lactamase Plasma membrane Phospholipid Penicillin binding protein (PBP) Proteins B Glycopeptide polymer outside the cell NAG NAM NAG NAM NAG NAM L-Alanine D-Glutamate L-Lysine/mDAP Peptidoglycan D-Alanine layer NAM = N-Acetyl-muramic acid NAG = N-Acetyl-glucosamine TP TP = Transpeptidase linker GT = Glucosyltransferase = (gly)5 bridge NAG NAM GT NAG NAM NAG NAM NAG NAM Plasma membrane PBP lipid II Cytosol Figure 58–1 A. Structure and composition of gram-positive and gram-negative cell envelope. B. Penicillin binding protein (PBP) activity and inhibition. PBPs have two enzymatic activities that are crucial to synthesis of the peptidoglycan layers of bacterial cell walls: a transpeptidase that cross-links amino acid side chains, as shown for gram-positives, and a glycosyltransferase that links subunits of the glycopeptide polymer. The transpeptidase and glycosyltransferase domains are separated by a linker region. The glycosyltransferase is thought to be partially embedded in the membrane.  Glycopeptide Glycopeptide the action of the β-lactam antibiotics, which limits the activity of these 1149 polymer polymer drugs against some important intracellular pathogens. NAM NAM β-Lactamase Inhibitors SECTION VII CHEMOTHERAPY OF INFECTIOUS DISEASES Because of the key role that β-lactamases play in conferring resis- tance to β-lactams, an increasing number of β-lactams are coformu- lated with molecules whose role is to “protect” the β-lactam from Reaction site the β-lactamase. These β-lactamase inhibitors bind to β-lactamases penicillins and prevent the enzymes from hydrolyzing β-lactam agents in the cephalosporins Transpeptidase (PBP) vicinity. Older-generation β-lactamase inhibitors (e.g., clavulanate, D-Alanine L-Alanine sulbactam, and tazobactam) inactivate many plasmid-encoded D-Glutamate β-lactamases but fail to provide protection at clinically achievable Glycopeptide Glycopeptide L-Lysine concentrations against the AmpC β-lactamases encoded chromo- polymer polymer Glycine D-Alanine somally in some gram-negative bacilli (e.g., Enterobacter, Citrobacter, NAM NAM NAM = and Pseudomonas), as well as carbapenemases of the Klebsiella pneumoniae carbapenemase (KPC)- and metallo-β-lactamase type. N-Acetyl- muramic acid Avibactam, vaborbactam, and relebactam are new β-lactamase inhib- itors that are structurally dissimilar from the older generation, with a broader spectrum of inhibition. Clavulanic acid has poor intrinsic antimicrobial activity but is an irreversible mechanism-based inhibitor that binds β-lactama- ses produced by a wide range of gram-positive and gram-negative Figure 58–2 Action of b-lactam antibiotics in S. aureus. The bacterial cell microorganisms. Clavulanic acid is well absorbed by mouth and also wall consists of glycopeptide polymers (an NAM-NAG amino-hexose back- can be given parenterally. It is combined with amoxicillin as an oral bone) linked via bridges between amino acid side chains. In S. aureus, the preparation and with ticarcillin as a parenteral preparation (ticarcillin/ bridge is (Gly)5-d-Ala between lysines. The cross-linking is catalyzed by a clavulanate, not available in the U.S.). transpeptidase, the enzyme that penicillins and cephalosporins inhibit. COOH H O C N CH2OH valves) produce biofilms. Bacteria in biofilms secrete a protective O extracellular matrix, which can consist of secreted exopolysaccha- H rides, proteinaceous fibers, and DNA and, in part owing to decreased CLAVULANIC ACID growth rates and drug penetrance, are much less sensitive to antibi- otic therapy (Donlan, 2001). The β-lactam antibiotics are most active Sulbactam is a β-lactamase inhibitor similar in structure to against bacteria in the logarithmic phase of growth and have little clavulanic acid. It is available for intravenous or intramuscular use effect on microorganisms in the stationary phase. Similarly, bacteria combined with ampicillin and with cefoperazone (not available in the that survive inside viable cells of the host generally are protected from U.S.). Sulbactam also possesses intrinsic activity against Acinetobacter spp. and has been used in high dosages to treat multidrug-resistant Acinetobacter infections. Tazobactam is a β-lactamase inhibitor with good activity against many Amphiphillic of the plasmid-mediated β-lactamases, including some of the extended- drug spectrum class. It is available as parenteral combination products with piperacillin and with ceftolozane. Channel Avibactam and relebactam are novel, structurally similar non–β- Outer lactam β-lactamase inhibitors that provide clinically useful inhibition membrane against both narrow- and extended-spectrum β-lactamase (ESBL)-type, Accessory chromosomal AmpC, and KPC-type β-lactamases (although not metallo- protein β-lactamases). Avibactam is coformulated with ceftazidime, while Periplasm relebactam is coformulated with imipenem/cilastatin. Vaborbactam is a novel, boronic acid–based non–β-lactam β-lactamase Cytoplasmic inhibitor that provides broad inhibition of β-lactamases similar to membrane avibactam and relebactam. Vaborbactam is coformulated with meropenem. Efflux transporter The Penicillins Despite the emergence of resistance, the penicillins remain the drugs Figure 58–3 Antibiotic efflux pumps of gram-negative bacteria. Multi- of choice for a significant number of infectious diseases. Penicillins drug efflux pumps traverse both the inner and outer membranes of gram- (Figure 58–4) consist of a thiazolidine ring (A) connected to a β-lactam negative bacteria. The pumps are composed of a minimum of three proteins ring (B) to which is attached a side chain (R). The penicillin nucleus and are energized by the proton motive force. Increased expression of these itself is the chief structural requirement for biological activity. Side pumps is an important cause of antibiotic resistance. (Reprinted with permis- chains can be added that alter the susceptibility of the resulting com- sion from Oxford University Press. Nikaido H. Antibiotic resistance caused pounds to inactivating enzymes (β-lactamases), improve affinity for by gram-negative multidrug efflux pumps. Clin Infect Dis, 1998, 27(suppl 1): PBPs, enhance the ability of the drug to traverse the outer membrane of S32–S41. © 1998 by the Infectious Diseases Society of America. All rights gram-negative bacteria, and change the pharmacokinetic properties of reserved.) the drug (Table 58–1). https://ebooksmedicine.net/  1150 O S CH3 1 Site of action of penicillinase R C NH CH CH C 2 Site of action of amidase B A CH3 A Thiazoline ring 2 B β-lactam ring O C N CH COOH Penicillins CHAPTER 58 CELL ENVELOPE DISRUPTORS: β-LACTAM, GLYCOPEPTIDE, AND LIPOPEPTIDE ANTIBACTERIALS 1 Penicillinase Amidase O S CH3 O S CH3 R CH NH2 CH CH C R C NH CH CH C CH3 CH3 O C N CH COOH O C N CH COOH O OH H R CH 6-Aminopenicillanic acid Penicilloic acids Figure 58–4 Structure of penicillins and products of their enzymatic hydrolysis. Classification of the Penicillins and Summary of are preferred agents for treatment of penicillinase-producing S. aureus and Staphylococcus epidermidis that are not methicillin resistant. Their Pharmacological Properties Ampicillin, amoxicillin, and others such as bacampicillin and pivampicillin Penicillins are classified according to their spectra of antimicrobial (not currently marketed in the U.S.) are the aminopenicillins, whose activity. antimicrobial activity is similar to penicillin G but extends to include Penicillin G and its close congener penicillin V are highly active some gram-negative microorganisms (e.g., Haemophilus influenzae, against sensitive strains of gram-positive cocci, but they are readily Escherichia coli, and Proteus mirabilis) when those pathogens do not hydrolyzed by penicillinases. Thus, they are ineffective against most produce β-lactamases. These drugs are also available as coformulations strains of S. aureus. with a β-lactamase inhibitor, such as clavulanate or sulbactam, which The penicillinase-resistant penicillins methicillin (discontinued in restores activity against some β-lactamase–producing organisms. the U.S.), cloxacillin and flucloxacillin (not currently marketed in the Agents with extended antimicrobial activity against Pseudomonas, U.S.), nafcillin, oxacillin, and dicloxacillin have less-potent antimicrobial Enterobacter, and Proteus spp. include older agents largely out of use: activity against microorganisms that are sensitive to penicillin G, but they azlocillin, carbenicillin, mezlocillin, ticarcillin, ticarcillin/clavulanate, and carbenicillin indanyl sodium (all discontinued in the U.S.). Piperacillin and the coformulation of piperacillin/tazobactam have antimicrobial activity against many isolates of Pseudomonas, E. coli, TABLE 58–1 CHEMICAL STRUCTURES OF SELECTED Klebsiella, and other gram-negative microorganisms. Piperacillin PENICILLINS retains the activity of ampicillin against gram-positive cocci and Listeria monocytogenes. O S CH3 R C NH2 CH CH C CH3 General Common Properties O C N CH COOH Following absorption of an oral dose, penicillins are distributed widely Penicillins are substituted 6-aminopenicillanic acid throughout the body. Therapeutic concentrations of penicillins are achieved readily in tissues and in secretions such as joint fluid, pleural Addition of the substituents (R groups) shown below to the parent fluid, pericardial fluid, and bile. Penicillins do not penetrate living phago- structure produces penicillins with altered susceptibility to inactivating cytic cells to a significant extent, and only low concentrations of these enzymes (β-lactamases), antibacterial activity, and pharmacological drugs are found in prostatic secretions, brain tissue, and intraocular fluid. properties. Concentrations of penicillins in CSF are variable but are less than 1% of R1 those in plasma when the meninges are normal. When there is inflamma- tion, concentrations in CSF may increase to as much as 5% of the plasma value. Penicillins are eliminated rapidly by glomerular filtration and renal Penicillin G tubular secretion, such that their half-lives in the body are short, typically (Benzylpenicillin) R2 30 to 90 min. As a consequence, concentrations of these drugs in urine Oxacillin (R1=R2=H)/Cloxacillin are high. (R1=Cl, R2=H) /Dicloxacillin (R1=R2=Cl) Penicillin G and Penicillin V R Antimicrobial Activity The antimicrobial spectra of penicillin G (benzylpenicillin) and penicillin V (the phenoxymethyl derivative) are similar for aerobic gram-positive Ampicillin (R=-H)/ microorganisms. Most streptococci remain susceptible, but penicillin- Amoxicillin (R=-OH) resistant viridans streptococci and S. pneumoniae are becoming more common. Penicillin-resistant pneumococci are especially common in pediatric populations and may also be resistant to third-generation cephalosporins. Greater than 90% of strains of S. aureus, most strains Piperacillin of S. epidermidis, and many strains of gonococci are now resistant to penicillin G. With rare exceptions, the meningococcus (Neisseria menin- 1151 gitidis) remains quite sensitive to penicillin G. HISTORY Most anaerobic gram-positive microorganisms, including Clostridium spp., are highly sensitive. Activity against gram-negative anaerobes is The history of the brilliant research that led to the discovery and more variable, with the intestinal anaerobe Bacteroides fragilis display- development of penicillin is well chronicled (Lax, 2004). In 1928, SECTION VII CHEMOTHERAPY OF INFECTIOUS DISEASES ing resistance to penicillins and cephalosporins by virtue of expressing while studying Staphylococcus variants in the laboratory at St. Mary’s a broad-spectrum cephalosporinase. Actinomyces israelii, Streptobacillus Hospital in London, Alexander Fleming observed that a mold con- moniliformis, Pasteurella multocida, and L. monocytogenes are inhib- taminating one of his cultures caused the bacteria in its vicinity to ited by clinically achievable concentrations of penicillin G. Spirochetes, undergo lysis. Broth in which the fungus was grown was markedly including Leptospira spp. (leptospirosis), Treponema pallidum (syphilis), inhibitory for many microorganisms. Because the mold belonged to and Borrelia burgdorferi (Lyme disease), are typically penicillin suscep- the genus Penicillium, Fleming named the antibacterial substance tible. Penicillins are not effective against amebae, plasmodia, rickettsiae, penicillin. fungi, or viruses. A decade later, penicillin was developed as a systemic therapeutic agent by the concerted research of a group of investigators at Oxford ADME University headed by Florey, Chain, and Abraham. By May 1940, a Oral Administration of Penicillin G and V. The virtue of penicillin V in crude preparation was found to produce dramatic therapeutic effects comparison with penicillin G is that it is more stable in an acidic medium when administered parenterally to mice with streptococcal infections. and therefore is better absorbed from the gastrointestinal (GI) tract, Sufficient penicillin was accumulated by 1941 to conduct therapeutic yielding plasma concentrations two to five times those provided by pen- trials in several patients desperately ill with staphylococcal and strep- icillin G. Thus, penicillin V is used for oral administration. Absorption is tococcal infections refractory to all other therapy. At this stage, the rapid, and maximal concentrations in blood are attained in 30 to 60 min. crude, amorphous penicillin was only about 10% pure, and it required Ingestion of food may interfere with enteric absorption of all penicillins. nearly 100 L of growth broth to obtain enough of the antibiotic to Thus, oral penicillins should generally be administered at least 30 min treat one patient for 24 h. Bedpans were used by the Oxford group for before a meal or 2 h after. growing cultures of Penicillium notatum. Case 1 in the 1941 report from Oxford was that of a policeman, who was suffering from a severe Parenteral Administration of Penicillin G. After intramuscular injec- mixed staphylococcal and streptococcal infection. He was treated tion, peak concentrations in plasma are reached within 15 to 30 min, with penicillin, some of which had been recovered from the urine of declining rapidly thereafter (t1/2 ~30 min). Repository preparations of other patients who had been given the drug. It is said that an Oxford penicillin G (penicillin G benzathine, penicillin G procaine) increase the professor referred to penicillin as a remarkable substance grown in duration of the effect. The repository compound favored for most indi- bedpans and purified by passage through the Oxford Police Force. cations is penicillin G benzathine, which releases penicillin G slowly from A vast research program soon was initiated in the U.S. There the injection site and produces relatively low but persistent concentrations were 122 million units of penicillin made available during 1942, in the blood. The average duration of demonstrable antimicrobial activ- and the first clinical trials were conducted at Yale University and ity in the plasma is about 26 days for benzathine penicillin G. Penicillin G the Mayo Clinic, with dramatic results. By the spring of 1943, there procaine has a prolonged t1/2 compared to penicillin G, but shorter than that were 200 patients who had been treated with the drug. The results of benzathine formulations; it is typically dosed once daily. Neither depot were so impressive that the surgeon general of the U.S. Army formulation should be given intravenously as serious toxicity can result. authorized a trial of the antibiotic in a military hospital. Soon Distribution. Penicillin G is distributed extensively throughout the thereafter, penicillin was adopted throughout the medical services body, but the concentrations in various fluids and tissues differ widely. Its of the U.S. Armed Forces. apparent volume of distribution is about 0.35 L/kg. Approximately 60% The deep-fermentation procedure for the biosynthesis of penicillin of the penicillin G in plasma is reversibly bound to albumin. Significant marked a crucial advance in the large-scale production of the antibi- amounts appear in liver, bile, kidney, semen, joint fluid, lymph, and intes- otic. From a total production of a few hundred million units a month in tine. Probenecid markedly decreases the tubular secretion of the penicil- the early days, the quantity manufactured rose to over 200 trillion units lins and also produces a significant decrease in the apparent volume of (nearly 150 tons) by 1950. The first marketable penicillin cost several distribution of the penicillins (see Figure 42–2). dollars per 100,000 units; today, the same dose costs only a few cents. Penetration Into Cerebrospinal Fluid. Penicillin does not readily enter the CSF but penetrates more easily when the meninges are inflamed. The concentrations are usually in the range of 5% of the value in plasma and of renal excretion of penicillin G is considerably more rapid than in adults. are therapeutically effective against susceptible microorganisms if the Anuria increases the t1/2 of penicillin G from 0.5 to about 10 h. When renal minimum inhibitory concentration (MIC) of the organism is sufficiently function is impaired, 7% to 10% of the antibiotic may be inactivated each low. Penicillin and other organic acids are secreted rapidly from the CSF hour by the liver. The dose of the drug must be adjusted in patients with into the bloodstream by an active transport process. Probenecid com- renal insufficiency or receiving dialysis. If hepatic insufficiency also is petitively inhibits this transport and thus elevates the concentration of present, the t1/2 will be prolonged even further. penicillin in CSF. In uremia, other organic acids accumulate in the CSF and compete with penicillin for secretion; the drug occasionally reaches Therapeutic Uses toxic concentrations in the brain and can produce convulsions. Pneumococcal Infections. Penicillin G remains the agent of choice for Excretion. Approximately 60% to 90% of an intramuscular dose of pen- the management of infections caused by sensitive strains of S. pneumoniae, icillin G in aqueous solution is eliminated in the urine, largely within the but resistance is an increasing concern. For parenteral therapy of sensi- first hour after injection. The remainder is metabolized to penicilloic tive isolates of pneumococci, penicillin G is favored. Because of concerns acid. The t1/2 for elimination of penicillin G is about 30 min in normal for β-lactam resistance, pneumococcal meningitis should be treated with adults. Approximately 10% of the drug is eliminated by glomerular fil- a combination of vancomycin and a third-generation cephalosporin until tration and 90% by tubular secretion. Renal clearance approximates the it is established that the infecting pneumococcus is penicillin sensitive. total renal plasma flow. Clearance values are considerably lower in neo- Dexamethasone given prior to or at the same time as antibiotics is asso- nates and infants; as a result, penicillin persists in the blood several times ciated with an improved outcome in pneumococcal meningitis (de Gans longer in premature infants than in children and adults. The t1/2 of the et al., 2002). The recommended regimens for severe pneumococcal infec- antibiotic in children less than 1 week of age is 3 h; by 14 days of age, it is tions range from 12 to 24 million units of penicillin G per day by constant 1.4 h. After renal function is fully established in young children, the rate intravenous infusion or divided into boluses every 4 to 6 h for 7 to 14 days. https://ebooksmedicine.net/  1152 β-Hemolytic Streptococcal Infections. Streptococcal pharyngitis is meningitis—are the drugs of choice in the management of infections a common respiratory manifestation of infection due to Streptococcus owing to L. monocytogenes. The recommended dose of penicillin G is 18 pyogenes (group A β-hemolytic Streptococcus). Penicillin-resistant iso- to 24 million units parenterally per day for at least 2 weeks. For endocar- lates have yet to be observed. The preferred oral therapy is with penicillin V, ditis, the dose is the same, but the duration of treatment should be no less 500 mg twice daily for 10 days. Penicillin therapy of streptococcal phar- than 4 weeks. CHAPTER 58 CELL ENVELOPE DISRUPTORS: β-LACTAM, GLYCOPEPTIDE, AND LIPOPEPTIDE ANTIBACTERIALS yngitis reduces the risk of subsequent acute rheumatic fever; however, Pasteurella multocida. P. multocida is a cause of wound infections current evidence suggests that the incidence of glomerulonephritis that after a cat or dog bite. It is susceptible to penicillin G and ampicillin follows streptococcal infections is not reduced to a significant degree by and resistant to penicillinase-resistant penicillins and first-generation treatment with penicillin (Shulman et al., 2012). S. pyogenes is also a com- cephalosporins. mon cause of skin infections, ranging in severity from erysipelas and cel- lulitis to toxic shock and necrotizing fasciitis. The former two infections Prophylactic Uses of the Penicillins can be treated with oral penicillin V. The latter two are life-threatening Patients with anatomic or functional asplenia are at risk for infection infections associated with toxin production. Recommended treatment is with encapsulated bacteria including S. pneumoniae and N. meningitidis. with penicillin plus clindamycin, which may provide benefit by decreasing In addition to vaccination, some asplenic patients receive antibacterial streptococcal toxin production (Stevens et al., 2014). prophylaxis with penicillin V. The oral administration of 200,000 units of penicillin G or penicillin V every 12 h decreases the incidence of recurrences Infections Caused by Other Streptococci and Enterococci. The viri- of rheumatic fever in susceptible individuals. The intramuscular injection dans group of streptococci is the most common cause of native valve of 1.2 million units of penicillin G benzathine once a month also yields infectious endocarditis. These are nongroupable α-hemolytic microor- excellent results. Prophylaxis must be continued throughout the year. Some ganisms that are increasingly resistant to penicillin G. In patients with suggest that prophylaxis should be continued for life because instances of endocarditis, it is important to determine quantitative microbial sensi- acute rheumatic fever have been observed in the fifth and sixth decades, tivities to penicillin G, which guides drug selection, dosing, and use of but the necessity of lifetime prophylaxis has not been established. combination therapy. Patients with highly penicillin-susceptible viridans group streptococcal native valve endocarditis can be treated successfully with daily doses of 12 to 20 million units of intravenous penicillin G for The Penicillinase-Resistant Penicillins 4 weeks or for 2 weeks if given in combination with gentamicin. Penicillin The penicillinase-resistant penicillins are resistant to hydrolysis by staph- G is a less-preferred alternative to ampicillin for the treatment of suscep- ylococcal penicillinase. However, an increasing number of isolates of tible enterococcal infections. S. aureus, around half in most U.S. hospitals, and S. epidermidis, more than three-quarters, express a low-affinity PBP, giving them the MRSA Infections With Anaerobes. Pulmonary and periodontal infections or methicillin-resistant S. epidermidis (MRSE) phenotype. This term usually respond well to penicillin G. Mild-to-moderate infections at these denotes resistance of these bacteria to all β-lactams, with the exception of sites may be treated with oral medication (either penicillin G or penicillin ceftaroline and ceftobiprole (not available in the U.S.). Note that because V 250 mg four times daily). More severe infections should be treated with methicillin was the first penicillinase-resistant penicillin in widespread 12 to 24 million units of penicillin G IV. Penicillin G (12–24 million units use, the terms MRSA and MRSE are commonly used, despite the fact per day given parenterally) plus clindamycin is recommended for clostri- methicillin is currently rarely used. Alternative agents such as vancomycin dial gas gangrene. Adequate debridement of the infected areas is essen- or daptomycin, discussed below, may be used for infections due to organ- tial. Antibiotics probably have no effect on the outcome of tetanus due to isms with this resistance mechanism. Clostridium tetani. Debridement and administration of human tetanus immune globulin may be indicated. The Isoxazolyl Penicillins: Oxacillin, Cloxacillin, and Neisseria spp. Infections. Penicillin G is an alternative to third- Dicloxacillin Oxacillin, cloxacillin (not available in the U.S.), and dicloxacillin are generation cephalosporins for treatment of infections due to N. meningitidis. semisynthetic isoxazolyl penicillin congeners that are markedly resistant Patients should be treated with high doses of penicillin given IV. The to cleavage by penicillinase. Nafcillin is a similar congener of a slightly occurrence of penicillin-resistant strains should be considered in patients different structure. These drugs are not substitutes for penicillin G in the who are slow to respond to treatment. Penicillin G does not eliminate the treatment of diseases amenable to it and are not active against entero- meningococcal carrier state, and its administration thus is ineffective as a cocci, Listeria, or gram-negative organisms. prophylactic measure. Gonococci gradually have become more resistant to penicillin G, and penicillins are no longer the therapy of choice. Pharmacological Properties. The isoxazolyl penicillins are potent inhibitors of the growth of most penicillinase-producing staphylococci. Syphilis. Therapy of syphilis with penicillin G is highly effective. Pri- Dicloxacillin is the most active, and many strains of S. aureus are inhibited mary, secondary, and latent syphilis of less than 1 year in duration may be by concentrations of 0.05 to 0.8 μg/mL. Nafcillin is slightly more active than treated with one to three weekly intramuscular doses of 2.4 million units oxacillin against penicillin G–resistant S. aureus (most strains are inhib- of penicillin G benzathine. Patients with neurosyphilis or cardiovascular ited by 0.06–2 μg/mL). Although it is the most active of the penicillinase- syphilis typically receive intensive therapy with 18 to 24 million units of resistant penicillins against other microorganisms, it is not as potent as penicillin G daily for 10 to 14 days. There are no proven alternatives for penicillin G. treating syphilis in pregnant women, so penicillin-allergic individuals Dicloxacillin and cloxacillin are available for oral administration; these must be acutely desensitized to prevent anaphylaxis. agents are absorbed rapidly but incompletely (30%–80%) from the GI Patients with secondary syphilis may develop the Jarisch-Herxheimer tract. Absorption increases when administered 1 h before or 2 h after reaction, including chills, fever, headache, myalgias, and arthralgias meals. Peak concentrations in plasma are attained by 1 h. Nafcillin is only occurring several hours after the first dose of penicillin. This reaction is available for parenteral administration. All these congeners are bound to thought to be due to release of spirochetal antigens with subsequent host plasma albumin to a great extent (~90%–95%); none is removed from reactions to the products. Antipyretics give symptomatic relief, and ther- the circulation to a significant degree by hemodialysis. Concentrations apy with penicillin should not be discontinued. of the drug in CSF appear to be adequate for therapy of staphylococcal Actinomycosis. Penicillin G is the agent of choice for the treatment of meningitis. The isoxazolyl penicillins are excreted by the kidney; there is all forms of actinomycosis (18–24 million units of penicillin G IV per day also significant hepatic degradation and elimination in the bile. The t1/2 for 6 weeks). Surgical drainage or excision of the lesion may be necessary for all are between 30 and 60 min. No dosing adjustments are needed for before cure is accomplished. patients with renal failure. Nafcillin is a known inducer of the cytochrome Listeria Infections. Ampicillin or penicillin G—with consideration for P450 enzyme system, and caution should be used during coadministra- addition of gentamicin to both for immunosuppressed patients with tion with drugs metabolized via this pathway. Therapeutic Indications Ampicillin/Sulbactam and Amoxicillin/Clavulanate. The pharma- 1153 For mild to moderate skin and soft-tissue infections, the penicillinase- cokinetic properties of the coformulated agents (ampicillin/sulbactam resistant penicillins can be administered orally (e.g., dicloxacillin 500 mg IV, amoxicillin/clavulanate by mouth) are broadly similar to those of the every 6 h) or parenterally (e.g., nafcillin 1–2 g every 6 h). For treatment of single-agent formulations. serious methicillin-susceptible S. aureus infections such as endocarditis, Therapeutic Indications SECTION VII CHEMOTHERAPY OF INFECTIOUS DISEASES higher doses (e.g., oxacillin 2 g IV every 4 h) are employed. Respiratory Infections. Ampicillin and amoxicillin are active against S. pyogenes and many strains of S. pneumoniae and H. influenzae. The The Aminopenicillins: Ampicillin and Amoxicillin drugs constitute effective therapy for sinusitis, otitis media, acute exac- Aminopenicillins expand the spectrum of activity of penicillin G in a dif- erbations of chronic bronchitis, epiglottitis, and pneumonia caused ferent direction from the penicillinase-resistant penicillins—they allow for by sensitive strains of these organisms. Amoxicillin is the most active useful activity against more gram-negative organisms. They are hydrolyzed of all the oral β-lactam antibiotics against both penicillin-susceptible by β-lactamases (from both gram-positive and gram-negative bacteria); and penicillin-nonsusceptible S. pneumoniae. Based on the increas- thus, further expansion of their activity is enabled through coformulation ing prevalence of pneumococcal resistance to penicillin, an increase in with β-lactamase inhibitors (see the end of the chapter for further discus- dose of oral amoxicillin (from 40 to 45 up to 80 to 90 mg/kg per day) for sion of the chemistry and activity of β-lactamase inhibitors). empirical treatment of acute otitis media in children is recommended. Ampicillin-resistant H. influenzae is a problem in many areas; use of Antimicrobial Activity ampicillin/sulbactam or amoxicillin/clavulanate can provide coverage Ampicillin and amoxicillin are generally bactericidal for susceptible for these organisms as well as for Moraxella (which universally produces gram-positive and gram-negative bacteria. The antimicrobial spectrum a β-lactamase). Amoxicillin is also an option for empiric treatment of of amoxicillin is essentially identical to that of ampicillin, except that community-acquired pneumonia when patients are at low risk for drug- amoxicillin is less active and less effective than ampicillin for shigellosis. resistant pathogens or complications at a dose of 1 g every 8 h. Amoxicillin Gram-positive activity is broadly similar to that of the natural penicil- is an alternative treatment to penicillin for bacterial pharyngitis. lins. Pneumococcal and viridans group streptococci isolates have varying levels of resistance to ampicillin, and penicillin-resistant strains should Urinary Tract Infections. Most uncomplicated urinary tract infections be considered ampicillin/amoxicillin resistant. Enterococci are about are caused by Enterobacterales, and E. coli is the most common species iso- twice as sensitive to ampicillin as they are to penicillin G. That fraction lated from urinary tract infection patients. Aminopenicillins can be effec- of H. influenzae isolates that do not produce β-lactamases (between 60% tive agents for urinary tract infections, but the high prevalence of resistance and 80%) are typically aminopenicillin susceptible. From 30% to 60% of among E. coli and Klebsiella makes empiric use of these drugs for urinary E. coli, a significant number of P. mirabilis, and all Klebsiella are resistant. tract infections challenging; using amoxicillin/clavulanate can provide Most strains of Shigella, Pseudomonas, Serratia, Acinetobacter, B. fragilis, broader coverage of these organisms. Cure rates generally with oral β-lactam and indole-positive Proteus also are resistant to this group of penicillins. agents for cystitis are lower than those with other drug classes such as flu- Resistant strains of Salmonella are recovered with increasing frequency. oroquinolones or trimethoprim-sulfamethoxazole. Enterococcal urinary tract Concurrent administration of a β-lactamase inhibitor such as clavulanate infections can be treated effectively with an aminopenicillin alone. or sulbactam expands their spectrum of activity, particularly against Enterococcal Bloodstream Infections and Endocarditis. Ampicillin at S. aureus, H. influenzae, E. coli, Klebsiella, Proteus, and B. fragilis. high doses (2 g IV every 4–6 h) is the drug of choice for treatment of serious enterococcal infections including endocarditis. The vast majority of isolates ADME of Enterococcus faecalis are susceptible to aminopenicillins. Aminopenicillins Ampicillin. An oral dose of 0.5 g of ampicillin produces peak concen- as single agents may not provide bactericidal activity against enterococci; trations in plasma of about 3 μg/mL at 2 h. Intake of food prior to inges- thus, for treatment of enterococcal endocarditis, synergistic combinations tion of ampicillin diminishes absorption. Intramuscular injection of 0.5 are recommended. Historically, this would be the combination of ampicillin to 1 g of sodium ampicillin yields peak plasma concentrations of about plus gentamicin, but recent data suggest the combination of ampicillin and 7 to 10 μg/mL, respectively, at 1 h. Plasma levels decline with a t1/2 of ceftriaxone provides similar therapeutic effect with less toxicity (Fernandez- about 80 min. Severe renal impairment markedly prolongs the t1/2. Peri- Hidalgo et al., 2013). Addition of a β-lactamase inhibitor rarely adds to toneal dialysis is ineffective in removing the drug from the blood, but the activity an aminopenicillin alone against Enterococcus, as resistance in hemodialysis removes approximately 40% of the body store in about 7 h. enterococci is almost exclusively mediated by PBP changes. Adjustment of the dose of ampicillin is required in the presence of renal Meningitis. Acute bacterial meningitis in children is frequently due dysfunction. Ampicillin appears in the bile, undergoes enterohepatic cir- to S. pneumoniae or N. meningitidis. Because 20% to 30% of strains of culation, and is excreted in the feces. S. pneumoniae now may be resistant to ampicillin, it is not indicated Amoxicillin. Amoxicillin is a close chemical and pharmacological rela- for empiric single-agent treatment of meningitis. Ampicillin has excel- tive of ampicillin. Amoxicillin is stable in acid, designed for oral use, and lent activity against L. monocytogenes, a cause of meningitis in immu- absorbed more rapidly and completely from the GI tract than ampicillin. nocompromised persons. The combination of high-dose ampicillin and The absorption of amoxicillin appears to be partly saturable, with less frac- vancomycin plus a third-generation cephalosporin is a recommended tional absorption at higher doses. Peak plasma concentrations of amoxicil- regimen for empirical treatment of suspected bacterial meningitis in lin are 2 to 2.5 times greater than for ampicillin after oral administration of patients at risk for L. monocytogenes. the same dose. Food does not interfere with absorption. Perhaps because of more complete absorption of this congener, the incidence of diarrhea Antipseudomonal Penicillins: The with amoxicillin is less than that following administration of ampicillin. The Carboxypenicillins and the Ureidopenicillins incidence of other adverse effects appears to be similar. Although the t1/2 of Antimicrobial Activity amoxicillin is similar to that for ampicillin, effective concentrations of orally This class contains a number of agents no longer in widespread use, administered amoxicillin are detectable in the plasma for twice as long as including carbenicillin, ticarcillin, and mezlocillin (all discontinued in with ampicillin because of the more complete absorption. For all these rea- the U.S.). These agents are active against some isolates of Pseudomonas sons, amoxicillin is generally preferred over ampicillin for oral administra- aeruginosa and certain indole-positive Proteus spp. that are resistant to tion. About 20% of amoxicillin is protein bound in plasma, a value similar ampicillin and its congeners but are ineffective against most strains of to that for ampicillin. Most of a dose of the antibiotic is excreted in an active S. aureus, E. faecalis, Klebsiella, and L. monocytogenes. The ureidopen- form in the urine, and dose adjustment is required in renal dysfunction. icillin piperacillin is used most commonly as the combination product Probenecid delays excretion of the drug. piperacillin/tazobactam and has broad activity against streptococci, https://ebooksmedicine.net/  1154 enterococci, and enteric gram-negative rods and good activity against the “major determinant”), which is formed when the β-lactam ring is P. aeruginosa. opened. A large percentage of IgE-mediated reactions are to the major determinant, but a significant fraction are to other breakdown products. ADME The terms major and minor determinants refer to the frequency with Carbenicillin Indanyl Sodium. This indanyl ester of carbenicillin is acid which antibodies to these haptens appear to be formed, not the severity stable and is suitable for oral administration. After absorption, the ester of the reaction that may result. Antipenicillin antibodies are detectable CHAPTER 58 CELL ENVELOPE DISRUPTORS: β-LACTAM, GLYCOPEPTIDE, AND LIPOPEPTIDE ANTIBACTERIALS is converted rapidly to carbenicillin by hydrolysis of the ester linkage. The in virtually all patients who have received the drug as well as some who active moiety is excreted rapidly in the urine, where it achieves effective have never knowingly been exposed to it. Immediate allergic reactions concentrations. Thus, where available, the only use of this drug is for the are mediated by skin-sensitizing or IgE antibodies, usually of minor- management of urinary tract infections caused by Proteus spp. other than determinant specificities. Accelerated and late urticarial reactions usually P. mirabilis and by P. aeruginosa. are mediated by major determinant–specific skin-sensitizing antibodies. Ticarcillin and Ticarcillin/Clavulanate. The semisynthetic penicillin The most serious hypersensitivity reactions produced by the penicillins ticarcillin is more active than carbenicillin versus P. aeruginosa but less are angioedema and anaphylaxis. Acute anaphylactic or anaphylactoid active than piperacillin. The combination of ticarcillin and clavulanate reactions induced by various preparations of penicillin constitute the most has activity against other gram-negative aerobic and anaerobic organisms, important immediate danger connected with their use. Anaphylactoid such as Stenotrophomonas maltophilia, and has been used for intra-abdom- reactions may occur at any age. Their incidence is thought to be 0.004% inal and urinary tract infections. In the U.S., the manufacture of ticarcillin to 0.04%. About 0.001% of patients treated with these agents die from ana- alone and in combination with clavulanate has been discontinued. phylaxis. Anaphylaxis most often has followed the injection of penicillin, Piperacillin and Piperacillin/Tazobactam. Piperacillin extends although it also has been observed after oral or intradermal administration. the spectrum of ampicillin to include most strains of P. aeruginosa, The most dramatic reaction is sudden, severe hypotension and rapid death. Enterobacterales (non–β-lactamase producing), many Bacteroides spp., In other instances, bronchoconstriction with severe asthma; abdominal and E. faecalis. Combined with a β-lactamase inhibitor (piperacillin/ pain, nausea, and vomiting; extreme weakness; or diarrhea and purpuric tazobactam), it has the broadest antibacterial spectrum of the penicillins, skin eruptions have characterized the anaphylactic episodes. including activity against methicillin-susceptible S. aureus, H. influenzae, Skin rashes of all types may be caused by allergy to penicillin. The inci- B. fragilis, and most E. coli and Klebsiella. The drug is only available for dence of skin rashes appears to be highest following the use of ampicillin, parenteral administration. High biliary concentrations are achieved. Dis- at about 9%. Rashes follow the administration of ampicillin frequently in tribution into the CNS by piperacillin is similar to that of other penicil- patients with infectious mononucleosis, but in such cases, patients can tol- lins, but CSF concentrations of tazobactam may be inadequate to protect erate subsequent courses of ampicillin without experiencing a rash (Kerns et piperacillin against β-lactamase–producing organisms. The drug is elimi- al., 1973). Serum sickness of variable intensity and severity, mediated by IgG nated renally and requires adjustment in renal dysfunction. antibodies, is rare; when it occurs,