187-2017

INTRODUCTIONTO ANTIMICROBIAL AGENTS

Antimicrobial agents provide some of the most dramatic examples of the advances of modern medicine. Many infectious diseases once considered incurable and potentially lethal can now be treated effectively with antibiotics. The remarkably powerful and specific activity of antimicrobial drugs is due to their selectivity for targets that are either unique to prokaryote and fungal microorganisms or much more important in these organisms than in humans. Among these targets are bacterial and fungal cell wall-synthesizing enzymes (Chapters 43 and 48), the bacterial ribosome (Chapters 44 and 45), the enzymes required for nucleotide synthesis and DNA replication (Chapter 46), and the machinery of viral replication (Chapter 49). The special group of drugs used in mycobacterial infections is discussed in Chapter 47. Cytotoxic antiseptics and disinfectants are discussed in Chapter 50. The clinical uses of many antimicrobial agents are summarized in Chapter 51.

The major problem threatening the continued success of antimicrobial drugs is the development of resistant organisms. Antibiotic resistance mechanisms existed long before the clinical use of antibiotics, even resistance to synthetic drugs that were created in the 20th century. Because resistance mechanisms are already present in nature, an inevitable consequence of antimicrobial use is the selection of resistant microorganisms. Since the start of the antibiotic era, antibiotic use in patients and animals has fueled a major increase in the prevalence of drug-resistant pathogens. In recent years, highly resistant Gram-negative organisms with novel mechanisms of resistance have been increasingly reported. Some of these strains have spread over vast geographic areas as a result of patients seeking medical care in different countries.

Much attention has been focused on eliminating the misuse of antibiotics to slow the tide of resistance. Antibiotics are misused in a variety of ways, including use in patients who are unlikely

to have bacterial infections, use over unnecessarily prolonged periods, and use of multiple agents or broad-spectrum agents when not needed. Large quantities of antibiotics have been used in agriculture to stimulate growth and prevent infection in livestock, and this has added to the selection pressure that results in resistant organisms. In December 2013, the U.S. Food and Drug Administration (FDA) announced a program to phase out the nontherapeutic use of antibiotics in livestock. In 2015, President Obama announced a 5-year National Action Plan with the goals of improving antimicrobial stewardship efforts, tools for diagnosing infectious diseases, and surveillance for resistant organisms. However, even if these programs are successful, it will take years before the benefits are apparent.

Antibiotic resistance has many negative consequences. The prevalence of resistant organisms drives the use of broader-spectrum, less efficacious, or more toxic antibiotics. Not surprisingly, infections caused by antibiotic-resistant pathogens are associated with increased costs, morbidity, and mortality. The Centers for Disease Control and Prevention estimates that every year in the United States at least 2 million people acquire infections due to and 23,000 people die from infections caused by resistant bacteria.

Unfortunately, as the need has grown in recent years, development of novel antibiotics has slowed. Several of the largest pharmaceutical companies have abandoned research and development in this area because of diminished success and profits; the resulting reduction in new drug introductions is shown in the figure below, which shows new systemic antibacterial agents approved by the FDA per 5-year period through 2012. Several new antimicrobial agents have been approved between 2013 and 2015; however, most are slight modifications of existing drugs. Some novel targets are under investigation. For example, tarocin was found to successfully inhibit teichoic acid, a structure essential for bacterial cell wall synthesis. When combined with a β-lactam antibiotic in a mouse model, tarocin effectively killed methicillin-resistant strains of Staphylococcus aureus that were resistant to either agent alone.

These compounds have not yet been studied in humans. Pending the identification and development of new targets and compounds, we will have to rely on currently available families

of drugs. In the face of continuing development of resistance, considerable effort will be required to maintain the effectiveness of these drug groups.

Approvals

18

16

14

12

10

8

6

4

2

0

C A S E S T U D Y

A 45-year-old man is brought to the local hospital emergency department by ambulance. His wife reports that he had been in his normal state of health until 3 days ago when he developed a fever and a productive cough. During the last 24 hours he has complained of a headache and is increasingly confused. His wife reports that his medical history is significant only for hypertension, for which he takes hydrochlorothiazide and lisinopril, and that he is allergic to amoxicillin. She says that he developed a rash many years ago when prescribed amoxicillin for bronchitis. In the emergency department, the man is febrile

■ BETA LACTAM COMPOUNDS

PENICILLINS

The penicillins share features of chemistry, mechanism of action, pharmacology, and immunologic characteristics with cephalosporins, monobactams, carbapenems, and β-lactamase inhibitors. All are β-lactam compounds, so named because of their fourmembered lactam ring.

Chemistry

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 a secondary amino group (RNH–). Substituents (R; examples shown in Figure 43–2) can be attached to the amino group.

The authors thank Dr. Henry F. Chambers and Dr. Daniel Deck for their contributions to this chapter in previous editions.

(38.7°C [101.7°F]), hypotensive (90/54 mmHg), tachypneic (36/min), and tachycardic (110/min). He has no signs of meningismus but is oriented only to person. A stat chest x-ray shows a left lower lung consolidation consistent with pneumonia. A CT scan is not concerning for lesions or elevated intracranial pressure. The plan is to start empiric antibiotics and perform a lumbar puncture to rule out bacterial meningitis. What antibiotic regimen should be prescribed to treat both pneumonia and meningitis? Does the history of amoxicillin rash affect the antibiotic choice? Why or why not?

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 penicilloic acid, which lacks antibacterial activity.

A. Classification

Substituents of the 6-aminopenicillanic acid moiety determine the essential pharmacologic and antibacterial properties of the resulting 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, eg, penicillin V, dicloxacillin, and amoxicillin. The side chains of some representatives of each group are shown in Figure 43–2.

1. Penicillins (eg, penicillin G)—These have greatest activity against Gram-positive organisms, Gram-negative cocci, and non-β-lactamase-producing anaerobes. However, they have little activity against Gram-negative rods, and they are susceptible to hydrolysis by β-lactamases.

BMonobactam

NH

R:CH2 CH2 NH CH

Substituted 3-hydroxyethylcarbapenemic acid (imipenem)

FIGURE 43 1 Core structures of four β-lactam antibiotic 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 a different stereochemical configuration in the lactam ring that imparts resistance to most common β-lactamases. Substituents for the penicillin and cephalosporin families are shown in Figures 43–2 and 43–6, respectively.

2.Antistaphylococcal penicillins (eg, nafcillin)—These penicillins are resistant to staphylococcal β-lactamases. They are active against staphylococci and streptococci but not against enterococci, anaerobic bacteria, and Gram-negative cocci and rods.

3.Extended-spectrum penicillins (aminopenicillins and antipseudomonal penicillins)—These drugs retain the anti-

bacterial spectrum of penicillin and have improved activity against Gram-negative rods. Like penicillin, however, they are relatively susceptible to hydrolysis by β-lactamases.

6-Aminopenicillanic acid

The following structures can each be substituted at the R to produce a new penicillin.

R

NO

NO

C2H5

FIGURE 43 2 Side chains of some penicillins (R groups).

B. Penicillin Units and Formulations

The activity of penicillin G was originally defined in units. Crystalline sodium penicillin G contains approximately 1600 units per mg (1 unit = 0.6 mcg; 1 million units of penicillin = 0.6 g). Semisynthetic penicillins are prescribed by weight rather than units. The minimum inhibitory concentration (MIC) of any penicillin (or other antimicrobial) is usually given in mcg/mL. Most penicillins are formulated as the sodium or potassium salt of the free acid. Potassium penicillin G contains about 1.7 mEq of K+ per million units of penicillin (2.8 mEq/g). Nafcillin contains Na+, 2.8 mEq/g. Procaine salts and benzathine salts of penicillin G provide repository forms for intramuscular injection. In dry crystalline form, penicillin salts are stable for years at 4°C. Solutions lose their activity rapidly (eg, within 24 hours at 20°C) and must be prepared fresh for administration.

polysaccharides and peptides known as peptidoglycan. The polysaccharide contains alternating amino sugars, N-acetylglucosamine and N-acetylmuramic acid (Figure 43–4). A five-amino-acid peptide is linked to the N-acetylmuramic acid sugar. This peptide terminates in -alanyl- -alanine. Penicillin-binding protein (PBP, an enzyme) removes the terminal alanine in the process of forming a cross-link with a nearby peptide. Cross-links give the cell wall its rigidity. Beta-lactam antibiotics, structural analogs of the natural -Ala- -Ala substrate, covalently bind to the active site of PBPs. This binding inhibits the transpeptidation reaction (Figure 43–5) and halts peptidoglycan synthesis, and the cell dies. The exact mechanism of cell death is not completely understood, but autolysins are involved in addition to the disruption of cross linking of the cell wall. Beta-lactam antibiotics kill bacterial cells only when they are actively growing and synthesizing cell wall.

Mechanism of Action

Penicillins, like all β-lactam antibiotics, inhibit bacterial growth by interfering with the transpeptidation reaction of bacterial cell wall synthesis. The cell wall is a rigid outer layer that completely surrounds the cytoplasmic membrane (Figure 43–3), maintains cell integrity, and prevents cell lysis from high osmotic pressure. The cell wall is composed of a complex, cross-linked polymer of

Resistance

Resistance to penicillins and other β-lactams is due to one of four general mechanisms: (1) inactivation of antibiotic by β-lactamase,

(2) modification of target PBPs, (3) impaired penetration of drug to target PBPs, and (4) antibiotic efflux. Beta-lactamase production is the most common mechanism of resistance. Hundreds of different β-lactamases have been identified. Some, such as

M

ML-Ala

L-Ala R

G

R

G

M

ML-Ala

D-Ala

Transpeptidase

M

ML-Ala

L-Ala R

G

R

G

M

ML-Ala

FIGURE 43 4 The transpeptidation reaction in Staphylococcus aureusthat is inhibited by β-lactam antibiotics. The cell wall of Grampositive bacteria is made up of long peptidoglycan polymer chains consisting of the alternating aminohexoses N-acetylglucosamine (G) and N-acetylmuramic acid (M) with pentapeptide side chains linked (in Saureus) by pentaglycine bridges. The exact composition of the side chains varies among species.The diagram illustrates small segments of two such polymer chains and their amino acid side chains. These linear polymers must be cross-linked by transpeptidation of the side chains at the points indicated by the asterisk to achieve the strength necessary for cell viability.

those produced by Staphylococcus aureus, Haemophilus influenzae, and Escherichia coli, are relatively narrow in substrate specificity, preferring penicillins to cephalosporins. Other β-lactamases, eg, AmpC β-lactamase produced by Pseudomonas aeruginosa and Enterobacter sp and extended-spectrum β-lactamases (ESBLs) in Enterobacteriaceae, hydrolyze both cephalosporins and penicillins. Carbapenems are highly resistant to hydrolysis by penicillinases and cephalosporinases, but they are hydrolyzed by metallo-β-lactamases and carbapenemases.

Altered target PBPs are the basis of methicillin resistance in staphylococci and of penicillin resistance in pneumococci and most resistant enterococci. These resistant organisms produce PBPs that have low affinity for binding β-lactam antibiotics, and they are not inhibited except at relatively high, often clinically unachievable, drug concentrations.

Resistance due to impaired penetration of antibiotic occurs only in Gram-negative species because of the impermeable outer membrane of their cell wall, which is absent in Gram-positive bacteria. Beta-lactam antibiotics cross the outer membrane and enter Gram-negative organisms via outer membrane protein channels called porins. Absence of the proper channel or down-regulation of its production can greatly impair drug entry into the cell. Poor 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 presence of a β-lactamase, even a relatively inefficient one, as long as it can hydrolyze drug faster than it enters the cell. Gram-negative organisms also may produce an efflux pump, which consists of cytoplasmic and periplasmic protein components that efficiently transport some β-lactam antibiotics from the periplasm back across the cell wall outer membrane.

Pharmacokinetics

Absorption of orally administered drug differs greatly for individual penicillins, depending in part on their acid stability and protein binding. Gastrointestinal absorption of nafcillin is erratic, so it is not suitable for oral administration. Dicloxacillin, ampicillin, and amoxicillin are acid-stable and relatively well absorbed, producing serum concentrations in the range of 4–8 mcg/mL after a 500-mg oral dose. Absorption of most oral penicillins (amoxicillin being an exception) is impaired by food, and the drugs should be administered at least 1–2 hours before or after a meal.

Intravenous administration of penicillin G is preferred to the intramuscular route because of irritation and local pain from intramuscular injection of large doses. Serum concentrations 30 minutes after an intravenous injection of 1 g of penicillin G (equivalent to approximately 1.6 million units) are 20–50 mcg/mL. Only a fraction of the total drug in serum is present as free drug, the concentration of which is determined by protein binding. Highly protein-bound penicillins (eg, nafcillin) generally achieve lower free-drug concentrations in serum than less protein-bound penicillins (eg, penicillin G or ampicillin). Penicillins are widely distributed in body fluids and tissues with a few exceptions. They are polar molecules, so intracellular concentrations are well below those found in extracellular fluids.

Schematic of normal bacterial cell wall peptidoglycan synthesis transpeptidation reaction.

G M + M G

Beta-lactams bind the transpeptidase at the Penicillin Binding Protein site, resulting in inhibition of transpeptidation, thus halting peptidoglycan synthesis.

G M + M G

Benzathine and procaine penicillins are formulated to delay absorption, resulting in prolonged blood and tissue concentrations. A single intramuscular injection of 1.2 million units of benzathine penicillin maintains serum levels above 0.02 mcg/mL for 10 days, sufficient to treat β-hemolytic streptococcal infections. After 3 weeks, levels still exceed 0.003 mcg/mL, which is enough to prevent most β-hemolytic streptococcal infections. A 600,000-unit dose of procaine penicillin yields peak concentrations of 1–2 mcg/mL and clinically useful concentrations for 12–24 hours after a single intramuscular injection.

Penicillin concentrations in most tissues are equal to those in serum. Penicillin is also excreted into sputum and breast milk to levels 3–15% of those in the serum. Penetration into the eye, the prostate, and the central nervous system is poor. However, with active inflammation of the meninges, as in bacterial meningitis, penicillin concentrations of 1–5 mcg/mL can be achieved with a daily parenteral dose of 18–24 million units. These concentrations are sufficient to kill susceptible strains of pneumococci and meningococci.

Penicillin is rapidly excreted by the kidneys; small amounts are excreted by other routes. Tubular secretion accounts for about 90% of renal excretion, and glomerular filtration accounts for the remainder. The normal half-life of penicillin G is approximately 30 minutes but, in renal failure, may be as long as 10 hours. Ampicillin and the extended-spectrum penicillins are secreted more slowly than penicillin G and have half-lives of 1 hour. For penicillins that are cleared by the kidney, the dose must be adjusted according to renal function, with approximately one-fourth to one-third the normal dose being administered if creatinine clearance is 10 mL/min or less (Table 43–1).

Nafcillin is primarily cleared by biliary excretion. Oxacillin, dicloxacillin, and cloxacillin are eliminated by both the kidney and biliary excretion, and no dosage adjustment is required for these drugs in patients in renal failure. Because clearance of penicillins is less efficient in the newborn, doses adjusted for weight alone result in higher systemic concentrations for longer periods than in the adult.

Clinical Uses

Except for amoxicillin, oral penicillins should be given 1–2 hours before or after a meal; they should not be given with food to minimize binding to food proteins and acid inactivation. Amoxicillin may be given without regard to meals. Blood levels of all penicillins can be raised by simultaneous administration of probenecid, 0.5 g (10 mg/kg in children) every 6 hours orally, which impairs renal tubular secretion of weak acids such as β-lactam compounds. Penicillins, like all antibacterial antibiotics, should never be used for viral infections and should be prescribed only when there is reasonable suspicion of, or documented infection with, susceptible organisms.

A. Penicillin

Penicillin G is a drug of choice for infections caused by streptococci, meningococci, some enterococci, penicillin-susceptible pneumococci, staphylococci confirmed to be non-β-lactamase- producing, Treponema pallidum and certain other spirochetes, some Clostridium species, Actinomyces and certain other Grampositive rods, and non-β-lactamase-producing Gram-negative anaerobic organisms. Depending on the organism, the site, and the severity of infection, effective doses range between 4 and 24 million units per day administered intravenously in four to six divided doses. High-dose penicillin G can also be given as a continuous intravenous infusion.

Penicillin V, the oral form of penicillin, is indicated only in minor infections because of its relatively poor bioavailability, the need for dosing four times a day, and its narrow antibacterial spectrum. Amoxicillin (see below) is often used instead.

Benzathine penicillin and procaine penicillin G for intramuscular injection yield low but prolonged drug levels. A single intramuscular injection of benzathine penicillin, 1.2 million units, is effective treatment for β-hemolytic streptococcal pharyngitis. Given intramuscularly once every 3–4 weeks, it prevents reinfection. Benzathine penicillin G, 2.4 million units intramuscularly once a week for 1–3 weeks, is effective in the treatment of syphilis. Procaine penicillin G was once a commonly used treatment for pneumococcal pneumonia and gonorrhea; however, it is rarely used now because many gonococcal strains are penicillin-resistant, and many pneumococci require higher doses of penicillin G or the use of more potent β-lactams.

B. Penicillins Resistant to Staphylococcal BetaLactamase(Methicillin,Nafcillin,andIsoxazolylPenicillins)

These semisynthetic penicillins are indicated for infections caused by β-lactamase-producing staphylococci, although penicillinsusceptible strains of streptococci and pneumococci are also susceptible to these agents. Listeria monocytogenes, enterococci, and methicillin-resistant strains of staphylococci are resistant. In recent years the empirical use of these drugs has decreased substantially

because of increasing rates of methicillin resistance in staphylococci. However, for infections caused by methicillin-susceptible and penicillin-resistant strains of staphylococci, these are considered drugs of choice.

An isoxazolyl penicillin such as dicloxacillin, 0.25–0.5 g orally every 4–6 hours (15–25 mg/kg/d for children), is suitable for treatment of mild to moderate localized staphylococcal infections. These drugs are relatively acid-stable and have reasonable bioavailability. However, food interferes with absorption, and the drugs should be administered 1 hour before or after meals.

Methicillin, the first antistaphylococcal penicillin to be developed, is no longer used clinically due to high rates of adverse effects. Oxacillin and nafcillin, 8–12 g/d, given by intermittent intravenous infusion of 1–2 g every 4–6 hours (50–200 mg/kg/d for children), are considered drugs of choice for serious staphylococcal infections such as endocarditis.

C. Extended-Spectrum Penicillins (Aminopenicillins, Carboxypenicillins, and Ureidopenicillins)

These drugs have greater activity than penicillin against Gramnegative bacteria because of their enhanced ability to penetrate the Gram-negative outer membrane. Like penicillin G, they are inactivated by many β-lactamases.

The aminopenicillins, ampicillin and amoxicillin, have very similar spectrums of activity, but amoxicillin is better absorbed orally. Amoxicillin, 250–500 mg three times daily, is equivalent to the same amount of ampicillin given four times daily. Amoxicillin is given orally to treat bacterial sinusitis, otitis, and lower respiratory tract infections. Ampicillin and amoxicillin are the most active of the oral β-lactam antibiotics against pneumococci with elevated MICs to penicillin and are the preferred β-lactam antibiotics for treating infections suspected to be caused by these strains. Ampicillin (but not amoxicillin) is effective for shigellosis. Ampicillin, at dosages of 4–12 g/d intravenously, is useful for treating serious infections caused by susceptible organisms, including anaerobes, enterococci, L monocytogenes, and β-lactamase-negative strains of Gram-negative cocci and bacilli such as E coli, and Salmonella sp. Non-β-lactamase-producing strains of H influenzae are generally susceptible, but strains that are resistant because of altered PBPs are emerging. Due to production of β-lactamases by Gramnegative bacilli, ampicillin can no longer be used for empirical therapy of urinary tract infections and typhoid fever. Ampicillin is not active against Klebsiella sp, Enterobacter sp, P aeruginosa, Citrobacter sp, Serratia marcescens, indole-positive Proteus species, and other Gram-negative aerobes that are commonly encountered in hospital-acquired infections. These organisms intrinsically produce β-lactamases that inactivate ampicillin.

The carboxypenicillins, carbenicillin and ticarcillin, were developed to broaden the spectrum of penicillins against Gramnegative pathogens, including P aeruginosa; however, neither agent is available in the USA. The ureidopenicillin piperacillin is also active against many Gram-negative bacilli, such as Klebsiella pneumoniae and P aeruginosa. Piperacillin is available only as a co-formulation with the β-lactamase inhibitor tazobactam. Due to the propensity of P aeruginosa to develop resistance during

therapy, an antipseudomonal β-lactam is sometimes used in combination with an aminoglycoside or fluoroquinolone, particularly in infections outside the urinary tract, despite a lack of data supporting combination therapy over single-drug therapy.

Ampicillin, amoxicillin, piperacillin, and, historically, ticarcillin, are available in combination with one of several β-lactamase inhibitors: clavulanic acid, sulbactam, or tazobactam. The addition of a β-lactamase inhibitor extends the activity of these penicillins to include β-lactamase-producing strains of S aureus as well as some β-lactamase-producing Gram-negative bacteria (see Beta-Lactamase Inhibitors).

Adverse Reactions

The penicillins are generally well tolerated, and, unfortunately, this may encourage inappropriate use. Most of the serious adverse effects are due to hypersensitivity. The antigenic determinants are degradation products of penicillins, particularly penicilloic acid and products of alkaline hydrolysis bound to host protein. A history of a penicillin reaction is not reliable. About 5–8% of people claim such a history, but only a small number of these will have a serious reaction when given penicillin. Less than 1% of persons who previously received penicillin without incident will have an allergic reaction when given penicillin. Because of the potential for anaphylaxis, however, penicillin should be administered with caution or a substitute drug given if the person has a history of serious penicillin allergy. Penicillin skin testing may also be used to evaluate Type I hypersensitivity. If skin testing is negative, most patients can safely receive penicillin.

Allergic reactionsinclude anaphylactic shock (very rare—0.05% of recipients); serum sickness–type reactions (now rare—urticaria, fever, joint swelling, angioedema, pruritus, and respiratory compromise occurring 7–12 days after exposure); and a variety of skin rashes. Oral lesions, fever, interstitial nephritis (an autoimmune reaction to a penicillin-protein complex), eosinophilia, hemolytic anemia and other hematologic disturbances, and vasculitis may also occur. Most patients allergic to penicillins can be treated with alternative drugs. However, if necessary (eg, treatment of enterococcal endocarditis or neurosyphilis in a patient with serious penicillin allergy), desensitization can be accomplished with gradually increasing doses of penicillin.

In patients with renal failure, penicillin in high doses can cause seizures. Nafcillin is associated with neutropenia and interstitial nephritis; oxacillin can cause hepatitis; and methicillin commonly caused interstitial nephritis (and is no longer used for this reason). Large doses of penicillins given orally may lead to gastrointestinal upset, particularly nausea, vomiting, and diarrhea. Ampicillin has been associated with pseudomembranous colitis. Secondary infections such as vaginal candidiasis may occur. Ampicillin and amoxicillin can be associated with skin rashes when prescribed in the setting of viral illnesses, particularly noted during acute Epstein-Barr virus infection, but the incidence of rash may be lower than originally reported. Piperacillin-tazobactam, when combined with vancomycin, has been associated with greater incidence of acute kidney injury compared to alternate β-lactam agents.

802 SECTION VIII Chemotherapeutic Drugs

■ CEPHALOSPORINS & CEPHAMYCINS

Cephalosporins are similar to penicillins but are more stable to many bacterial β-lactamases and, therefore, have a broader spectrum of activity. However, strains of E coli and Klebsiella sp expressing extended-spectrum β-lactamases that can hydrolyze most cephalosporins are a growing clinical concern. Cephalosporins are not active against L monocytogenes, and of the available cephalosporins, only ceftaroline has some activity against enterococci.

Chemistry

The nucleus of the cephalosporins, 7-aminocephalosporanic acid (Figure 43–6), bears a close resemblance to 6-aminopenicillanic acid (Figure 43–1). The intrinsic antimicrobial activity of natural cephalosporins is low, but the attachment of various R1 and R2 groups has yielded hundreds of potent compounds, many with low toxicity. Cephalosporins have traditionally been classified into four major groups or generations, depending mainly on the spectrum of antimicrobial activity. Several cephalosporins developed more recently do not fit the traditional classification groups. Their unique characteristics and spectra of activity are outlined below.

FIRST GENERATION CEPHALOSPORINS

First-generation cephalosporins include cefazolin, cefadroxil, cephalexin, cephalothin, cephapirin, and cephradine; cefazolin and cephalexin are the only two available in the USA. These drugs are very active against Gram-positive cocci, such as streptococci and staphylococci. Traditional cephalosporins are not active against methicillin-resistant strains of staphylococci; however, new compounds have been developed that have activity against methicillin-resistant strains (see below). E coli, K pneumoniae, and Proteus mirabilis are often sensitive to first-generation cephalosporins, but activity against P aeruginosa, indole-positive Proteus species, Enterobacter sp, S marcescens, Citrobacter sp, and Acinetobacter sp is poor. Anaerobic cocci (eg, peptococci, peptostreptococci) are usually sensitive, but Bacteroides fragilis is not.

Pharmacokinetics & Dosage

A. Oral

Cephalexin is the oral first generation agent widely used in the USA. After oral doses of 500 mg, peak serum levels are 15–20 mcg/mL. Urine concentration is usually very high, but in most tissues levels are variable and generally lower than in serum. Cephalexin is typically given in oral dosages of 0.25–0.5 g four times daily (15–30 mg/kg/d). Excretion is mainly by glomerular filtration and tubular secretion into the urine. Drugs that block tubular secretion, eg, probenecid, may increase serum levels substantially. In patients with impaired renal function, dosage must be reduced (Table 43–2).