beta lactam

43 C H A P T E R Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics Camille E. Beauduy, PharmD, & Lisa G. Winston, MD* C ASE STUDY A 45-year-old man is brought to th...

43 C H A P T E R Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics Camille E. Beauduy, PharmD, & Lisa G. Winston, MD* C ASE STUDY A 45-year-old man is brought to the local hospital emer- (38.7°C [101.7°F]), hypotensive (90/54 mmHg), tachypneic gency department by ambulance. His wife reports that (36/min), and tachycardic (110/min). He has no signs of he had been in his normal state of health until 3 days ago meningismus but is oriented only to person. A stat chest when he developed a fever and a productive cough. Dur- x-ray shows a left lower lung consolidation consistent with ing the last 24 hours he has complained of a headache and pneumonia. A CT scan is not concerning for lesions or is increasingly confused. His wife reports that his medical elevated intracranial pressure. The plan is to start empiric history is significant only for hypertension, for which he antibiotics and perform a lumbar puncture to rule out takes hydrochlorothiazide and lisinopril, and that he is bacterial meningitis. What antibiotic regimen should be allergic to amoxicillin. She says that he developed a rash prescribed to treat both pneumonia and meningitis? Does many years ago when prescribed amoxicillin for bron- the history of amoxicillin rash affect the antibiotic choice? chitis. In the emergency department, the man is febrile Why or why not? BETA-LACTAM COMPOUNDS Structural integrity of the 6-aminopenicillanic acid nucleus (rings A plus B) is essential for the biologic activity of these compounds. Hydrolysis of the β-lactam ring by bacterial β-lactamases yields PENICILLINS penicilloic acid, which lacks antibacterial activity. The penicillins share features of chemistry, mechanism of action, A. Classification pharmacology, and immunologic characteristics with cephalospo- rins, monobactams, carbapenems, and β-lactamase inhibitors. Substituents of the 6-aminopenicillanic acid moiety determine the All are β-lactam compounds, so named because of their four- essential pharmacologic and antibacterial properties of the result- membered lactam ring. ing molecules. Penicillins can be assigned to one of three groups (below). Within each of these groups are compounds that are relatively stable to gastric acid and suitable for oral administration, Chemistry eg, penicillin V, dicloxacillin, and amoxicillin. The side chains of All penicillins have the basic structure shown in Figure 43–1. A some representatives of each group are shown in Figure 43–2. thiazolidine ring (A) is attached to a β-lactam ring (B) that car- ries a secondary amino group (RNH–). Substituents (R; examples 1. Penicillins (eg, penicillin G)—These have greatest activ- shown in Figure 43–2) can be attached to the amino group. ity against Gram-positive organisms, Gram-negative cocci, and non-β-lactamase-producing anaerobes. However, they have little ∗ The authors thank Dr. Henry F. Chambers and Dr. Daniel Deck for activity against Gram-negative rods, and they are susceptible to their contributions to this chapter in previous editions. hydrolysis by β-lactamases. 795 796 SECTION VIII Chemotherapeutic Drugs H H H H Amidase S S CH3 CH3 R N C C C R N CH CH C CH3 Penicillin CH3 B A H C N C C N CH COOH O COOH Lactamase O Substituted 6-aminopenicillanic acid 6-Aminopenicillanic acid The following structures can each be substituted O H H H at the R to produce a new penicillin. S H R1 C N C C C R B A H Cephalosporin C N C O C CH2 R2 CH2 Penicillin G COOH Substituted 7-aminocephalosporanic acid OCH2 Penicillin V O H H H R C N C C CH3 B Monobactam C N C C Oxacillin O SO3H N C Substituted 3-amino-4-methylmonobactamic acid O CH3 (aztreonam) Cl HO H H C C Dicloxacillin HC C C N C B S R Cl O CH3 H3C C N Carbapenem O COOH OC2H5 NH Nafcillin R: CH2 CH2 NH CH Substituted 3-hydroxyethylcarbapenemic acid (imipenem) CH Ampicillin FIGURE 43–1 Core structures of four β-lactam antibiotic NH2 families. The ring marked B in each structure is the β-lactam ring. The penicillins are susceptible to inactivation by amidases and lactamases at the points shown. Note that the carbapenems have HO CH Amoxicillin a different stereochemical configuration in the lactam ring that imparts resistance to most common β-lactamases. Substituents for NH2 the penicillin and cephalosporin families are shown in Figures 43–2 and 43–6, respectively. CH NHCO 2. Antistaphylococcal penicillins (eg, nafcillin)—These Piperacillin penicillins are resistant to staphylococcal β-lactamases. They N O are active against staphylococci and streptococci but not against enterococci, anaerobic bacteria, and Gram-negative cocci and rods. O N 3. Extended-spectrum penicillins (aminopenicillins and C2H5 antipseudomonal penicillins)—These drugs retain the anti- bacterial spectrum of penicillin and have improved activity against FIGURE 43–2 Side chains of some penicillins (R groups). Gram-negative rods. Like penicillin, however, they are relatively susceptible to hydrolysis by β-lactamases.  CHAPTER 43 Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics 797 B. Penicillin Units and Formulations polysaccharides and peptides known as peptidoglycan. The poly- The activity of penicillin G was originally defined in units. Crys- saccharide contains alternating amino sugars, N-acetylglucosamine talline sodium penicillin G contains approximately 1600 units and N-acetylmuramic acid (Figure 43–4). A five-amino-acid per mg (1 unit = 0.6 mcg; 1 million units of penicillin = 0.6 g). peptide is linked to the N-acetylmuramic acid sugar. This peptide Semisynthetic penicillins are prescribed by weight rather than terminates in d-alanyl-d-alanine. Penicillin-binding protein (PBP, units. The minimum inhibitory concentration (MIC) of any an enzyme) removes the terminal alanine in the process of forming penicillin (or other antimicrobial) is usually given in mcg/mL. a cross-link with a nearby peptide. Cross-links give the cell wall its Most penicillins are formulated as the sodium or potassium salt of rigidity. Beta-lactam antibiotics, structural analogs of the natural the free acid. Potassium penicillin G contains about 1.7 mEq of d-Ala-d-Ala substrate, covalently bind to the active site of PBPs. K+ per million units of penicillin (2.8 mEq/g). Nafcillin contains This binding inhibits the transpeptidation reaction (Figure 43–5) Na+, 2.8 mEq/g. Procaine salts and benzathine salts of penicillin G and halts peptidoglycan synthesis, and the cell dies. The exact provide repository forms for intramuscular injection. In dry crys- mechanism of cell death is not completely understood, but auto- talline form, penicillin salts are stable for years at 4°C. Solutions lysins are involved in addition to the disruption of cross linking of lose their activity rapidly (eg, within 24 hours at 20°C) and must the cell wall. Beta-lactam antibiotics kill bacterial cells only when be prepared fresh for administration. they are actively growing and synthesizing cell wall. Mechanism of Action Resistance Penicillins, like all β-lactam antibiotics, inhibit bacterial growth Resistance to penicillins and other β-lactams is due to one of four by interfering with the transpeptidation reaction of bacterial cell general mechanisms: (1) inactivation of antibiotic by β-lactamase, wall synthesis. The cell wall is a rigid outer layer that completely (2) modification of target PBPs, (3) impaired penetration of drug surrounds the cytoplasmic membrane (Figure 43–3), maintains to target PBPs, and (4) antibiotic efflux. Beta-lactamase produc- cell integrity, and prevents cell lysis from high osmotic pressure. tion is the most common mechanism of resistance. Hundreds The cell wall is composed of a complex, cross-linked polymer of of different β-lactamases have been identified. Some, such as Porin Outer membrane Cell wall Peptidoglycan β Lactamase Periplasmic space PBP PBP Cytoplasmic membrane FIGURE 43–3 A highly simplified diagram of the cell envelope of a Gram-negative bacterium. The outer membrane, a lipid bilayer, is present in Gram-negative but not Gram-positive organisms. It is penetrated by porins, proteins that form channels providing hydrophilic access to the cytoplasmic membrane. The peptidoglycan layer is unique to bacteria and is much thicker in Gram-positive organisms than in Gram-negative ones. Together, the outer membrane and the peptidoglycan layer constitute the cell wall. Penicillin-binding proteins (PBPs) are membrane proteins that cross-link peptidoglycan. Beta-lactamases, if present, reside in the periplasmic space or on the outer surface of the cytoplasmic membrane, where they may destroy β-lactam antibiotics that penetrate the outer membrane. 798 SECTION VIII Chemotherapeutic Drugs those produced by Staphylococcus aureus, Haemophilus influenzae, and Escherichia coli, are relatively narrow in substrate specificity, preferring penicillins to cephalosporins. Other β-lactamases, eg, M AmpC β-lactamase produced by Pseudomonas aeruginosa and M L-Ala Enterobacter sp and extended-spectrum β-lactamases (ESBLs) in Enterobacteriaceae, hydrolyze both cephalosporins and penicil- L-Ala R G lins. Carbapenems are highly resistant to hydrolysis by peni- R cillinases and cephalosporinases, but they are hydrolyzed by G metallo-β-lactamases and carbapenemases. Altered target PBPs are the basis of methicillin resistance in M staphylococci and of penicillin resistance in pneumococci and L-Ala most resistant enterococci. These resistant organisms produce M PBPs that have low affinity for binding β-lactam antibiotics, and L-Ala + D-Glu they are not inhibited except at relatively high, often clinically G unachievable, drug concentrations. G D-Glu L-Lys [Gly]5 Resistance due to impaired penetration of antibiotic occurs only in Gram-negative species because of the impermeable outer L-Lys [Gly]5* D-Ala * membrane of their cell wall, which is absent in Gram-positive bac- R teria. Beta-lactam antibiotics cross the outer membrane and enter D-Ala D-Ala Gram-negative organisms via outer membrane protein channels called porins. Absence of the proper channel or down-regulation D-Ala of its production can greatly impair drug entry into the cell. Poor Transpeptidase penetration alone is usually not sufficient to confer resistance because enough antibiotic eventually enters the cell to inhibit growth. However, this barrier can become important in the pres- ence of a β-lactamase, even a relatively inefficient one, as long as M it can hydrolyze drug faster than it enters the cell. Gram-negative M L-Ala organisms also may produce an efflux pump, which consists of R cytoplasmic and periplasmic protein components that efficiently L-Ala G transport some β-lactam antibiotics from the periplasm back R across the cell wall outer membrane. G M Pharmacokinetics M L-Ala Absorption of orally administered drug differs greatly for indi- vidual penicillins, depending in part on their acid stability and L-Ala G protein binding. Gastrointestinal absorption of nafcillin is erratic, D-Glu D-Glu so it is not suitable for oral administration. Dicloxacillin, ampicil- G lin, and amoxicillin are acid-stable and relatively well absorbed, producing serum concentrations in the range of 4–8 mcg/mL after L-Lys [Gly]5 D-Ala L-Lys [Gly]5 a 500-mg oral dose. Absorption of most oral penicillins (amoxicil- lin being an exception) is impaired by food, and the drugs should D-Ala be administered at least 1–2 hours before or after a meal. Intravenous administration of penicillin G is preferred to D-Ala + D-Ala the intramuscular route because of irritation and local pain from intramuscular injection of large doses. Serum concen- FIGURE 43–4 The transpeptidation reaction in Staphylococcus trations 30 minutes after an intravenous injection of 1 g of aureus that is inhibited by β-lactam antibiotics. The cell wall of Gram- penicillin G (equivalent to approximately 1.6 million units) are positive bacteria is made up of long peptidoglycan polymer chains 20–50 mcg/mL. Only a fraction of the total drug in serum is consisting of the alternating aminohexoses N-acetylglucosamine (G) present as free drug, the concentration of which is determined by and N-acetylmuramic acid (M) with pentapeptide side chains linked (in protein binding. Highly protein-bound penicillins (eg, nafcillin) S aureus) by pentaglycine bridges. The exact composition of the side generally achieve lower free-drug concentrations in serum than chains varies among species. The diagram illustrates small segments of less protein-bound penicillins (eg, penicillin G or ampicillin). two such polymer chains and their amino acid side chains. These linear polymers must be cross-linked by transpeptidation of the side chains at Penicillins are widely distributed in body fluids and tissues with a the points indicated by the asterisk to achieve the strength necessary for few exceptions. They are polar molecules, so intracellular concen- cell viability. trations are well below those found in extracellular fluids.  CHAPTER 43 Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics 799 Peptidoglycan Amino acid peptide G = N-acetylglucos-amine (N-Ag) G M G M G M G M Bacterial cell wall M = N-acetylmuramic acid (N-Am) Periplasmic space M G M G M G M G Cytoplasmic membrane G M G M G M G M Cytoplasm Schematic of normal bacterial cell wall peptidoglycan synthesis transpeptidation reaction. G M + M G G M G M Transpeptidase M G M G Beta-lactams bind the transpeptidase at the Penicillin Binding Protein site, resulting in inhibition of transpeptidation, thus halting peptidoglycan synthesis. No transpeptidation reaction Transpeptidase β-lactam G M + M G G M + M G FIGURE 43–5 Schematic of a bacterial cell wall and normal synthesis of cell wall peptidoglycan via transpeptidation; M, N-acetylmuramic acid; Glc, glucose; NAcGlc or G, N-acetylglucosamine. Beta-lactams work by binding the transpeptidase at the penicillin-binding protein site, resulting in inhibition of transpeptidation, thus halting peptidoglycan synthesis. Benzathine and procaine penicillins are formulated to delay Penicillin is rapidly excreted by the kidneys; small amounts absorption, resulting in prolonged blood and tissue concentra- are excreted by other routes. Tubular secretion accounts tions. A single intramuscular injection of 1.2 million units of for about 90% of renal excretion, and glomerular filtration benzathine penicillin maintains serum levels above 0.02 mcg/mL accounts for the remainder. The normal half-life of penicillin for 10 days, sufficient to treat β-hemolytic streptococcal infec- G is approximately 30 minutes but, in renal failure, may be tions. After 3 weeks, levels still exceed 0.003 mcg/mL, which is as long as 10 hours. Ampicillin and the extended-spectrum enough to prevent most β-hemolytic streptococcal infections. A penicillins are secreted more slowly than penicillin G and 600,000-unit dose of procaine penicillin yields peak concentra- have half-lives of 1 hour. For penicillins that are cleared by the tions of 1–2 mcg/mL and clinically useful concentrations for kidney, the dose must be adjusted according to renal function, 12–24 hours after a single intramuscular injection. with approximately one-fourth to one-third the normal dose Penicillin concentrations in most tissues are equal to those in being administered if creatinine clearance is 10 mL/min or less serum. Penicillin is also excreted into sputum and breast milk to (Table 43–1). levels 3–15% of those in the serum. Penetration into the eye, the Nafcillin is primarily cleared by biliary excretion. Oxacillin, prostate, and the central nervous system is poor. However, with dicloxacillin, and cloxacillin are eliminated by both the kidney active inflammation of the meninges, as in bacterial meningitis, and biliary excretion, and no dosage adjustment is required for penicillin concentrations of 1–5 mcg/mL can be achieved with these drugs in patients in renal failure. Because clearance of peni- a daily parenteral dose of 18–24 million units. These concentra- cillins is less efficient in the newborn, doses adjusted for weight tions are sufficient to kill susceptible strains of pneumococci and alone result in higher systemic concentrations for longer periods meningococci. than in the adult. 800 SECTION VIII Chemotherapeutic Drugs TABLE 43–1 Guidelines for dosing of some commonly used penicillins. Adjusted Dose as a Percentage of Normal Dose for Renal Failure Based on Creatinine Clearance (Clcr) Antibiotic (Route of Clcr Approx Clcr Approx Administration) Adult Dose Pediatric Dose1 Neonatal Dose2 50 mL/min 10 mL/min Penicillins Penicillin G (IV) 1–4 × 106 units 25,000–400,000 units/kg/d 75,000–150,000 units/ 50–75% 25% q4–6h in 4–6 doses kg/d in 2 or 3 doses Penicillin V (PO) 0.25–0.5 g qid 25–75 mg/kg/d in 4 doses None None Antistaphylococcal penicillins Cloxacillin, 0.25–0.5 g qid 15–25 mg/kg/d in 4 doses 100% 100% dicloxacillin (PO) Nafcillin (IV) 1–2 g q4–6h 100–200 mg/kg/d in 50–75 mg/kg/d in 100% 100% 4–6 doses 2 or 3 doses Oxacillin (IV) 1–2 g q4–6h 50–100 mg/kg/d in 50–75 mg/kg/d in 100% 100% 4–6 doses 2 or 3 doses Extended-spectrum penicillins Amoxicillin (PO) 0.25–0.5 g tid 20–40 mg/kg/d in 3 doses 66% 33% Amoxicillin/potassium 500/125 mg tid– 20–40 mg/kg/d in 3 doses 66% 33% clavulanate (PO) 875/125 mg bid 3 Piperacillin/ 3.375–4.5 g q4–6h 300 mg/kg/d in 4–6 doses 150 mg/kg/d in 50–75% 25–33% tazobactam (IV) 2 doses3 1 The total dose should not exceed the adult dose. 2 The dose shown is during the first week of life. The daily dose should be increased by approximately 33–50% after the first week of life. The lower dosage range should be used for neonates weighing less than 2 kg. After the first month of life, pediatric doses may be used. 3 Dose is based on piperacillin component. Clinical Uses Penicillin V, the oral form of penicillin, is indicated only in minor infections because of its relatively poor bioavailability, the Except for amoxicillin, oral penicillins should be given 1–2 hours need for dosing four times a day, and its narrow antibacterial spec- before or after a meal; they should not be given with food to mini- trum. Amoxicillin (see below) is often used instead. mize binding to food proteins and acid inactivation. Amoxicillin Benzathine penicillin and procaine penicillin G for intra- may be given without regard to meals. Blood levels of all penicil- muscular injection yield low but prolonged drug levels. A single lins can be raised by simultaneous administration of probenecid, intramuscular injection of benzathine penicillin, 1.2 million units, 0.5 g (10 mg/kg in children) every 6 hours orally, which impairs is effective treatment for β-hemolytic streptococcal pharyngitis. renal tubular secretion of weak acids such as β-lactam compounds. Given intramuscularly once every 3–4 weeks, it prevents reinfec- Penicillins, like all antibacterial antibiotics, should never be used tion. Benzathine penicillin G, 2.4 million units intramuscularly for viral infections and should be prescribed only when there is once a week for 1–3 weeks, is effective in the treatment of syphilis. reasonable suspicion of, or documented infection with, susceptible Procaine penicillin G was once a commonly used treatment for organisms. pneumococcal pneumonia and gonorrhea; however, it is rarely used now because many gonococcal strains are penicillin-resistant, A. Penicillin and many pneumococci require higher doses of penicillin G or the Penicillin G is a drug of choice for infections caused by strep- use of more potent β-lactams. tococci, meningococci, some enterococci, penicillin-susceptible pneumococci, staphylococci confirmed to be non-β-lactamase- producing, Treponema pallidum and certain other spirochetes, B. Penicillins Resistant to Staphylococcal Beta- some Clostridium species, Actinomyces and certain other Gram- Lactamase (Methicillin, Nafcillin, and Isoxazolyl Penicillins) positive rods, and non-β-lactamase-producing Gram-negative These semisynthetic penicillins are indicated for infections caused anaerobic organisms. Depending on the organism, the site, and by β-lactamase-producing staphylococci, although penicillin- the severity of infection, effective doses range between 4 and susceptible strains of streptococci and pneumococci are also sus- 24 million units per day administered intravenously in four to ceptible to these agents. Listeria monocytogenes, enterococci, and six divided doses. High-dose penicillin G can also be given as a methicillin-resistant strains of staphylococci are resistant. In recent continuous intravenous infusion. years the empirical use of these drugs has decreased substantially  CHAPTER 43 Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics 801 because of increasing rates of methicillin resistance in staphylo- therapy, an antipseudomonal β-lactam is sometimes used in com- cocci. However, for infections caused by methicillin-susceptible bination with an aminoglycoside or fluoroquinolone, particularly and penicillin-resistant strains of staphylococci, these are consid- in infections outside the urinary tract, despite a lack of data sup- ered drugs of choice. porting combination therapy over single-drug therapy. An isoxazolyl penicillin such as dicloxacillin, 0.25–0.5 g orally Ampicillin, amoxicillin, piperacillin, and, historically, ticarcil- every 4–6 hours (15–25 mg/kg/d for children), is suitable for lin, are available in combination with one of several β-lactamase treatment of mild to moderate localized staphylococcal infections. inhibitors: clavulanic acid, sulbactam, or tazobactam. The These drugs are relatively acid-stable and have reasonable bioavail- addition of a β-lactamase inhibitor extends the activity of these ability. However, food interferes with absorption, and the drugs penicillins to include β-lactamase-producing strains of S aureus as should be administered 1 hour before or after meals. well as some β-lactamase-producing Gram-negative bacteria (see Methicillin, the first antistaphylococcal penicillin to be devel- Beta-Lactamase Inhibitors). oped, is no longer used clinically due to high rates of adverse effects. Oxacillin and nafcillin, 8–12 g/d, given by intermittent Adverse Reactions intravenous infusion of 1–2 g every 4–6 hours (50–200 mg/kg/d The penicillins are generally well tolerated, and, unfortunately, for children), are considered drugs of choice for serious staphylo- this may encourage inappropriate use. Most of the serious adverse coccal infections such as endocarditis. effects are due to hypersensitivity. The antigenic determinants are degradation products of penicillins, particularly penicilloic acid C. Extended-Spectrum Penicillins (Aminopenicillins, and products of alkaline hydrolysis bound to host protein. A his- Carboxypenicillins, and Ureidopenicillins) tory of a penicillin reaction is not reliable. About 5–8% of people These drugs have greater activity than penicillin against Gram- claim such a history, but only a small number of these will have negative bacteria because of their enhanced ability to penetrate a serious reaction when given penicillin. Less than 1% of persons the Gram-negative outer membrane. Like penicillin G, they are who previously received penicillin without incident will have an inactivated by many β-lactamases. allergic reaction when given penicillin. Because of the potential The aminopenicillins, ampicillin and amoxicillin, have very for anaphylaxis, however, penicillin should be administered with similar spectrums of activity, but amoxicillin is better absorbed caution or a substitute drug given if the person has a history of orally. Amoxicillin, 250–500 mg three times daily, is equivalent to serious penicillin allergy. Penicillin skin testing may also be used the same amount of ampicillin given four times daily. Amoxicillin to evaluate Type I hypersensitivity. If skin testing is negative, most is given orally to treat bacterial sinusitis, otitis, and lower respira- patients can safely receive penicillin. tory tract infections. Ampicillin and amoxicillin are the most active Allergic reactions include anaphylactic shock (very rare—0.05% of the oral β-lactam antibiotics against pneumococci with elevated of recipients); serum sickness–type reactions (now rare—urticaria, MICs to penicillin and are the preferred β-lactam antibiotics for fever, joint swelling, angioedema, pruritus, and respiratory com- treating infections suspected to be caused by these strains. Ampi- promise occurring 7–12 days after exposure); and a variety of skin cillin (but not amoxicillin) is effective for shigellosis. Ampicillin, rashes. Oral lesions, fever, interstitial nephritis (an autoimmune at dosages of 4–12 g/d intravenously, is useful for treating serious reaction to a penicillin-protein complex), eosinophilia, hemolytic infections caused by susceptible organisms, including anaerobes, anemia and other hematologic disturbances, and vasculitis may enterococci, L monocytogenes, and β-lactamase-negative strains of also occur. Most patients allergic to penicillins can be treated Gram-negative cocci and bacilli such as E coli, and Salmonella sp. with alternative drugs. However, if necessary (eg, treatment of Non-β-lactamase-producing strains of H influenzae are generally enterococcal endocarditis or neurosyphilis in a patient with seri- susceptible, but strains that are resistant because of altered PBPs ous penicillin allergy), desensitization can be accomplished with are emerging. Due to production of β-lactamases by Gram- gradually increasing doses of penicillin. negative bacilli, ampicillin can no longer be used for empirical In patients with renal failure, penicillin in high doses can therapy of urinary tract infections and typhoid fever. Ampicillin cause seizures. Nafcillin is associated with neutropenia and is not active against Klebsiella sp, Enterobacter sp, P aeruginosa, interstitial nephritis; oxacillin can cause hepatitis; and methi- Citrobacter sp, Serratia marcescens, indole-positive Proteus species, cillin commonly caused interstitial nephritis (and is no longer and other Gram-negative aerobes that are commonly encountered used for this reason). Large doses of penicillins given orally may in hospital-acquired infections. These organisms intrinsically pro- lead to gastrointestinal upset, particularly nausea, vomiting, and duce β-lactamases that inactivate ampicillin. diarrhea. Ampicillin has been associated with pseudomembra- The carboxypenicillins, carbenicillin and ticarcillin, were nous colitis. Secondary infections such as vaginal candidiasis developed to broaden the spectrum of penicillins against Gram- may occur. Ampicillin and amoxicillin can be associated with negative pathogens, including P aeruginosa; however, neither skin rashes when prescribed in the setting of viral illnesses, agent is available in the USA. The ureidopenicillin piperacillin is particularly noted during acute Epstein-Barr virus infection, also active against many Gram-negative bacilli, such as Klebsiella but the incidence of rash may be lower than originally reported. pneumoniae and P aeruginosa. Piperacillin is available only as a Piperacillin-tazobactam, when combined with vancomycin, has co-formulation with the β-lactamase inhibitor tazobactam. Due been associated with greater incidence of acute kidney injury to the propensity of P aeruginosa to develop resistance during compared to alternate β-lactam agents. 802 SECTION VIII Chemotherapeutic Drugs CEPHALOSPORINS & O CEPHAMYCINS R1 C NH B S A N R2 O Cephalosporins are similar to penicillins but are more stable COO – to many bacterial β-lactamases and, therefore, have a broader N N R1 R2 N N spectrum of activity. However, strains of E coli and Klebsiella sp Cefazolin N CH2 CH2 S CH3 expressing extended-spectrum β-lactamases that can hydrolyze N S most cephalosporins are a growing clinical concern. Cephalo- Cephalexin CH CH3 sporins are not active against L monocytogenes, and of the avail- NH2 able cephalosporins, only ceftaroline has some activity against Cefadroxil HO CH CH3 enterococci. NH2 O Cefoxitin Chemistry S CH2 CH2 O C NH2 The nucleus of the cephalosporins, 7-aminocephalosporanic acid Cefaclor CH Cl (Figure 43–6), bears a close resemblance to 6-aminopenicillanic NH2 acid (Figure 43–1). The intrinsic antimicrobial activity of HO natural cephalosporins is low, but the attachment of various R1 Cefprozil CH CH CH3 and R2 groups has yielded hundreds of potent compounds, many O NH C 2 O with low toxicity. Cephalosporins have traditionally been classi- Cefuroxime O N CH2 C NH2 fied into four major groups or generations, depending mainly O OCH3 N N on the spectrum of antimicrobial activity. Several cephalosporins 1 H2NC C C S C CH2 S N Cefotetan N developed more recently do not fit the traditional classification HOOC S CH3 groups. Their unique characteristics and spectra of activity are N C O Cefotaxime outlined below. H 2N S N OCH3 CH2 O C CH3 N C 1 Cefpodoxime N CH2 O CH3 FIRST-GENERATION CEPHALOSPORINS H 2N O S OH OCH3 C First-generation cephalosporins include cefazolin, cefadroxil, Ceftibuten C H N cephalexin, cephalothin, cephapirin, and cephradine; cefazolin H2N S and cephalexin are the only two available in the USA. These drugs H2N OH S are very active against Gram-positive cocci, such as streptococci Cefdinir N CH CH2 N and staphylococci. Traditional cephalosporins are not active C H N C H3C against methicillin-resistant strains of staphylococci; however, Ceftriaxone N N N O new compounds have been developed that have activity against H2N S OCH3 N O CH2 S methicillin-resistant strains (see below). E coli, K pneumoniae, and N C CH3 N Proteus mirabilis are often sensitive to first-generation cephalo- Ceftazidime H2N S O C COOH CH2 N sporins, but activity against P aeruginosa, indole-positive Proteus CH3 species, Enterobacter sp, S marcescens, Citrobacter sp, and Acineto- N C CH2 N+ bacter sp is poor. Anaerobic cocci (eg, peptococci, peptostrepto- Cefepime H2N S N OCH3 CH3 cocci) are usually sensitive, but Bacteroides fragilis is not. O N N+ CH3 N N Pharmacokinetics & Dosage Ceftaroline S N S S H2N A. Oral S H2N N Cephalexin is the oral first generation agent widely used in N the USA. After oral doses of 500 mg, peak serum levels are N O Ceftolozane R1 NH 15–20 mcg/mL. Urine concentration is usually very high, but in O N NH most tissues levels are variable and generally lower than in serum. H3C OH H3C N N H 3C Cephalexin is typically given in oral dosages of 0.25–0.5 g four O times daily (15–30 mg/kg/d). Excretion is mainly by glomerular filtration and tubular secretion into the urine. Drugs that block FIGURE 43–6 Structures of some cephalosporins. R1 and R2 tubular secretion, eg, probenecid, may increase serum levels sub- structures are substituents on the 7-aminocephalosporanic acid stantially. In patients with impaired renal function, dosage must nucleus pictured at the top. Other structures (cefoxitin and below) be reduced (Table 43–2). are complete in themselves. 1Additional substituents not shown.  CHAPTER 43 Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics 803 TABLE 43–2 Guidelines for dosing of some commonly used cephalosporins and other cell-wall inhibitor antibiotics. Adjusted Dose as a Percentage of Normal Dose for Renal Failure Based on Creatinine Clearance (Clcr) Antibiotic (Route of Clcr Approx Clcr Approx Administration) Adult Dose Pediatric Dose1 Neonatal Dose2 50 mL/min 10 mL/min First-generation cephalosporins Cephalexin (PO) 0.25–0.5 g qid 25–50 mg/kg/d in 4 doses 50% 25% Cefazolin (IV) 0.5–2 g q8h 25–100 mg/kg/d in 3 or 4 50% 25% doses Second-generation cephalosporins Cefoxitin (IV) 1–2 g q6–8h 75–150 mg/kg/d in 3 or 4 50–75% 25% doses Cefotetan (IV) 1–2 g q12h 50% 25% Cefuroxime (IV) 0.75–1.5 g q8h 50–100 mg/kg/d in 3 or 66% 25–33% 4 doses Third- and fourth-generation cephalosporins including ceftaroline fosamil Cefotaxime (IV) 1–2 g q6–12h 50–200 mg/kg/d in 4–6 doses 100 mg/kg/d in 2 doses 50% 25% Ceftazidime (IV) 1–2 g q8–12h 75–150 mg/kg/d in 3 doses 100–150 mg/kg/d in 50% 25% 2 or 3 doses Ceftriaxone (IV) 1–4 g q24h 50–100 mg/kg/d in 1 or 50 mg/kg/d qd None None 2 doses Cefepime (IV) 0.5–2 g q12h 75–120 mg/kg/d in 2 or 50% 25% 3 divided doses Ceftaroline fosamil (IV) 600 mg q12h 50–66% 33% Cephalosporin–β-lactamase inhibitor combinations Ceftazidime- 2.5 g q8h 25–50% 6.25–12.5% avibactam (IV) Ceftolozane- 1.5 g q8h 25–50% Not studied tazobactam (IV) Carbapenems Ertapenem (IM or IV) 1 g q24h 100%3 50% Doripenem 500 mg q8h 50% 33% Imipenem (IV) 0.25–0.5 g q6–8h 75% 50% Meropenem (IV) 1 g q8h (2 g q8h 60–120 mg/kg/d in 3 doses 66% 50% for meningitis) (maximum of 2 g q8h) Glycopeptides Vancomycin (IV) 30–60 mg/kg/d in 40 mg/kg/d in 3 or 4 doses 15 mg/kg load, then 40% 10% 2–3 doses 20 mg/kg/d in 2 doses Telavancin (IV) 10 mg/kg daily 75% 50% Dalbavancin (IV) 1000 mg on day 1, None 75% 500 mg day 8 >30 mL/min Alternative: 1500 mg × 1 Oritavancin (IV) 1200 mg × 1 None Not studied >30 mL/min Lipopeptides (IV) Daptomycin 4–6 mg/kg IV daily None 50% >30 mL/min 1 The total dose should not exceed the adult dose. 2 The dose shown is during the first week of life. The daily dose should be increased by approximately 33–50% after the first week of life. The lower dosage range should be used for neonates weighing less than 2 kg. After the first month of life, pediatric doses may be used. 3 50% of dose for Clcr 1 mcg/mL may not respond even to these see the subsequent section for more information on β-lactamase agents, and addition of vancomycin is recommended. Other inhibitors. Ceftolozane-tazobactam and ceftazidime-avibactam potential indications include empirical therapy of sepsis in both were both FDA-approved for the treatment of complicated the immunocompetent and the immunocompromised patient intra-abdominal infections and urinary tract infections. Both and treatment of infections for which a cephalosporin is the least agents have potent in vitro activity against Gram-negative organ- toxic drug available. isms, including P aeruginosa and AmpC and extended-spectrum 806 SECTION VIII Chemotherapeutic Drugs β-lactamase producing Enterobacteriaceae. While neither agent is reactions; consequently, alcohol and alcohol-containing medica- active against organisms producing metallo-β-lactamases, ceftazi- tions must be avoided. dime-avibactam may be an option for carbapenemase-producing organisms. Due to limited activity against anaerobic pathogens, both should be combined with metronidazole when treating OTHER BETA-LACTAM DRUGS complicated intra-abdominal infections. Both agents have short half-lives of 2–3 hours and are dosed every 8 hours. Both are MONOBACTAMS primarily renally excreted and require dose adjustment in patients with impaired renal clearance. Monobactams are drugs with a monocyclic β-lactam ring (Figure 43–1). Their spectrum of activity is limited to aerobic Gram-negative organisms (including P aeruginosa). Unlike other ADVERSE EFFECTS OF β-lactam antibiotics, they have no activity against Gram-positive CEPHALOSPORINS bacteria or anaerobes. Aztreonam is the only monobactam avail- able in the USA. It has structural similarities to ceftazidime, A. Allergy and its Gram-negative spectrum is similar to that of the third- Like penicillins, cephalosporins may elicit a variety of hyper- generation cephalosporins. It is stable to many β-lactamases with sensitivity reactions, including anaphylaxis, fever, skin rashes, notable exceptions being AmpC β-lactamases and extended- nephritis, granulocytopenia, and hemolytic anemia. Patients spectrum β-lactamases. It penetrates well into the cerebrospinal with documented penicillin anaphylaxis have an increased risk fluid. Aztreonam is given intravenously every 8 hours in a dose of of reacting to cephalosporins compared with patients without a 1–2 g, providing peak serum levels of 100 mcg/mL. The half-life history of penicillin allergy. However, the chemical nucleus of is 1–2 hours and is greatly prolonged in renal failure. cephalosporins is sufficiently different from that of penicillins Penicillin-allergic patients tolerate aztreonam without reaction. such that many individuals with a history of penicillin allergy tol- Notably, because of its structural similarity to ceftazidime, there is erate cephalosporins. Overall, the frequency of cross-allergenicity potential for cross-reactivity; aztreonam should be used with caution between the two groups of drugs is low (∼1%). Cross-allergenicity in the case of documented severe allergies to ceftazidime. Occasional appears to be most common among penicillin, aminopenicillins, skin rashes and elevations of serum aminotransferases occur during and early-generation cephalosporins, which share similar R-1 side administration of aztreonam, but major toxicity is uncommon. In chains. Patients with a history of anaphylaxis to penicillins should patients with a history of penicillin anaphylaxis, aztreonam may be not receive first- or second-generation cephalosporins, while third- used to treat serious infections such as pneumonia, meningitis, and and fourth-generation cephalosporins should be administered sepsis caused by susceptible Gram-negative pathogens. with caution, preferably in a monitored setting. B. Toxicity BETA-LACTAMASE INHIBITORS Local irritation can produce pain after intramuscular injection (CLAVULANIC ACID, SULBACTAM, and thrombophlebitis after intravenous injection. Renal toxicity, TAZOBACTAM, & AVIBACTAM) including interstitial nephritis and tubular necrosis, may occur uncommonly. Traditional β-lactamase inhibitors (clavulanic acid, sulbactam, Cephalosporins that contain a methylthiotetrazole group may and tazobactam) resemble β-lactam molecules (Figure 43–7), but cause hypoprothrombinemia and bleeding disorders. Historically, they have very weak antibacterial action. They are potent inhibi- this group included cefamandole, cefmetazole, and cefoperazone; tors of many but not all bacterial β-lactamases and can protect however, cefotetan is the only methylthiotetrazole-containing hydrolyzable penicillins from inactivation by these enzymes. The agent used in the USA. Oral administration of vitamin K, 10 mg traditional β-lactamase inhibitors are most active against Ambler twice weekly, can prevent this uncommon problem. Drugs with class A β-lactamases (plasmid-encoded transposable element the methylthiotetrazole ring can also cause severe disulfiram-like [TEM] β-lactamases in particular), such as those produced by – O O O S C CH3 H2C CH O H2C CH H 2N CH2 R C N C N C N O CH CH2OH O COOH R= N N C N COOH R=H N O OSO3– Clavulanic acid Sulbactam Tazobactam Avibactam FIGURE 43–7 Beta-lactamase inhibitors.  CHAPTER 43 Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics 807 staphylococci, H influenzae, N gonorrhoeae, Salmonella, Shigella, dosage of doripenem is 0.5 g administered as a 1- or 4-hour infu- E coli, and K pneumoniae. They are not good inhibitors of class sion every 8 hours. Ertapenem has the longest half-life (4 hours) C β-lactamases, which typically are chromosomally encoded and is administered as a once-daily dose of 1 g intravenously or and inducible, produced by Enterobacter sp, Citrobacter sp, intramuscularly. Intramuscular ertapenem is irritating, and the drug S marcescens, and P aeruginosa, but they do inhibit chromosomal is formulated with 1% lidocaine for administration by this route. β-lactamases of B fragilis and M catarrhalis. The novel non-β- A carbapenem is indicated for infections caused by suscep- lactam β-lactamase inhibitor avibactam is active against Ambler tible organisms that are resistant to other available drugs, eg, class A β-lactamases but also active against Ambler class C and P aeruginosa, and for treatment of mixed aerobic and anaerobic some Ambler class D β-lactamases. infections. Carbapenems are active against many penicillin-non- Beta-lactamase inhibitors are available only in fixed combi- susceptible strains of pneumococci. Carbapenems are highly nations with specific penicillins and cephalosporins. (The fixed active in the treatment of Enterobacter infections because they combinations available in the USA are listed in Preparations are resistant to destruction by the β-lactamase produced by these Available.) An inhibitor extends the spectrum of its compan- organisms. Clinical experience suggests that carbapenems are also ion β-lactam provided that the inactivity against a particular the treatment of choice for serious infections caused by extended- organism is due to destruction by a β-lactamase and that the spectrum β-lactamase-producing Gram-negative bacteria. Ertape- inhibitor is active against the β-lactamase that is produced. Thus, nem is insufficiently active against P aeruginosa and should not ampicillin-sulbactam is active against β-lactamase-producing be used to treat infections caused by this organism. Imipenem, S aureus and H influenzae but not against Serratia, which produces meropenem, or doripenem, with or without an aminoglycoside, a β-lactamase that is not inhibited by sulbactam. Similarly, if a may be effective treatment for febrile neutropenic patients. strain of P aeruginosa is resistant to piperacillin, it is also resistant The most common adverse effects of carbapenems—which to piperacillin-tazobactam because tazobactam does not inhibit tend to be more common with imipenem—are nausea, vomiting, the chromosomal β-lactamase produced by P aeruginosa. diarrhea, skin rashes, and reactions at the infusion sites. Exces- Beta-lactam–β-lactamase inhibitor combinations are fre- sive levels of imipenem in patients with renal failure may lead quently used as empirical therapy for infections caused by a wide to seizures. Meropenem, doripenem, and ertapenem are much range of potential pathogens in both immunocompromised and less likely to cause seizures than imipenem. Patients allergic to immunocompetent patients. Adjustments for renal insufficiency penicillins may be allergic to carbapenems, but the incidence of are made based on the β-lactam component. cross-reactivity is thought to be less than 1%. CARBAPENEMS GLYCOPEPTIDE ANTIBIOTICS The carbapenems are structurally related to other β-lactam anti- VANCOMYCIN biotics (Figure 43–1). Doripenem, ertapenem, imipenem, and meropenem are licensed for use in the USA. Imipenem, the first Vancomycin is an antibiotic isolated from the bacterium now drug of this class, has a wide spectrum with good activity against known as Amycolatopsis orientalis. It is active primarily against most Gram-negative rods, including P aeruginosa, Gram-positive Gram-positive bacteria due to its large molecular weight and organisms, and anaerobes. It is resistant to most β-lactamases but lack of penetration through Gram-negative cell membranes. The not carbapenemases or metallo-β-lactamases. Enterococcus faecium, intravenous product is water soluble and stable for 14 days in the methicillin-resistant strains of staphylococci, Clostridium difficile, refrigerator following reconstitution. Burkholderia cepacia, and Stenotrophomonas maltophilia are resistant. Imipenem is inactivated by dehydropeptidases in renal tubules, Mechanisms of Action & Basis of resulting in low urinary concentrations. Consequently, it is admin- istered together with an inhibitor of renal dehydropeptidase, cilas- Resistance tatin, for clinical use. Doripenem and meropenem are similar to Vancomycin inhibits cell wall synthesis by binding firmly to the imipenem but have slightly greater activity against Gram-negative d-Ala-d-Ala terminus of nascent peptidoglycan pentapeptide aerobes and slightly less activity against Gram-positives. They are (Figure 43–8). This inhibits the transglycosylase, preventing not significantly degraded by renal dehydropeptidase and do not further elongation of peptidoglycan and cross-linking. The pep- require an inhibitor. Unlike the other carbapenems, ertapenem does tidoglycan is thus weakened, and the cell becomes susceptible to not have appreciable activity against P aeruginosa and Acinetobacter lysis. The cell membrane is also damaged, which contributes to species. It is not degraded by renal dehydropeptidase. the antibacterial effect. Carbapenems penetrate body tissues and fluids well, including Resistance to vancomycin in enterococci is due to modifica- the cerebrospinal fluid for all but ertapenem. All are cleared renally, tion of the d-Ala-d-Ala binding site of the peptidoglycan building and the dose must be reduced in patients with renal insufficiency. block in which the terminal d-Ala is replaced by d-lactate. This The usual dosage of imipenem is 0.25–0.5 g given intravenously results in the loss of a critical hydrogen bond that facilitates high- every 6–8 hours (half-life 1 hour). The usual adult dosage of affinity binding of vancomycin to its target and loss of activity. meropenem is 0.5–1 g intravenously every 8 hours. The usual adult This mechanism is also present in vancomycin-resistant S aureus 808 SECTION VIII Chemotherapeutic Drugs Peptidoglycan Amino acid peptide G = N-acetylglucos-amine (N-Ag) G M G M G M G M Bacterial cell wall M = N-acetylmuramic acid (N-Am) Periplasmic space M G M G M G M G Cytoplasmic membrane G M G M G M G M Cytoplasm Schematic of normal bacterial cell wall peptidoglycan synthesis transpeptidation reaction. G M + M G G M G M Transpeptidase Crosslinking M G M G Vancomycin binds the D-Alanine D-Alanine terminus of the amino acid peptide, inhibiting V crosslinkage. V A A N N Vancomycin G M + M G G M M G V No crosslinking A N FIGURE 43–8 Schematic of a bacterial cell wall and normal synthesis of cell wall peptidoglycan via transpeptidation; M, N-acetylmuramic acid; Glc, glucose; NAcGlc or G, N-acetylglucosamine. Vancomycin binds the D-Alanine D-Alanine (D-Ala D-Ala) terminus of the amino acid peptide, inhibiting cross-linkage of the cell wall. strains (MIC ≥ 16 mcg/mL), which have acquired the enterococcal dividing; the rate is less than that of the penicillins both in vitro resistance determinants. The underlying mechanism for reduced and in vivo. Vancomycin is synergistic in vitro with gentamicin vancomycin susceptibility in vancomycin-intermediate strains and streptomycin against Enterococcus faecium and Enterococcus (MIC = 4–8 mcg/mL) of S aureus is not fully known. However, faecalis strains that do not exhibit high levels of aminoglycoside these strains have altered cell wall metabolism that results in a resistance. Vancomycin is active against many Gram-positive thickened cell wall with increased numbers of d-Ala-d-Ala resi- anaerobes including C difficile. dues, which serve as dead-end binding sites for vancomycin. Van- comycin is sequestered within the cell wall by these false targets Pharmacokinetics and may be unable to reach its site of action. Vancomycin is poorly absorbed from the intestinal tract and is administered orally only for the treatment of colitis caused by Antibacterial Activity C difficile. Parenteral doses must be administered intravenously. Vancomycin is bactericidal for Gram-positive bacteria in con- A 1-hour intravenous infusion of 1 g produces blood levels of centrations of 0.5–10 mcg/mL. Most pathogenic staphylococci, 15–30 mcg/mL for 1–2 hours. The drug is widely distributed including those producing β-lactamase and those resistant to naf- in the body including adipose tissue. Cerebrospinal fluid levels cillin and methicillin, are killed by 2 mcg/mL or less. Vancomycin 7–30% of simultaneous serum concentrations are achieved if there kills staphylococci relatively slowly and only if cells are actively is meningeal inflammation. Ninety percent of the drug is excreted  CHAPTER 43 Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics 809 by glomerular filtration. In the presence of renal insufficiency, Administration with another ototoxic or nephrotoxic drug, such striking accumulation may occur (Table 43–2). In functionally as an aminoglycoside, increases the risk of these toxicities. Ototox- anephric patients, the half-life of vancomycin is 6–10 days. A icity can be minimized by maintaining peak serum concentrations significant amount of vancomycin is removed during a standard below 60 mcg/mL. Among the more common reactions is the hemodialysis run using a high-flux membrane. so-called “red man” syndrome. This infusion-related flushing is caused by release of histamine. It can be largely prevented by pro- Clinical Uses longing the infusion period to 1–2 hours (preferred) or pretreat- ment with an antihistamine such as diphenhydramine. Important indications for parenteral vancomycin are bloodstream infections and endocarditis caused by methicillin-resistant staphy- lococci. However, vancomycin is not as effective as an antistaphy- TEICOPLANIN lococcal penicillin for treatment of serious infections such as endocarditis caused by methicillin-susceptible strains. Vancomy- Teicoplanin is a glycopeptide antibiotic that is very similar to cin in combination with gentamicin is an alternative regimen for vancomycin in mechanism of action and antibacterial spectrum. treatment of enterococcal endocarditis in a patient with serious Unlike vancomycin, it can be given intramuscularly as well as penicillin allergy. Vancomycin (in combination with cefotaxime, intravenously. Teicoplanin has a long half-life (45–70 hours), ceftriaxone, or rifampin) is also recommended for treatment permitting once-daily dosing. This drug is available in Europe but of meningitis suspected or known to be caused by a penicillin- has not been approved for use in the USA. resistant strain of pneumococcus. The recommended dosage in a patient with normal renal function is 30–60 mg/kg/d in two or three divided doses. The traditional dosing regimen in adults TELAVANCIN with normal renal function is 1 g every 12 hours (∼30 mg/kg/d); however, this dose will not typically achieve the trough concentra- Telavancin is a semisynthetic lipoglycopeptide derived from van- tions (15–20 mcg/mL) recommended for serious infections. For comycin. Telavancin is active versus Gram-positive bacteria and serious infections (see below), a starting dose of 45–60 mg/kg/d has in vitro activity against many strains with reduced susceptibil- should be given with titration of the dose to achieve trough levels ity to vancomycin. Telavancin has two mechanisms of action. Like of 15–20 mcg/mL. The dosage in children is 40 mg/kg/d in vancomycin, telavancin inhibits cell wall synthesis by binding to three or four divided doses. Clearance of vancomycin is directly the d-Ala-d-Ala terminus of peptidoglycan in the growing cell proportional to creatinine clearance, and the dosage is reduced wall. In addition, it disrupts the bacterial cell membrane potential accordingly in patients with renal insufficiency. For patients and increases membrane permeability. The half-life of telavancin receiving hemodialysis, a common dosing regimen is a 1-g load- is approximately 8 hours, which supports once-daily intravenous ing dose followed by 500 mg after each dialysis session. Patients dosing. The drug is approved for treatment of complicated skin receiving a prolonged course of therapy should have serum trough and soft tissue infections and hospital-acquired pneumonia at a concentrations checked. For S aureus infections, recommended dose of 10 mg/kg IV daily. Unlike vancomycin therapy, monitor- trough concentrations are 10–15 mcg/mL for mild to moderate ing of serum telavancin levels is not required. Telavancin was asso- infections and 15–20 mcg/mL for more serious infections such as ciated with substantial nephrotoxicity and concern for increased endocarditis, meningitis, and necrotizing pneumonia. mortality associated with renal impairment in clinical trials, lead- Oral vancomycin, 0.125–0.5 g every 6 hours, is used to treat ing to boxed warnings. It is potentially teratogenic, so administra- colitis caused by C difficile. Because of the emergence of vancomy- tion to pregnant women must be avoided. cin-resistant enterococci and the potential selective pressure of oral vancomycin for these resistant organisms, metronidazole had been preferred as initial therapy. However, use of oral vancomycin does DALBAVANCIN AND ORITAVANCIN not appear to be a significant risk factor for acquisition of van- Dalbavancin and oritavancin are semisynthetic lipoglycopeptides comycin-resistant enterococci. Additionally, recent clinical data derived from teicoplanin. Dalbavancin and oritavancin inhibit cell suggest that vancomycin is associated with higher initial response wall synthesis via the same mechanism of action as vancomycin rates than metronidazole, particularly for moderate to severe cases and teicoplanin; oritavancin works by additional mechanisms, of C difficile colitis. Therefore, oral vancomycin may be used as a including disruption of cell membrane permeability and inhibi- first-line treatment, especially for severe cases. tion of RNA synthesis. Compared with vancomycin, both agents have lower MICs against many Gram-positive bacteria including Adverse Reactions methicillin-resistant and vancomycin-intermediate S aureus. Dal- Adverse reactions with parenteral administration of vancomycin bavancin is not active against most strains of vancomycin-resistant are encountered fairly frequently. Most reactions are relatively enterococci (VRE). Oritavancin has in vitro activity against VRE, minor and reversible. Vancomycin is irritating to tissue, resulting but its clinical utility in treating VRE infections remains unclear. in phlebitis at the site of injection. Chills and fever may occur. Both agents have extremely long half-lives of greater than 10 days, Ototoxicity is rare but nephrotoxicity is still encountered regu- which allows for once-weekly intravenous administration. Dal- larly with current preparations, especially with high trough levels. bavancin and oritavancin have been approved for the treatment 810 SECTION VIII Chemotherapeutic Drugs of skin and soft tissue infections. There are limited clinical data evidence supporting increased efficacy is lacking. In clinical tri- supporting the use of dalbavancin for uncomplicated catheter- als, daptomycin was noninferior in efficacy to vancomycin. It associated bloodstream infections, though it is not approved for can cause myopathy, and creatine phosphokinase levels should be use in this setting. Dalbavancin was originally approved as a two- monitored weekly. Pulmonary surfactant antagonizes daptomycin, dose, once-weekly intravenous regimen (1000 mg infused on day and it should not be used to treat pneumonia. Daptomycin can 1 and 500 mg infused on day 8), but a subsequent phase 3 study also cause an allergic pneumonitis in patients receiving prolonged comparing the two-dose regimen with a single, 1500-mg intra- therapy (>2 weeks). Treatment failures have been reported in venous dose showed that the single-dose regimen is noninferior. association with an increase in daptomycin MIC during therapy. The results of this study allowed for updated labelling, making Daptomycin is an effective alternative to vancomycin, and its role both dalbavancin and oritavancin appropriate for single-dose continues to unfold. treatments for complicated skin and soft tissue infections. A prac- tical difference between the two is the infusion time: dalbavancin can be administered over 30 minutes, while oritavancin must be FOSFOMYCIN infused over 3 hours. Neither requires dose adjustment in mild to moderate renal or hepatic impairment, and neither is removed Fosfomycin trometamol, a stable salt of fosfomycin (phosphono- by dialysis. mycin), inhibits a very early stage of bacterial cell wall synthesis. An analog of phosphoenolpyruvate, it is structurally unrelated to any other antimicrobial agent. It inhibits the cytoplasmic enzyme enolpyruvate transferase by covalently binding to the cysteine resi- OTHER CELL WALL- OR due of the active site and blocking the addition of phosphoenol- MEMBRANE-ACTIVE AGENTS pyruvate to UDP-N-acetylglucosamine. This reaction is the first step in the formation of UDP-N-acetylmuramic acid, the precur- DAPTOMYCIN sor of N-acetylmuramic acid, which is found only in bacterial cell walls. The drug is transported into the bacterial cell by glycero- Daptomycin is a novel cyclic lipopeptide fermentation product of phosphate or glucose 6-phosphate transport systems. Resistance is Streptomyces roseosporus (Figure 43–9). Its spectrum of activity is due to inadequate transport of drug into the cell. similar to that of vancomycin except that it may be active against Fosfomycin is active against both Gram-positive and Gram- vancomycin-resistant strains of enterococci and S aureus. In vitro, negative organisms at concentrations ≥ 125 mcg/mL. Susceptibil- it has more rapid bactericidal activity than vancomycin. The pre- ity tests should be performed in growth medium supplemented cise mechanism of action is not fully understood, but it is known with glucose 6-phosphate to minimize false-positive indications of to bind to the cell membrane via calcium-dependent insertion of resistance. In vitro synergism occurs when fosfomycin is combined its lipid tail. This results in depolarization of the ce