Katzung Pharmacology: Beta-Lactam Antibiotics PDF

43 C H A P T E R Beta-Lactam & Other Cell Wall- & Membrane- Active Antibiotics Daniel H. Deck, PharmD & Lisa G. Winston, MD∗ CASE STUDY A 55-year-old man is brought to the l...

43 C H A P T E R Beta-Lactam & Other Cell Wall- & Membrane- Active Antibiotics Daniel H. Deck, PharmD & Lisa G. Winston, MD∗ CASE STUDY A 55-year-old man is brought to the local hospital emer- emergency department, the man is febrile (38.7°C [101.7°F]), gency department by ambulance. His wife reports that he hypotensive (90/54 mm Hg), tachypneic (36/min), and had been in his normal state of health until 3 days ago when tachycardic (110/min). He has no signs of meningismus but he developed a fever and a productive cough. During the is oriented only to person. A stat chest x-ray shows a left last 24 hours he has complained of a headache and is lower lung consolidation consistent with pneumonia. The increasingly confused. His wife reports that his medical his- plan is to start empiric antibiotics and perform a lumbar tory is significant only for hypertension, for which he takes puncture to rule out bacterial meningitis. What antibiotic hydrochlorothiazide and lisinopril, and that he is allergic to regimen should be started to treat both pneumonia and amoxicillin. She says that he developed a rash many years meningitis? Does the history of amoxicillin rash affect the ago when prescribed amoxicillin for bronchitis. In the antibiotic choice? Why or why not? Hydrolysis of the β-lactam ring by bacterial β-lactamases yields BETALACTAM COMPOUNDS penicilloic acid, which lacks antibacterial activity. PENICILLINS A. Classification The penicillins share features of chemistry, mechanism of action, Substituents of the 6-aminopenicillanic acid moiety determine the pharmacology, and immunologic characteristics with cephalosporins, essential pharmacologic and antibacterial properties of the result- monobactams, carbapenems, and β-lactamase inhibitors. All are ing molecules. Penicillins can be assigned to one of three groups β-lactam compounds, so named because of their four-membered (below). Within each of these groups are compounds that are rela- lactam ring. tively stable to gastric acid and suitable for oral administration, eg, penicillin V, dicloxacillin, and amoxicillin. The side chains of Chemistry some representatives of each group are shown in Figure 43–2, with a few distinguishing characteristics. All penicillins have the basic structure shown in Figure 43–1. A thiazolidine ring (A) is attached to a β-lactam ring (B) that carries 1. Penicillins (eg, penicillin G)—These have greatest activity a secondary amino group (RNH–). Substituents (R; examples against gram-positive organisms, gram-negative cocci, and non- shown in Figure 43–2) can be attached to the amino group. β-lactamase producing anaerobes. However, they have little activ- Structural integrity of the 6-aminopenicillanic acid nucleus (rings A ity against gram-negative rods, and they are susceptible to plus B) is essential for the biologic activity of these compounds. hydrolysis by β-lactamases. ∗ 2. Antistaphylococcal penicillins (eg, nafcillin)—These The authors thank Dr. Henry F. Chambers for his contributions to this chapter in previous editions. penicillins are resistant to staphylococcal β-lactamases. They are 790  CHAPTER 43 Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics 791 H H H Site of amidase action H Amidase S S CH3 CH3 R N C C C R N CH CH C B A CH3 Penicillin CH3 H C N C C N CH COOH O COOH Lactamase O Site of penicillinase action Substituted 6-aminopenicillanic acid (break in β-lactam ring) 6-Aminopenicillanic acid O H H H The following structures can each be substituted S H at the R to produce a new penicillin. R1 C N C C C B A H R 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 O SO3H C C Oxacillin Substituted 3-amino-4-methylmonobactamic acid N C (aztreonam) O CH3 Cl HO H H C C Dicloxacillin HC C C B S R N C H3C C N Cl O CH3 Carbapenem O COOH NH OC2H5 R: CH2 CH2 NH CH Nafcillin Substituted 3-hydroxyethylcarbapenemic acid (imipenem) FIGURE 43–1 Core structures of four β-lactam antibiotic families. CH Ampicillin The ring marked B in each structure is the β-lactam ring. The penicil- NH2 lins are susceptible to bacterial metabolism and inactivation by amidases and lactamases at the points shown. Note that the carba- penems have a different stereochemical configuration in the lactam HO CH Amoxicillin ring that imparts resistance to most common β lactamases. Substituents for the penicillin and cephalosporin families are shown NH2 in Figures 43–2 and 43–6, respectively. CH active against staphylococci and streptococci but not against NHCO enterococci, anaerobic bacteria, and gram-negative cocci and rods. Piperacillin N O 3. Extended-spectrum penicillins (ampicillin and the antipseudomonal penicillins)—These drugs retain the anti- bacterial spectrum of penicillin and have improved activity against N O gram-negative organisms. Like penicillin, however, they are rela- tively susceptible to hydrolysis by β-lactamases. C2H5 B. Penicillin Units and Formulations FIGURE 43–2 Side chains of some penicillins (R groups of The activity of penicillin G was originally defined in units. Figure 43–1). Crystalline sodium penicillin G contains approximately 792 SECTION VIII Chemotherapeutic Drugs 1600 units per mg (1 unit = 0.6 mcg; 1 million units of penicillin = N-acetylglucosamine and N-acetylmuramic acid (Figure 43–4). A 0.6 g). Semisynthetic penicillins are prescribed by weight rather five-amino-acid peptide is linked to the N-acetylmuramic acid than units. The minimum inhibitory concentration (MIC) of sugar. This peptide terminates in D-alanyl-D-alanine. Penicillin- any penicillin (or other antimicrobial) is usually given in mcg/mL. binding protein (PBP, an enzyme) removes the terminal alanine in Most penicillins are formulated as the sodium or potassium salt of the process of forming a cross-link with a nearby peptide. Cross- the free acid. Potassium penicillin G contains about 1.7 mEq of links give the cell wall its structural rigidity. Beta-lactam antibiot- + K per million units of penicillin (2.8 mEq/g). Nafcillin contains ics, structural analogs of the natural D-Ala-D-Ala substrate, + Na , 2.8 mEq/g. Procaine salts and benzathine salts of penicillin covalently bind to the active site of PBPs. This inhibits the trans- G provide repository forms for intramuscular injection. In dry peptidation reaction (Figure 43–5), halting peptidoglycan synthe- crystalline form, penicillin salts are stable for years at 4°C. sis, and the cell dies. The exact mechanism of cell death is not Solutions lose their activity rapidly (eg, 24 hours at 20°C) and completely understood, but autolysins and disruption of cell wall must be prepared fresh for administration. morphogenesis are involved. Beta-lactam antibiotics kill bacterial cells only when they are actively growing and synthesizing cell Mechanism of Action wall. Penicillins, like all β-lactam antibiotics, inhibit bacterial growth by interfering with the transpeptidation reaction of bacterial cell Resistance wall synthesis. The cell wall is a rigid outer layer unique to bacte- Resistance to penicillins and other β-lactams is due to one of four rial species. It completely surrounds the cytoplasmic membrane general mechanisms: (1) inactivation of antibiotic by β-lactamase, (Figure 43–3), maintains cell shape and integrity, and prevents cell (2) modification of target PBPs, (3) impaired penetration of drug to lysis from high osmotic pressure. The cell wall is composed of target PBPs, and (4) efflux. Beta-lactamase production is the most a complex, cross-linked polymer of polysaccharides and common mechanism of resistance. Hundreds of different polypeptides, peptidoglycan (also known as murein or mucopep- β-lactamases have been identified. Some, such as those produced by tide). The polysaccharide contains alternating amino sugars, Staphylococcus aureus, Haemophilus influenzae, and Escherichia coli, 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.  CHAPTER 43 Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics 793 are relatively narrow in substrate specificity, preferring penicillins to cephalosporins. Other β-lactamases, eg, AmpC β-lactamase pro- duced by Pseudomonas aeruginosa and Enterobacter sp, and extended- M spectrum β-lactamases (ESBLs), hydrolyze both cephalosporins and M L-Ala penicillins. Carbapenems are highly resistant to hydrolysis by peni- cillinases and cephalosporinases, but they are hydrolyzed by L-Ala R G metallo-β lactamase and carbapenemases. R Altered target PBPs are the basis of methicillin resistance in G staphylococci and of penicillin resistance in pneumococci and enterococci. These resistant organisms produce PBPs that have M low affinity for binding β-lactam antibiotics, and consequently, M L-Ala they are not inhibited except at relatively high, often clinically unachievable, drug concentrations. L-Ala + G D-Glu Resistance due to impaired penetration of antibiotic to target PBPs occurs only in gram-negative species because of their imper- D-Glu G L-Lys [Gly]5 meable outer cell wall membrane, which is absent in gram-positive bacteria. Beta-lactam antibiotics cross the outer membrane and L-Lys [Gly]5* D-Ala * enter gram-negative organisms via outer membrane protein R channels called porins. Absence of the proper channel or down- D-Ala D-Ala regulation of its production can greatly impair drug entry into the cell. Poor penetration alone is usually not sufficient to confer D-Ala resistance because enough antibiotic eventually enters the cell to Transpeptidase inhibit growth. However, this barrier can become important in the presence of a β-lactamase, even a relatively inactive one, as long as it can hydrolyze drug faster than it enters the cell. Gram-negative M organisms also may produce an efflux pump, which consists of L-Ala cytoplasmic and periplasmic protein components that efficiently M transport some β-lactam antibiotics from the periplasm back L-Ala R across the outer membrane. G R G Pharmacokinetics M Absorption of orally administered drug differs greatly for different penicillins, depending in part on their acid stability and protein L-Ala M binding. Gastrointestinal absorption of nafcillin is erratic, so it is L-Ala not suitable for oral administration. Dicloxacillin, ampicillin, and G D-Glu amoxicillin are acid-stable and relatively well absorbed, producing D-Glu serum concentrations in the range of 4–8 mcg/mL after a 500-mg G oral dose. Absorption of most oral penicillins (amoxicillin being L-Lys [Gly]5 D-Ala L-Lys [Gly]5 an exception) is impaired by food, and the drugs should be admin- istered at least 1–2 hours before or after a meal. D-Ala Intravenous administration of penicillin G is preferred to the intramuscular route because of irritation and local pain from intra- D-Ala + D-Ala muscular injection of large doses. Serum concentrations 30 minutes after an intravenous injection of 1 g of a penicillin (equivalent to approximately 1.6 million units of penicillin G) are 20–50 mcg/ FIGURE 43–4 The transpeptidation reaction in Staphylococcus mL. Only a small amount of the total drug in serum is present as aureus that is inhibited by β-lactam antibiotics. The cell wall of gram- free drug, the concentration of which is determined by protein positive bacteria is made up of long peptidoglycan polymer chains consisting of the alternating aminohexoses N-acetylglucosamine binding. Highly protein-bound penicillins (eg, nafcillin) generally (G) and N-acetylmuramic acid (M) with pentapeptide side chains achieve lower free-drug concentrations in serum than less protein- linked (in S aureus) by pentaglycine bridges. The exact composition bound penicillins (eg, penicillin G or ampicillin). Protein binding of the side chains varies among species. The diagram illustrates small becomes clinically relevant when the protein-bound percentage is segments of two such polymer chains and their amino acid side approximately 95% or more. Penicillins are widely distributed in chains. These linear polymers must be cross-linked by transpeptida- body fluids and tissues with a few exceptions. They are polar mol- tion of the side chains at the points indicated by the asterisk to ecules, so intracellular concentrations are well below those found in achieve the strength necessary for cell viability. extracellular fluids. 794 SECTION VIII Chemotherapeutic Drugs MG MG MG MG 1 Fosfomycin MG 2 Cycloserine MG 3 Bacitracin 4 Vancomycin 5 ␤-Lactams 5 PP MG PP MG MG MG 4 PP MG MG MG MG PP Periplasmic space + BP BP BP BP Cytoplasmic membrane BP BP BP BP BP Cytoplasm GM PP GM PP M PP P 3 PP UDP UMP Pc L-Ala L-Ala L-Ala 5-Gly tRNA UDP M D-Glu D-Glu D-Glu L-Ala = L-Lys [Gly]5 L-Lys L-Lys D-Glu D-Ala D-Ala D-Ala L-Lys UMP D-Ala D-Ala D-Ala L-Ala D-Ala UDP UDP M 2 D-Ala PPi D-Ala L-Ala UTP UDP G UDP M D-Glu 1 L-Ala D-Glu L-Lys D-Ala D-Ala 2 L-Lys NAcGlc-1-P Glc-6-P FIGURE 43–5 The biosynthesis of cell wall peptidoglycan, showing the sites of action of five antibiotics (shaded bars; 1 = fosfomycin, 2 = cycloserine, 3 = bacitracin, 4 = vancomycin, 5 = β-lactam antibiotics). Bactoprenol (BP) is the lipid membrane carrier that transports building blocks across the cytoplasmic membrane; M, N-acetylmuramic acid; Glc, glucose; NAcGlc or G, N-acetylglucosamine. Benzathine and procaine penicillins are formulated to delay are sufficient to kill susceptible strains of pneumococci and absorption, resulting in prolonged blood and tissue concentra- meningococci. tions. A single intramuscular injection of 1.2 million units of Penicillin is rapidly excreted by the kidneys; small amounts are benzathine penicillin maintains serum levels above 0.02 mcg/mL excreted by other routes. About 10% of renal excretion is by for 10 days, sufficient to treat β-hemolytic streptococcal infection. glomerular filtration and 90% by tubular secretion. The normal After 3 weeks, levels still exceed 0.003 mcg/mL, which is enough half-life of penicillin G is approximately 30 minutes; in renal to prevent β-hemolytic streptococcal infection. A 600,000 unit failure, it may be as long as 10 hours. Ampicillin and the dose of procaine penicillin yields peak concentrations of 1–2 mcg/ extended-spectrum penicillins are secreted more slowly than mL and clinically useful concentrations for 12–24 hours after a penicillin G and have half-lives of 1 hour. For penicillins that are single intramuscular injection. cleared by the kidney, the dose must be adjusted according to renal Penicillin concentrations in most tissues are equal to those in function, with approximately one fourth to one third the normal serum. Penicillin is also excreted into sputum and milk to levels dose being administered if creatinine clearance is 10 mL/min 3–15% of those in the serum. Penetration into the eye, the prostate, or less (Table 43–1). and the central nervous system is poor. However, with active Nafcillin is primarily cleared by biliary excretion. Oxacillin, inflammation of the meninges, as in bacterial meningitis, penicillin dicloxacillin, and cloxacillin are eliminated by both the kidney and concentrations of 1–5 mcg/mL can be achieved with a daily par- biliary excretion; no dosage adjustment is required for these drugs enteral dose of 18–24 million units. These concentrations in renal failure. Because clearance of penicillins is less efficient in  CHAPTER 43 Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics 795 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 1 2 Administration) Adult Dose Pediatric Dose Neonatal Dose 50 mL/min 10 mL/min Penicillins 6 Penicillin G (IV) 1–4 × 10 25,000–400,000 75,000–150,000 50–75% 25% units units/kg/d in units/kg/d in q4–6h 4–6 doses 2 or 3 doses Penicillin V (PO) 0.25–0.5 g qid 25–50 mg/kg/d in None None 4 doses Antistaphylococcal penicillins Cloxacillin, dicloxacillin 0.25–0.5 g qid 25–50 mg/kg/d in 100% 100% (PO) 4 doses Nafcillin (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 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 66% 33% 3 doses Amoxicillin/potassium 500/125 tid– 20–40 mg/kg/d in 66% 33% clavulanate (PO) 875/125 mg bid 3 doses Piperacillin (IV) 3–4 g q4–6h 300 mg/kg/d in 150 mg/kg/d in 50–75% 25–33% 4–6 doses 2 doses Ticarcillin (IV) 3 g q4–6h 200–300 mg/kg/d 150–200 mg/kg/d in 50–75% 25–33% in 4–6 doses 2 or 3 doses 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. the newborn, doses adjusted for weight alone result in higher sys- Actinomyces and certain other gram-positive rods, and non-β- temic concentrations for longer periods than in the adult. lactamase-producing gram-negative anaerobic organisms. Depend- ing on the organism, the site, and the severity of infection, effective doses range between 4 and 24 million units per day administered Clinical Uses intravenously in four to six divided doses. High-dose penicillin G Except for oral amoxicillin, penicillins should be given 1–2 hours can also be given as a continuous intravenous infusion. before or after a meal; they should not be given with food to Penicillin V, the oral form of penicillin, is indicated only in minimize binding to food proteins and acid inactivation. Blood minor infections because of its relatively poor bioavailability, the levels of all penicillins can be raised by simultaneous administra- need for dosing four times a day, and its narrow antibacterial tion of probenecid, 0.5 g (10 mg/kg in children) every 6 hours spectrum. Amoxicillin (see below) is often used instead. orally, which impairs renal tubular secretion of weak acids such as Benzathine penicillin and procaine penicillin G for intramus- β-lactam compounds. Penicillins should never be used for viral cular injection yield low but prolonged drug levels. A single intra- infections and should be prescribed only when there is reasonable muscular injection of benzathine penicillin, 1.2 million units, is suspicion of, or documented infection with, susceptible organisms. effective treatment for β-hemolytic streptococcal pharyngitis; given intramuscularly once every 3–4 weeks, it prevents reinfec- A. Penicillin tion. Benzathine penicillin G, 2.4 million units intramuscularly Penicillin G is a drug of choice for infections caused by streptococci, once a week for 1–3 weeks, is effective in the treatment of syphilis. meningococci, some enterococci, penicillin-susceptible pneumo- Procaine penicillin G, formerly a work horse for treating uncom- cocci, non-β-lactamase-producing staphylococci, Treponema plicated pneumococcal pneumonia or gonorrhea, is rarely used pallidum and certain other spirochetes, Clostridium species, now because many strains are penicillin-resistant. 796 SECTION VIII Chemotherapeutic Drugs B. Penicillins Resistant to Staphylococcal Beta Carbenicillin, the first antipseudomonal carboxypenicillin, is Lactamase (Methicillin, Nafcillin, and Isoxazolyl no longer used in the USA, as there are more active, better toler- Penicillins) ated alternatives. A carboxypenicillin with activity similar to that These semisynthetic penicillins are indicated for infection by of carbenicillin is ticarcillin. It is less active than ampicillin against β-lactamase-producing staphylococci, although penicillin- enterococci. The ureidopenicillins, piperacillin, mezlocillin, and susceptible strains of streptococci and pneumococci are also suscep- azlocillin, are also active against selected gram-negative bacilli, tible to these agents. Listeria monocytogenes, enterococci, and such as Klebsiella pneumoniae. Although supportive clinical data methicillin-resistant strains of staphylococci are resistant. In recent are lacking for superiority of combination therapy over single- years the empirical use of these drugs has decreased substantially drug therapy, because of the propensity of P aeruginosa to develop because of increasing rates of methicillin-resistance in staphylo- resistance during treatment, an antipseudomonal penicillin is fre- cocci. However, for infections caused by methicillin-susceptible quently used in combination with an aminoglycoside or fluoro- and penicillin-resistant strains of staphylococci, these are consid- quinolone for pseudomonal infections outside the urinary tract. ered the drugs of choice. Ampicillin, amoxicillin, ticarcillin, and piperacillin are also An isoxazolyl penicillin such as oxacillin, cloxacillin, or dicloxacil- available in combination with one of several β-lactamase inhib- lin, 0.25–0.5 g orally every 4–6 hours (15–25 mg/kg/d for children), itors: clavulanic acid, sulbactam, or tazobactam. The addition is suitable for treatment of mild to moderate localized staphylococcal of a β-lactamase inhibitor extends the activity of these penicil- infections. All are relatively acid-stable and have reasonable bioavail- lins to include β-lactamase-producing strains of S aureus as well ability. However, food interferes with absorption, and the drugs as some β-lactamase-producing gram-negative bacteria (see Beta- should be administered 1 hour before or after meals. Lactamase Inhibitors). For serious systemic staphylococcal infections, oxacillin or nafcillin, 8–12 g/d, is given by intermittent intravenous infusion Adverse Reactions of 1–2 g every 4–6 hours (50–100 mg/kg/d for children). The penicillins are generally well tolerated, and unfortunately, this encourages their misuse and inappropriate use. Most of the serious C. Extended-Spectrum Penicillins (Aminopenicillins, adverse effects are due to hypersensitivity. All penicillins are cross- Carboxypenicillins, and Ureidopenicillins) sensitizing and cross-reacting. The antigenic determinants are These drugs have greater activity than penicillin against gram- degradation products of penicillins, particularly penicilloic acid negative bacteria because of their enhanced ability to penetrate the and products of alkaline hydrolysis bound to host protein. A his- gram-negative outer membrane. Like penicillin G, they are inacti- tory of a penicillin reaction is not reliable; about 5–8% of people vated by many β lactamases. claim such a history, but only a small number of these will have an The aminopenicillins, ampicillin and amoxicillin, have nearly allergic reaction when given penicillin. Less than 1% of persons identical spectrums of activity, but amoxicillin is better absorbed who previously received penicillin without incident will have an orally. Amoxicillin, 250–500 mg three times daily, is equivalent to allergic reaction when given penicillin. Because of the potential for the same amount of ampicillin given four times daily. Amoxacillin anaphylaxis, however, penicillin should be administered with cau- is given orally to treat urinary tract infections, sinusitis, otitis, and tion or a substitute drug given if the person has a history of serious lower respiratory tract infections. Ampicillin and amoxicillin are penicillin allergy. The incidence of allergic reactions in young the most active of the oral β-lactam antibiotics against pneumo- children is negligible. cocci with elevated MICs to penicillin and are the preferred Allergic reactions include anaphylactic shock (very rare—0.05% β-lactam antibiotics for treating infections suspected to be caused of recipients); serum sickness-type reactions (now rare—urticaria, by these strains. Ampicillin (but not amoxicillin) is effective for fever, joint swelling, angioneurotic edema, intense pruritus, and shigellosis. Its use to treat uncomplicated salmonella gastroenteritis respiratory compromise occurring 7–12 days after exposure); and a is controversial because it may prolong the carrier state. variety of skin rashes. Oral lesions, fever, interstitial nephritis (an Ampicillin, at dosages of 4–12 g/d intravenously, is useful for autoimmune reaction to a penicillin-protein complex), eosino- treating serious infections caused by susceptible organisms, includ- philia, hemolytic anemia and other hematologic disturbances, and ing anaerobes, enterococci, L monocytogenes, and β-lactamase- vasculitis may also occur. Most patients allergic to penicillins can negative strains of gram-negative cocci and bacilli such as E coli, and be treated with alternative drugs. However, if necessary (eg, treat- Salmonella sp. Non-β-lactamase producing strains of H influenzae ment of enterococcal endocarditis or neurosyphilis in a patient are generally susceptible, but strains that are resistant because of with serious penicillin allergy), desensitization can be accomplished altered PBPs are emerging. Many gram-negative species produce β with gradually increasing doses of penicillin. lactamases and are resistant, precluding use of ampicillin for empir- In patients with renal failure, penicillin in high doses can cause ical therapy of urinary tract infections, meningitis, and typhoid seizures. Nafcillin is associated with neutropenia; oxacillin can fever. Ampicillin is not active against Klebsiella sp, Enterobacter cause hepatitis; and methicillin causes interstitial nephritis (and is sp, P aeruginosa, Citrobacter sp, Serratia marcescens, indole-posi- no longer used for this reason). Large doses of penicillins given tive proteus species, and other gram-negative aerobes that are orally may lead to gastrointestinal upset, particularly nausea, commonly encountered in hospital-acquired infections. These vomiting, and diarrhea. Ampicillin has been associated with organisms produce β lactamase that inactivates ampicillin. pseudomembranous colitis. Secondary infections such as vaginal  CHAPTER 43 Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics 797 candidiasis may occur. Ampicillin and amoxicillin can cause skin O rashes that are not allergic in nature. These rashes frequently occur R1 C NH S when aminopenicillins are inappropriately prescribed for a viral B N A R2 O illness. COO – R1 R2 N N N N CEPHALOSPORINS & Cefazolin N CH2 CH2 S CH3 N S CEPHAMYCINS Cephalexin CH CH3 NH2 Cephalosporins are similar to penicillins, but more stable to many bacterial β lactamases and therefore have a broader spectrum of Cefadroxil HO CH CH3 activity. However, strains of E coli and Klebsiella sp expressing NH2 extended-spectrum β lactamases that can hydrolyze most cepha- O Cefoxitin losporins are a growing clinical concern. Cephalosporins are not S CH2 CH2 O C NH2 active against enterococci and L monocytogenes. Cefaclor CH Cl NH2 Chemistry HO Cefprozil The nucleus of the cephalosporins, 7-aminocephalosporanic acid CH CH CH3 (Figure 43–6), bears a close resemblance to 6-aminopenicillanic O C NH2 O acid (Figure 43–1). The intrinsic antimicrobial activity of natural Cefuroxime N CH2 O C NH2 cephalosporins is low, but the attachment of various R1 and R2 O OCH3 N N groups has yielded hundreds of potent compounds of low toxicity. CH2 S N 1 H2NC C C S C N Cephalosporins can be classified into four major groups or gen- Cefotetan HOOC S CH3 erations, depending mainly on the spectrum of antimicrobial N C activity. O Cefotaxime N S CH2 O C CH3 H2N OCH3 FIRST-GENERATION CEPHALOSPORINS Cefpodoxime 1 N C N CH2 O CH3 H2N S OCH3 First-generation cephalosporins include cefazolin, cefadroxil, O OH cephalexin, cephalothin, cephapirin, and cephradine. These C C H drugs are very active against gram-positive cocci, such as pneumo- Ceftibuten N H2N cocci, streptococci, and staphylococci. Traditional cephalosporins are S not active against methicillin-resistant strains of staphylococci; how- H2N OH S ever, new compounds have been developed that have activity against Cefdinir N CH CH2 N C methicillin-resistant strains (see below). E coli, K pneumoniae, and Proteus mirabilis are often sensitive, but activity against N C H P aeruginosa, indole-positive proteus species, Enterobacter sp, Ceftizoxime H2N S N OCH3 H S marcescens, Citrobacter sp, and Acinetobacter sp is poor. Anaerobic N C H3C N O Ceftriaxone N cocci (eg, peptococci, peptostreptococci) are usually sensitive, but H2N S N OCH3 Bacteroides fragilis is not. N C CH2 S N O CH3 Ceftazidime N H2N S O C COOH Pharmacokinetics & Dosage CH3 CH2 N A. Oral N C Cefepime CH2 N+ Cephalexin, cephradine, and cefadroxil are absorbed from the gut to H2N S N OCH3 CH3 a variable extent. After oral doses of 500 mg, serum levels are 15–20 O mcg/mL. Urine concentration is usually very high, but in most tis- N N+ CH3 N N sues levels are variable and generally lower than in serum. Cephalexin Ceftaroline S S and cephradine are given orally in dosages of 0.25–0.5 g four times H2N N S daily (15–30 mg/kg/d) and cefadroxil in dosages of 0.5–1 g twice daily. Excretion is mainly by glomerular filtration and tubular secre- FIGURE 43–6 Structures of some cephalosporins. R1 and tion into the urine. Drugs that block tubular secretion, eg, R2 structures are substituents on the 7-aminocephalosporanic acid probenecid, may increase serum levels substantially. In patients with nucleus pictured at the top. Other structures (cefoxitin and below) impaired renal function, dosage must be reduced (Table 43–2). are complete in themselves. 1Additional substituents not shown. 798 SECTION VIII Chemotherapeutic Drugs 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 1 2 Administration) Adult Dose Pediatric Dose Neonatal Dose 50 mL/min 10 mL/min First-generation cephalosporins Cefadroxil (PO) 0.5–1 g qd–bid 30 mg/kg/d in 2 doses 50% 25% Cephalexin, 0.25–0.5 g qid 25–50 mg/kg/d in 4 doses 50% 25% cephradine (PO) Cefazolin (IV) 0.5–2 g q8h 25–100 mg/kg/d in 3 or 50% 25% 4 doses Second-generation cephalosporins Cefoxitin (IV) 1–2 g q6–8h 75–150 mg/kg/d in 3 or 50–75% 25% 4 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 50% 25% 2 doses Ceftazidime (IV) 1–2 g q8–12h 75–150 mg/kg/d in 100–150 mg/kg/d in 50% 25% 3 doses 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% Carbapenems 3 Ertapenem (IM or IV) 1 g q24h 100% 50% Doripenem 500 mg q8h 50% 33% Imipenem (IV) 0.25–0.5 g q6–8h 75% 50% Meropenem (IV) 1 g q8h 60–120 mg/kg/d in 3 doses 66% 50% (2 g q8h 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 Lipopeptides (IV) Daptomycin 4-6 mg/kg IV daily None 50% Telavancin 10 mg/kg IV daily 75% 50% 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< 30 mL/min.  CHAPTER 43 Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics 799 B. Parenteral a maximum of 1 g/d. Except for cefuroxime axetil, these drugs are Cefazolin is the only first-generation parenteral cephalosporin still not predictably active against penicillin-non-susceptible pneumo- in general use. After an intravenous infusion of 1 g, the peak level cocci and should be used cautiously, if at all, to treat suspected or of cefazolin is 90–120 mcg/mL. The usual intravenous dosage of proved pneumococcal infections. Cefaclor is more susceptible to cefazolin for adults is 0.5–2 g intravenously every 8 hours. β-lactamase hydrolysis compared with the other agents, and its Cefazolin can also be administered intramuscularly. Excretion is usefulness is correspondingly diminished. via the kidney, and dose adjustments must be made for impaired renal function. B. Parenteral After a 1-g intravenous infusion, serum levels are 75–125 mcg/mL Clinical Uses for most second-generation cephalosporins. Intramuscular admin- istration is painful and should be avoided. Doses and dosing Oral drugs may be used for the treatment of urinary tract infec- intervals vary depending on the specific agent (Table 43–2). There tions and staphylococcal or streptococcal infections, including are marked differences in half-life, protein binding, and interval cellulitis or soft tissue abscess. However, oral cephalosporins between doses. All are renally cleared and require dosage adjust- should not be relied on in serious systemic infections. ment in renal failure. Cefazolin penetrates well into most tissues. It is a drug of choice for surgical prophylaxis. Cefazolin may also be a choice in infections for which it is the least toxic drug (eg, penicillinase- Clinical Uses producing E coli or K pneumoniae) and in individuals with The oral second-generation cephalosporins are active against staphylococcal or streptococcal infections who have a history of β-lactamase-producing H influenzae or Moraxella catarrhalis and have penicillin allergy other than immediate hypersensitivity. Cefazolin been primarily used to treat sinusitis, otitis, and lower respiratory tract does not penetrate the central nervous system and cannot be used infections, in which these organisms have an important role. Because to treat meningitis. Cefazolin is an alternative to an antistaphylo- of their activity against anaerobes (including many B fragilis strains), coccal penicillin for patients who are allergic to penicillin. cefoxitin, cefotetan, or cefmetazole can be used to treat mixed anaero- bic infections such as peritonitis, diverticulitis, and pelvic inflamma- tory disease. Cefuroxime is used to treat community-acquired SECOND-GENERATION pneumonia because it is active against β-lactamase-producing H influenzae or K pneumoniae and some penicillin-non-susceptible CEPHALOSPORINS pneumococci. Although cefuroxime crosses the blood-brain barrier, it Members of the second-generation cephalosporins include cefaclor, is less effective in treatment of meningitis than ceftriaxone or cefo- cefamandole, cefonicid, cefuroxime, cefprozil, loracarbef, and taxime and should not be used. ceforanide; and the structurally related cephamycins cefoxitin, cefmetazole, and cefotetan, which have activity against anaer- THIRD-GENERATION CEPHALOSPORINS obes. This is a heterogeneous group with marked individual differ- ences in activity, pharmacokinetics, and toxicity. In general, they Third-generation agents include cefoperazone, cefotaxime, cef- are active against organisms inhibited by first-generation drugs, tazidime, ceftizoxime, ceftriaxone, cefixime, cefpodoxime prox- but in addition they have extended gram-negative coverage. etil, cefdinir, cefditoren pivoxil, ceftibuten, and moxalactam. Klebsiella sp (including those resistant to cephalothin) are usually sensitive. Cefamandole, cefuroxime, cefonicid, ceforanide, and Antimicrobial Activity cefaclor are active against H influenzae but not against serratia or B fragilis. In contrast, cefoxitin, cefmetazole, and cefotetan are Compared with second-generation agents, these drugs have active against B fragilis and some serratia strains but are less active expanded gram-negative coverage, and some are able to cross the against H influenzae. As with first-generation agents, none is active blood-brain barrier. Third-generation drugs are active against against enterococci or P aeruginosa. Second-generation cepha- Citrobacter, S marcescens, and Providencia (although resistance can losporins may exhibit in vitro activity against Enterobacter sp., but emerge during treatment of infections caused by these species due to resistant mutants that constitutively express a chromosomal selection of mutants that constitutively produce cephalosporinase). β lactamase that hydrolyzes these compounds (and third-generation They are also effective against β-lactamase-producing strains of cephalosporins) are readily selected, and they should not be used haemophilus and neisseria. Ceftazidime and cefoperazone are the to treat enterobacter infections. only two drugs with useful activity against P aeruginosa. Like the second-generation drugs, third-generation cephalosporins are hydrolyzed by constitutively produced AmpC β lactamase, and Pharmacokinetics & Dosage they are not reliably active against Enterobacter species. Serratia, A. Oral Providencia, and Citrobacter also produce a chromosomally Cefaclor, cefuroxime axetil, cefprozil, and loracarbef can be given encoded cephalosporinase that, when constitutively expressed, can orally. The usual dosage for adults is 10–15 mg/kg/d in two to confer resistance to third-generation cephalosporins. Ceftizoxime four divided doses; children should be given 20–40 mg/kg/d up to and moxalactam are active against B fragilis. Cefixime, cefdinir, 800 SECTION VIII Chemotherapeutic Drugs ceftibuten, and cefpodoxime proxetil are oral agents possessing FOURTH-GENERATION similar activity except that cefixime and ceftibuten are much less active against pneumococci and have poor activity against CEPHALOSPORINS S aureus. Cefepime is an example of a so-called fourth-generation cephalosporin. It is more resistant to hydrolysis by chromosomal Pharmacokinetics & Dosage β lactamases (eg, those produced by Enterobacter). However, like the third-generation compounds, it is hydrolyzed by extended- Intravenous infusion of 1 g of a parenteral cephalosporin produces spectrum β lactamases. Cefepime has good activity against serum levels of 60–140 mcg/mL. Third-generation cephalosporins P aeruginosa, Enterobacteriaceae, S aureus, and S pneumoniae. It penetrate body fluids and tissues well and, with the exception is highly active against Haemophilus and Neisseria sp. It penetrates of cefoperazone and all oral cephalosporins, achieve levels in well into cerebrospinal fluid. It is cleared by the kidneys and has the cerebrospinal fluid sufficient to inhibit most susceptible a half-life of 2 hours, and its pharmacokinetic properties are very pathogens. similar to those of ceftazidime. Unlike ceftazidime, however, The half-lives of these drugs and the necessary dosing intervals cefepime has good activity against most penicillin-non-susceptible vary greatly: Ceftriaxone (half-life 7–8 hours) can be injected once strains of streptococci, and it is useful in treatment of entero- every 24 hours at a dosage of 15–50 mg/kg/d. A single daily bacter infections. 1-g dose is sufficient for most serious infections, with 2 g every 12 hours recommended for treatment of meningitis. Cefoperazone (half-life 2 hours) can be infused every 8–12 hours in a dosage of Cephalosporins Active against 25–100 mg/kg/d. The remaining drugs in the group (half-life Methicillin-Resistant Staphylococci 1–1.7 hours) can be infused every 6–8 hours in dosages between Beta-lactam antibiotics with activity against methicillin-resistant 2 and 12 g/d, depending on the severity of infection. Cefixime can staphylococci are currently under development. Ceftaroline be given orally (200 mg twice daily or 400 mg once daily) for fosamil, the prodrug of the active metabolite ceftaroline, is the urinary tract infections and as a single 400 mg dose for uncompli- first such drug to be approved for clinical use in the USA. cated gonococcal urethritis and cervicitis. The adult dose for Ceftaroline has increased binding to penicillin-binding protein 2a, cefpodoxime proxetil or cefditoren pivoxil is 200–400 mg twice which mediates methicillin resistance in staphylococci, resulting daily; for ceftibuten, 400 mg once daily; and for cefdinir, in bactericidal activity against these strains. It has some activity 300 mg/12 h. The excretion of cefoperazone and ceftriaxone is against enterococci and a broad gram-negative spectrum, although mainly through the biliary tract, and no dosage adjustment is it is not active against extended-spectrum β-lactamase-producing required in renal insufficiency. The others are excreted by the kidney strains. Since clinical experience with this and similar investiga- and therefore require dosage adjustment in renal insufficiency. tional drugs is limited, their role in therapy is not yet defined. Clinical Uses ADVERSE EFFECTS OF CEPHALOSPORINS Third-generation cephalosporins are used to treat a wide variety of serious infections caused by organisms that are resistant to most A. Allergy other drugs. Strains expressing extended-spectrum β lactamases, Cephalosporins are sensitizing and may elicit a variety of hyper- however, are not susceptible. Third-generation cephalosporins sensitivity reactions that are identical to those of penicillins, should be avoided in treatment of enterobacter infections—even including anaphylaxis, fever, skin rashes, nephritis, granulocy- if the clinical isolate appears susceptible in vitro—because of topenia, and hemolytic anemia. However, the chemical nucleus emergence of resistance. Ceftriaxone and cefotaxime are approved of cephalosporins is sufficiently different from that of penicillins for treatment of meningitis, including meningitis caused by pneu- so that some individuals with a history of penicillin allergy may mococci, meningococci, H influenzae, and susceptible enteric tolerate cephalosporins. The frequency of cross-allergenicity gram-negative rods, but not by L monocytogenes. Ceftriaxone and between the two groups of drugs is uncertain but is probably cefotaxime are the most active cephalosporins against penicillin- around 5–10%. Cross-allergenicity appears to be more common non-susceptible strains of pneumococci and are recommended for with penicillins and early generation cephalosporins compared empirical therapy of serious infections that may be caused by these with later generation cephalosporins. However, patients with strains. Meningitis caused by strains of pneumococci with penicil- a history of anaphylaxis to penicillins should not receive lin MICs > 1 mcg/mL may not respond even to these agents, and cephalosporins. addition of vancomycin is recommended. Other potential indica- tions include empirical therapy of sepsis of unknown cause in B. Toxicity both the immunocompetent and the immunocompromised Local irritation can produce pain after intramuscular injection and patient and treatment of infections for which a cephalosporin is thrombophlebitis after intravenous injection. Renal toxicity, the least toxic drug available. In neutropenic, febrile immunocom- including interstitial nephritis and tubular necrosis, has been dem- promised patients, ceftazidime is often used in combination with onstrated with several cephalosporins and caused the withdrawal other antibiotics. of cephaloridine from clinical use.  CHAPTER 43 Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics 801 Cephalosporins that contain a methylthiotetrazole group (cefa- inhibitors are most active against Ambler class A β lactamases mandole, cefmetazole, cefotetan, and cefoperazone) may cause (plasmid-encoded transposable element [TEM] β lactamases in hypoprothrombinemia and bleeding disorders. Oral administra- particular), such as those produced by staphylococci, H influenzae, tion of vitamin K1, 10 mg twice weekly, can prevent this. Drugs N gonorrhoeae, salmonella, shigella, E coli, and K pneumoniae. They with the methylthiotetrazole ring can also cause severe disulfiram- are not good inhibitors of class C β lactamases, which typically are like reactions; consequently, alcohol and alcohol-containing chromosomally encoded and inducible, produced by Enterobacter sp, medications must be avoided. Citrobacter sp, S marcescens, and P aeruginosa, but they do inhibit chromosomal β lactamases of B fragilis and M catarrhalis. The three inhibitors differ slightly with respect to pharmacol- OTHER BETALACTAM DRUGS ogy, stability, potency, and activity, but these differences usually are of little therapeutic significance. Beta-lactamase inhibitors are available only in fixed combinations with specific penicillins. The MONOBACTAMS antibacterial spectrum of the combination is determined by the Monobactams are drugs with a monocyclic β-lactam ring companion penicillin, not the β-lactamase inhibitor. (The fixed (Figure 43–1). Their spectrum of activity is limited to aerobic combinations available in the USA are listed in Preparations gram-negative rods (including P aeruginosa). Unlike other β-lactam Available.) An inhibitor extends the spectrum of a penicillin pro- antibiotics, they have no activity against gram-positive bacteria or vided that the inactivity of the penicillin is due to destruction by anaerobes. Aztreonam is the only monobactam available in the β lactamase and that the inhibitor is active against the β lactamase USA. It has structural similarities to ceftazidime; hence, its gram- that is produced. Thus, ampicillin-sulbactam is active against negative spectrum is similar to that of the third-generation cepha- β-lactamase-producing S aureus and H influenzae but not against losporins. It is stable to many β lactamases with the notable serratia, which produces a β lactamase that is not inhibited exceptions being AmpC β lactamases and extended-spectrum by sulbactam. Similarly, if a strain of P aeruginosa is resistant to β lactamases. It penetrates well into the cerebrospinal fluid. piperacillin, it is also resistant to piperacillin-tazobactam because Aztreonam is given intravenously every 8 hours in a dose of tazobactam does not inhibit the chromosomal β lactamase pro- 1–2 g, providing peak serum levels of 100 mcg/mL. The half-life duced by P aeruginosa. is 1–2 hours and is greatly prolonged in renal failure. The indications for penicillin-β-lactamase inhibitor combina- Penicillin-allergic patients tolerate aztreonam without reaction. tions are empirical therapy for infections caused by a wide range Occasional skin rashes and elevations of serum aminotransferases of potential pathogens in both immunocompromised and immu- occur during administration of aztreonam, but major toxicity is nocompetent patients and treatment of mixed aerobic and anaero- uncommon. In patients with a history of penicillin anaphylaxis, aztre- bic infections, such as intra-abdominal infections. Doses are the onam may be used to treat serious infections such as pneumonia, same as those used for the single agents except that the recom- meningitis, and sepsis caused by susceptible gram-negative pathogens. mended dosage of piperacillin in the piperacillin-tazobactam combination is 3–4 g every 6 hours. Adjustments for renal insuf- ficiency are made based on the penicillin component. BETA-LACTAMASE INHIBITORS (CLAVULANIC ACID, SULBACTAM, CARBAPENEMS & TAZOBACTAM) The carbapenems are structurally related to β-lactam antibiotics These substances resemble β-lactam molecules (Figure 43–7), but (Figure 43–1). Doripenem, ertapenem, imipenem, and they have very weak antibacterial action. They are potent inhibitors meropenem are licensed for use in the USA. Imipenem, the first of many but not all bacterial β lactamases and can protect hydrolyz- drug of this class, has a wide spectrum with good activity against able penicillins from inactivation by these enzymes. Beta-lactamase many gram-negative rods, including P aeruginosa, gram-positive O O– S CH3 H2C CH O H2C CH CH2 R C N C C N O CH CH2OH O COOH R= N N COOH R=H N Clavulanic acid Sulbactam Tazobactam FIGURE 43–7 Beta-lactamase inhibitors. 802 SECTION VIII Chemotherapeutic Drugs organisms, and anaerobes. It is resistant to most β lactamases but glycopeptide of molecular weight 1500. It is water soluble and not carbapenemases or metallo-β lactamases. Enterococcus faecium, quite stable. methicillin-resistant strains of staphylococci, Clostridium difficile, Burkholderia cepacia, and Stenotrophomonas maltophilia are resis- Mechanisms of Action & Basis tant. Imipenem is inactivated by dehydropeptidases in renal tubules, resulting in low urinary concentrations. Consequently, it of Resistance is administered together with an inhibitor of renal dehydropepti- Vancomycin inhibits cell wall synthesis by binding firmly to the dase, cilastatin, for clinical use. Doripenem and meropenem are D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide similar to imipenem but have slightly greater activity against (Figure 43–5). This inhibits the transglycosylase, preventing fur- gram-negative aerobes and slightly less activity against gram- ther elongation of peptidoglycan and cross-linking. The peptido- positives. They are not significantly degraded by renal dehydro- glycan is thus weakened, and the cell becomes susceptible to lysis. peptidase and do not require an inhibitor. Ertapenem is less active The cell membrane is also damaged, which contributes to the than the other carbapenems against P aeruginosa and Acinetobacter antibacterial effect. species. It is not degraded by renal dehydropeptidase. Resistance to vancomycin in enterococci is due to modification Carbapenems penetrate body tissues and fluids well, including of the D-Ala-D-Ala binding site of the peptidoglycan building the cerebrospinal fluid. All are cleared renally, and the dose must be block in which the terminal D-Ala is replaced by D-lactate. This reduced in patients with renal insufficiency. The usual dosage of results in the loss of a critical hydrogen bond that facilitates high- imipenem is 0.25–0.5 g given intravenously every 6–8 hours (half- affinity binding of vancomycin to its target and loss of activity. life 1 hour). The usual adult dosage of meropenem is 0.5–1 g This mechanism is also present in vancomycin-resistant S aureus intravenously every 8 hours. The usual adult dosage of doripenem strains (MIC ≥ 16 mcg/mL), which have acquired the enterococ- is 0.5 g administered as a 1- or 4-hour infusion every 8 hours. cal resistance determinants. The underlying mechanism for Ertapenem has the longest half-life (4 hours) and is administered reduced vancomycin susceptibility in vancomycin-intermediate as a once-daily dose of 1 g intravenously or intramuscularly. strains (MICs = 4–8 mcg/mL) of S aureus is not fully known. Intramuscular ertapenem is irritating, and for that reason the drug However these strains have altered cell wall metabolism that is formulated with 1% lidocaine for administration by this route. results in a thickened cell wall with increased numbers of D-Ala- A carbapenem is indicated for infections caused by susceptible D-Ala residues, which serve as dead-end binding sites for vanco- organisms that are resistant to other available drugs, eg, P aeruginosa, mycin. Vancomycin is sequestered within the cell wall by these and for treatment of mixed aerobic and anaerobic infections. false targets and may be unable to reach its site of action. Carbapenems are active against many penicillin-non-susceptible strains of pneumococci. Carbapenems are highly active in the Antibacterial Activity treatment of enterobacter infections because they are resistant to Vancomycin is bactericidal for gram-positive bacteria in concentra- destruction by the β lactamase produced by these organisms. tions of 0.5–10 mcg/mL. Most pathogenic staphylococci, includ- Clinical experience suggests that carbapenems are also the treat- ing those producing β lactamase and those resistant to nafcillin and ment of choice for infections caused by extended-spectrum methicillin, are killed by 2 mcg/mL or less. Vancomycin kills β-lactamase-producing gram-negative bacteria. Ertapenem is staphylococci relatively slowly and only if cells are actively dividing; insufficiently active against P aeruginosa and should not be used to the rate is less than that of the penicillins both in vitro and in vivo. treat infections caused by that organism. Imipenem, meropenem, Vancomycin is synergistic in vitro with gentamicin and streptomy- or doripenem, with or without an aminoglycoside, may be effec- cin against Enterococcus faecium and Enterococcus faecalis strains that tive treatment for febrile neutropenic patients. do not exhibit high levels of aminoglycoside resistance. The most common adverse effects of carbapenems—which tend to be more common with imipenem—are nausea, vomiting, Pharmacokinetics diarrhea, skin rashes, and reactions at the infusion sites. Excessive levels of imipenem in patients with renal failure may lead to Vancomycin is poorly absorbed from the intestinal tract and is seizures. Meropenem, doripenem, and ertapenem are much less administered orally only for the treatment of antibiotic-associated likely to cause seizures than imipenem. Patients allergic to penicil- colitis caused by C difficile. Parenteral doses must be administered lins may be allergic to carbapenems as well. intravenously. A 1-hour intravenous infusion of 1 g produces blood levels of 15–30 mcg/mL for 1–2 hours. The drug is widely distributed in the body. Cerebrospinal fluid levels 7–30% of simultaneous serum concentrations are achieved if there is menin- GLYCOPEPTIDE ANTIBIOTICS geal inflammation. Ninety percent of the drug is excreted by glomerular filtration. In the presence of renal insufficiency, strik- VANCOMYCIN ing accumulation may occur (Table 43–2). In functionally anephric patients, the half-life of vancomycin is 6–10 days. A Vancomycin is an antibiotic produced by Streptococcus orientalis significant amount (roughly 50%) of vancomycin is removed and Amycolatopsis orientalis. With the exception of Flavobacterium, during a standard hemodialysis run when a modern, high-flux it is active only against gram-positive bacteria. Vancomycin is a membrane is used.  CHAPTER 43 Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics 803 Clinical Uses common reactions is the so-called “red man” or “red neck” syndrome. This infusion-related flushing is caused by release of Important indications for parenteral vancomycin are bloodstream histamine. It can be largely prevented by prolonging the infusion infections and endocarditis caused by methicillin-resistant staphy- period to 1–2 hours or pretreatment with an antihistamine such lococci. However, vancomycin is not as effective as an antistaphy- as diphenhydramine. lococcal penicillin for treatment of serious infections such as endocarditis caused by methicillin-susceptible strains. Vancomycin in combination with gentamicin is an alternative regimen for TEICOPLANIN treatment of enterococcal endocarditis in a patient with serious penicillin allergy. Vancomycin (in combination with cefotaxime, Teicoplanin is a glycopeptide antibiotic that is very similar to ceftriaxone, or rifampin) is also recommended for treatment of vancomycin in mechanism of action and antibacterial spectrum. meningitis suspected or known to be caused by a penicillin-resis- Unlike vancomycin, it can be given intramuscularly as