• Antibiotics
• β-Lactam Antibiotics
• Chemistry and Mechanisms of Action
• Key Points
• About b-Lactam Antibiotics
• Toxicity
• Key Points
• About β-Lactam Antibiotic Toxicity
• Penicillins
• Natural Penicillins
• Key Points
• About the Natural Penicillins
• Aminopenicillins
• Penicillinase-Resistant Penicillins
• Key Points
• About the Aminopenicillins
• Key Points
• About Penicillinase-Resistant Penicillins
• Carboxypenicillins and Ureidopenicillins
• Key Points
• About Carboxypenicillins and Ureidopenicillins
• Cephalosporins
• First-Generation Cephalosporins
• KeyPoints
• About First-Generation Cephalosporins
• Second-Generation Cephalosporins
• Key Points
• About Second-Generation Cephalosporins
• Third-Generation Cephalosporins
• Key Points
• About the Third-Generation Cephalosporins
• Fourth-Generation Cephalosporins
• Key Points
• About Fourth-Generation Cephalosporins
• Monobactams
• Aztreonam
• Key Points
• About Aztreonam
• Carbapenems
• Chemistry and Pharmacokinetics
• Key Points
• About the Carbapenems
• Spectrum of Activity and Treatment Recommendations
• Aminoglycosides
• Chemistry and Mechanism of Action
• Toxicity
• Pharmacokinetics
• Key Points
• About Aminoglycoside Toxicity
• Spectrum of Activity and Treatment Recommendations
• Key Points
• About Dosing and Serum Monitoring of Aminoglycosides
• Key Points
• About Aminoglycoside Antibacterial Activity
• Glycopeptide Antibiotics
• Chemistry and Mechanism of Action
• Toxicity
• Key Points
• About Glycopeptide Antibacterial Activity
• Pharmacokinetics
• Key Points
• About Vancomycin Toxicity
• Antimicrobial Spectrum and Treatment Recommendations
• Macrolides and Ketolides
• Key Points
• About the Treatment Recommendations for Vancomycin
• Chemistry and Mechanism of Action
• Toxicity
• Pharmacokinetics
• Key Points
• About Macrolide Chemistry, Mechanism of Action, and Toxicity
• Spectrum of Activity and Treatment Recommendations
• Clindamycin
• Chemistry and Mechanism of Action
• Key Points
• About the Spectrum and Treatment Indications for Macrolides and Ketolides
• Toxicity
• Pharmacokinetics
• Antimicrobial Spectrum and Treatment Recommendations
• Tetracyclines
• Chemistry and Mechanisms of Action
• Key Points
• About Clindamycin
• Toxicity
• Pharmacokinetics
• Antimicrobial Spectrum and Treatment Recommendations
• Key Points
• About the Tetracyclines
• Chloramphenicol
• Chemistry and Mechanisms of Action
• Toxicity
• Pharmacokinetics
• Antimicrobial Spectrum and Treatment Recommendations
• Key Points
• About Chloramphenicol
• Quinolones
• Chemical Structure and Mechanisms of Action
• Key Points
• About the Chemistry, Mechanisms of Action, and Toxicity of Quinolones
• Toxicity
• Pharmacokinetics
• Spectrum of Activity and Treatment Recommendations
• Oxazolidones (Linezolid)
• Chemistry and Mechanisms of Action
• Key Points
• About the Specific Quinolones
• Toxicity
• Pharmacokinetics
• Key Points
• About Linezolid
• Antimicrobial Activity and Treatment Recommendations
• Streptogramins
• Chemical Structure and Mechanism of Action
• Toxicity
• Pharmacokinetics
• Antimicrobial Activity and Treatment Indications
• Key Points
• About Synercid
• Daptomycin
• Chemical Structure and Mechanism of Action
• Toxicity
• Pharmacokinetics
• Spectrum of Activity and Treatment Recommendations
• Key Points
• About Daptomycin
• Metronidazole
• Chemical Structure and Mechanism of Action
• Toxicity
• Key Points
• About Metronidazole
• Pharmacokinetics
• Spectrum of Activity and Treatment Recommendations
• Sulfonamides and Trimethoprim
• Chemical Structure and Mechanisms of Action
• Toxicity
• Pharmacokinetics
• Spectrum of Activity and Treatment Recommendations
• Key Points
• About Sulfonamides

Antibiotics

Before prescribing a specific antibiotic, clinicians should be able to answer these questions:

•  How does the antibiotic kill or inhibit bacterial growth?

•  What are the antibiotic’s toxicities and how should they be monitored?

•  How is the drug metabolized, and what are the dosing recommendations? Does the dosing schedule need to be modified in patients with renal dysfunction?

•  What are the indications for using each specific antibiotic?

•  How broad is the antibiotic’s antimicrobial spectrum?

•  How much does the antibiotic cost?

Clinicians should be familiar with the general classes of antibiotics, their mechanisms of action, and their major toxicities. The differences between the specific antibiotics in each class can be subtle, often requiring the expertise of an infectious disease specialist to design the optimal anti-infective regimen. The general internist or physician-in-training should not attempt to memorize all the facts outlined here, but rather should read the pages that follow as an overview of anti-infectives. The chemistry, mechanisms of action, major toxicities, spectrum of activity, treatment indications, pharmacokinetics, dosing regimens, and cost are reviewed. The specific indications for each anti-infective are briefly covered here. A more complete discussion of specific regimens is included in the later chapters that cover infections of specific anatomic sites.

Upon prescribing a specific antibiotic, physicians should reread the specific sections on toxicity spectrum of activity, pharmacokinetics, dosing, and cost. Because new anti-infectives are frequently being introduced, prescribing physicians should also take advantage of handheld devices, online pharmacology databases, and antibiotic manuals so as to provide up-to-date treatment. When the proper therapeutic choice is unclear, on-the-job training can be obtained by requesting a consultation with an infectious disease specialist. Anti-infective agents are often considered to be safe; however, the multiple potential toxicities outlined below, combined with the likelihood of selecting for resistant organisms, emphasize the dangers of over-prescribing antibiotics.

β-Lactam Antibiotics

Chemistry and Mechanisms of Action

The β-Lactam antibiotics have a common central structure consisting of a β-lactam ring and a thiazolidine ring [in the penicillins and carbapenems, or a β-lactam ring and a dihydrothiazine ring [in the cephalosporin. The side chain attached to the β-lactam ring (R1) determines many of the antibacterial characteristics of the specific antibiotic, and the structure of the side chain attached to the dihydrothiazine ring (R₂) determines the pharmacokinetics and metabolism.

The β-lactam antibiotics bind to various penicillin-binding proteins. The penicillin-binding proteins represent a family of enzymes important for bacterial cell wall synthesis, including the car-boxypeptidases, endopeptidases, transglycolases, and transpeptidases. Strong binding to penicillin-binding protein-1, a cell wall transpeptidase and transglycolase causes rapid bacterial death. Inhibition of this transpeptidase prevents the cross-linking of the cell wall peptido-glycans, resulting in a loss of integrity of the bacterial cell wall. Without its protective outer coat, the hyperosmolar intracellular contents swell, and the bacterial cell membrane lyses. Inhibition of penicillin-binding protein-3, a transpeptidase and transglycolase that acts at the septum of the dividing bacterium, causes the formation of long filamentous chains of non-dividing bacteria and bacterial death.

Key Points

About b-Lactam Antibiotics

1. Penicillins, cephalosporins, and carbapenems are all b-lactam antibiotics:

a)  All contain a p-lactam ring.

b)  All bind to and inhibit penicillin-binding proteins, enzymes important for cross-linking bacterial cell wall peptidoglycans.

c)  All require active bacterial growth for bacteriocidal action.

d)  All are antagonized by bacteriostatic antibiotics.

Inhibition of other penicillin-binding proteins blocks cell wall synthesis in other ways, and activates bacterial lysis.

The activity of all β-lactam antibiotics requires active bacterial growth and active cell wall synthesis. Therefore, bacteria in a dormant or static phase will not be killed, but those in an active log phase of growth are quickly lysed. Bacteriostatic agents slow bacterial growth and antagonize β-lactam antibiotics, and therefore, in most cases, bacteriostatic antibiotics should not be combined with β-lactam antibiotics.

Toxicity

Hypersensitivity reactions are the most common side effects associated with the β-lactam antibiotics. Penicillins are the agents that most commonly cause allergic reactions, at rates ranging from 0.7% to 10%. Allergic reactions to cephalosporins have been reported in 1% to 3% of patients, and similar percentages have been reported with carbapenems. However, the incidence of serious, immediate immunoglobulin E-mediated hypersensitivity reactions is much lower with cephalosporins than with penicillins. Approximately 1% to 7% of patients with penicillin allergies also prove to be allergic to cephalosporins and carbapenems.

Penicillins are the most allergenic of the β-lactam antibiotics because their breakdown products, particularly penicilloyl and penicillanic acid, are able to form amide bonds with serum proteins. The resulting antigens increase the probability of a host immune response. Patients who have been sensitized by previous exposure to penicillin may develop an immediate immunoglobulin E-mediated hypersensitivity reaction that can result in anaphylaxis and urticaria. In the United States, penicillin-induced allergic reactions result in 400 to 800 fatalities annually. Because of the potential danger, patients with a history of an immediate hypersensitivity reaction to penicillin should never be given any β-lactam antibiotic, including a cephalosporin or carbapenem. High levels of immunoglobulin G anti-penicillin antibodies can cause serum sickness, a syndrome resulting in fever, arthritis, and arthralgias, urticaria, and diffuse edema.

Other less common toxicities are associated with individual β-lactam antibiotics. Natural penicillins and imipenem lower the seizure threshold and can result in grand mal seizures. Ceftriaxone is excreted in high concentrations in the bile and can crystallize, causing biliary sludging and cholecystitis. Antibiotics containing a specific methylthiotetrazole ring (cefamandole, cefoperazone, cefotetan) can induce hypoprothrombinemia and, in combination with poor nutrition, may increase postoperative bleeding. Cefepime has been associated with encephalopathy and myoclonus in elderly individuals. All broad-spectrum antibiotics increase the risk of pseudomembranous colitis. In combination with aminoglycosides, cephalosporins demonstrate increased nephrotoxicity.

Key Points

About β-Lactam Antibiotic Toxicity

1. Allergic reactions are most common toxicity, and they include both delayed and immediate hypersensitivity reactions.

2.  Allergy to penicillins seen in 1% to 10% of patients; 1% to 3% are allergic to cephalosporins and carbapenems. 1% to 7% of patients with a penicillin allergy are also allergic to cephalosporins and carbapenems.

3.  Seizures are associated with penicillins and imipenem, primarily in patients with renal dysfunction.

4.  Ceftriaxone is excreted in the bile and can crystallize to form biliary sludge.

5.  Cephalosporins with methylthiotetrazole rings (cefamandole, cefoperazone, moxalactam, cefotetan) can interfere with vitamin К and increase prothrombintime.

6.  Pseudomembranous colitis can develop as a result of overgrowth of Clostridium difficile.

7.  Nephrotoxicity sometimes occurs when cephalosporins are given in combination with aminoglycosides.

Penicillins

Penicillins vary in their spectrum of activity. Natural penicillins have a narrow spectrum. The aminopenicillins have an intermediate spectrum, and combined with β-lactamase inhibitors, the carboxy/ureidopenicillins have a very broad spectrum of activity.

Natural Penicillins

Pharmacokinetics — All natural penicillins are rapidly excreted by the kidneys, resulting in short half-lives. As a consequence, the penicillins must be dosed frequently, and dosing must be adjusted in patients with renal dysfunction. Probenecid slows renal excretion, and this agent can be used to sustain higher serum levels.

Key Points

About the Natural Penicillins

1.  Very short half-life (15-30 minutes).

2.  Excreted renally; adjust for renal dysfunction; probenecid delays excretion.

3.  Penetrates most inflamed body cavities.

4.  Narrow spectrum. Indicated for Streptococcus pyogenes, S. viridans Gp., mouth flora, Clostridia perfringens, Neisseria meningitidis, Pasteurella, and spirochetes.

5.  Recommended for penicillin-sensitive S. pneumoniae [however, penicillin resistant strains are now frequent (>30%)]; infections caused by mouth flora; Clostridium perfringens or spirochetes.

Table. Penicillins: Half-Life, Dosing, Renal Dosing, Cost, and Spectrum

Depending on the specific drug, penicillins can be given intravenously or intramuscularly. Some penicillins have been formulated to withstand the acidity of the stomach and are absorbed orally. Penicillins are well distributed in the body and are able to penetrate most inflamed body cavities. However, their ability to cross the blood-brain barrier in the absence of inflammation is poor. In the presence of inflammation, therapeutic levels are generally achievable in the cerebrospinal fluid.

Spectrum of Activity and Treatment Recommendations — PenciUin G remains the treatment of choice for S. pyogenes (“group A strep”) and the S. viridans group. It also remains the most effective agent for the treatment of infections caused by mouth flora. Penicillin G is also primarily recommended for Clostridium perfrin-gens, C. tetani, Erysipelothrix rhusiopathiae, Pasteurella multocida, and spirochetes including syphilis and Le-tospira. This antibiotic also remains the primary recommended therapy for S. pneumoniae sensitive to penicillin (minimum inhibitory concentration < 0.1µg/mL). However, in many areas of the United States, more than 30% of strains are moderately resistant to penicillin (minimum inhibitory concentration = 0.1-1 µg/mL). In these cases, ceftriaxone, cefotaxime, or high-dose penicillin (>12 million units daily) can be used. Moderately resistant strains of S. pneumoniae possess a lower-affinity penicillin-binding protein, and this defect in binding can be overcome by high serum levels of penicillin in the treatment of pneumonia, but not of meningitis. Infections with high-level penicillin-resistant S. pneumoniae (minimum inhibitory concentration > 2 µg/mL) require treatment with vancomycin or another alternative antibiotic.

Table Organisms That May Be Susceptible to Penicillins

Aminopenicillins

Pharmacokinetics — In aminopenicillins, a chemical modification of penicillin increases resistance to stomach acid, allowing these products to be given orally. They can also be given intramuscularly or intravenously. Amoxicillin has excellent oral absorption: 75% as compared with 40% for ampicillin. Absorption is not impaired by food. The higher peak levels achievable with aminopenicillins allow for a longer dosing interval, making them a more convenient oral antibiotic than ampicillin. As observed with the natural penicillins, the half-life is short (1 hour) and these drugs are primarily excreted unmodified in the urine.

Spectrum of Activity and Treatment Recommendations — The spectrum of activity in the aminopenicillins is slightly broader than in the natural penicillins. Intravenous ampicillin is recommended for treatment oIListeri monocytogenes, sensitive enterococci, Proteus   mirabilis, and   non-β-lactamase-producing Haemophilus influenzae. Aminopenicillins are also effective against Shigella flexneri and sensitive strains of nontyphoidal Salmonella. Amoxicillin can be used to treat otitis media and air sinus infections. When combined with a β-lactamase inhibitor (clavulanate or sulbactam), aminopenicillins are also effective against methicillin-sensitive S. aureus (MSSA), β-lactamase-producing strains of H. influenzae, and Moraxella catarrhalis. The latter two organisms are commonly cultured from middle ear and air sinus infections. However, the superiority of amoxicillin-clavulanate over amoxicillin for middle ear and air sinus infections has not been proven.

Penicillinase-Resistant Penicillins

Pharmacokinetics — The penicillinase-resistant penicillins have the same half-life as penicillin (30 minutes) and require dosing at 4-hour intervals or constant intravenous infusion. Unlike the natural penicillins, these agents are cleared hepatically, and doses of nafcillin and oxacillin usually do not need to be adjusted for renal dysfunction. But the efficient hepatic excretion of nafcillin means that the dose needs to be adjusted in patients with significant hepatic dysfunction. The liver excretes oxacillin less efficiently, and so dose adjustment is usually not required in liver disease.

Key Points

About the Aminopenicillins

1.  Short half-life (1 hour), and clearance similar to natural penicillins.

2.  Slightly broader spectrum of activity.

3.  Parenteral ampicillin indicated for Listeria monocytogenes, sensitive enterococci, Proteus mirabilis, and non-b-lactamase-producing Haemophilus influenzae.

4.  Ampicillin plus an aminoglycoside is the treatment of choice for enterococci. Whenever possible, vancomycin should be avoided.

5.  Amoxicillin has excellent oral absorption; it is the initial drug of choice for otitis media and bacterial sinusitis.

6.  Amoxicillin-clavulanate has improved coverage of Staphylococcus, H. influenzae, and Mora-xella catarrhalis, but it is expensive and has a high incidence of diarrhea. Increased efficacy compared with amoxicillin is not proven in otitis media. However, covers amoxicillin-resistant H. influenzae, a common pathogen in that disease.

Spectrum of Activity and Treatment Recommenda-tions-The synthetic modification of penicillin to render it resistant to the β-lactamases produced by S. aureus reduces the ability of these agents to kill anaerobic mouth flora and Neisseria species. These antibiotics are strictly recommended for the treatment of MSSA. They are also used to treat cellulitis when the most probable pathogens are S. aureus and S. pyogenes. Because oral preparations result in considerably lower serum concentration levels, cloxacillin or dicloxacillin should not be used to treat S. aureus bacteremia. These oral agents are used primarily for mild soft-tissue infections or to complete therapy of a resolving cellulitis.

Key Points

About Penicillinase-Resistant Penicillins

1.  Short half-life, hepatically metabolized.

2.  Very narrow spectrum, poor anaerobic activity.

3.  Primarily indicated for  methicillin-sensitive Staphylococcus aureus and cellulitis.

Carboxypenicillins and Ureidopenicillins

Pharmacokinetics — The half-lives of ticarcillin and piperacillin are short, and they require frequent dosing. Sale of ticarcillin and piperacillin alone has been discontinued in favor of ticarcillin-clavulanate and piperacillin-tazobactam.

Dosing every 6 hours is recommended for piperacillin-tazobactam to prevent accumulation of tazobactam. In P. aeruginosa pneumonia, the dose of piperacillin-tazobactam should be increased from 3.375 g Q6h to 4.5 g Q8h to achieve cidal levels of piperacillin in the sputum. In combination with an aminoglycoside, piperacillin-tazobactam often demonstrates synergy against P. aeruginosa. However, the administration of the piperacillin-tazobactam needs to be separated from the administration of the aminoglycoside by 30 to 60 minutes.

Spectrum of Activity and Treatment Recommendations — Ticarcillin and piperacillin are able to resist β-lactamases produced by Pseudomonas, Enterobacter, Morganella, and Proteus — Providencia species. At high doses, ticarcillin and piperacillin can also kill many strains of Bacteroides fragilis and provide effective anaerobic coverage. These antibiotics can be used for empiric coverage of moderate to severe intra-abdominal infections. They have been combined with a β-lactamase inhibitor (clavulanate or tazobactam) to provide effective killing of MSSA.

These agents are reasonable alternatives to nafcillin or   oxacillin  when  gram-negative   coverage   is   also required.

Key Points

About Carboxypenicillins and Ureidopenicillins

1.  More effective resistance to gram-negative p-lactamases.

2.  Carboxypenicillin or ureidopenicillin combined with aminoglycosides demonstrate synergistic killing of Pseudomonas aeruginosa.

3.  Ticarcillin-clavulanate and piperacillin-tazobactam have excellent broad-spectrum coverage, including methicillin-sensitive Staphylococcus aureus and anaerobes. They are also useful for intra-abdominal infections, acute prostatitis, in-hospital aspiration pneumonia, and mixed soft-tissue and bone infections.

Table Cephalosporins: Half-Life, Dosing, Renal Dosing, Cost, and Spectrum

Table Organisms That May Be Susceptible to Cephalosporins

Both agents can be used for in-hospital aspiration pneumonia to cover for mouth flora and gram-negative rods alike, and they can also be used for serious intra-abdominal, gynecologic,and acute prostate infections. They have been used for skin and bone infections thought to be caused by a combination of gram-negative and gram-positive organisms.

Cephalosporins

In an attempt to create some semblance of order, the cephalosporins have been classified into generations based on spectrum of activity. First-generation cephalosporins are predominantly effective against gram-positive cocci. Second-generation cephalosporins demonstrate increased activity against aerobic and anaerobic gram-negative bacilli, but have variable activity against gram-positive cocci. The third-generation cephalosporins demonstrate even greater activity against gram-negative bacilli, but only limited activity against gram-positive cocci. Finally, the fourth-generation cephalosporins demonstrate the broadest spectrum of activity, being effective against both gram-positive cocci and gram-negative bacilli.

Classification of the cephalosporins by generation naturally leads to the assumption that newer, later-generation cephalosporins are better than the older cephalosporins. However, it is important to keep in mind that, for many infections, earlier-generation, narrower-spectrum cephalosporins are preferred to the more recently developed broader-spectrum cephalosporins.

First-Generation Cephalosporins

Pharmacokinetics — Cefazolin, the preferred parenteral first-generation cephalosporin, has a longer half-life than penicillin, and it is primarily excreted by the kidneys. The first-generation cephalosporins penetrate most body cavities, but they fail to cross the blood-brain barrier. Oral preparations (cephalexin, cephradine, cefadroxil) are very well absorbed, achieving excellent peak serum concentrations (0.5 g cephalexin results in a 18 µg/mL peak). Absorption is not affected by food. The half-lives of cephalexin and cephradine are short, requiring frequent administration. These agents need to be corrected for renal dysfunction.

KeyPoints

About First-Generation Cephalosporins

1.  Excellent gram-positive coverage, some gram-negative coverage.

2.  Do not cross the blood-brain barrier.

3.  Inexpensive.

4.  Useful for treating soft-tissue infections and for surgical prophylaxis. Can often be used as an alternative to oxacillin or nafcillin.

Spectrum of Activity and Treatment Recommendations — The first-generation cephalosporins are very active against gram-positive cocci, including MSSA, and they also have moderate activity against some community-acquired gram-negative bacilli. They are active against oral cavity anaerobes, but are ineffective for treating B. fagilis, H. influenzae, L. monocytogenes, methicillin-resistant Staphylococcus aureus, penicillin-resistant S. pneumo-niae, and Enterococcus.

First-generation cephalosporins are an effective alternative to nafcillin or oxacillin for soft-tissue infections thought to be caused by MSSA or S. pyogenes. Cefazolin is also the antibiotic of choice for surgical prophylaxis. Because of its inability to cross the blood-brain barrier, cefazolin should never be used to treat bacterial meningitis. Oral preparations are commonly used to treat less severe soft-tissue infections, including impetigo, early cellulitis, and mild diabetic foot ulcers.

Second-Generation Cephalosporins

Pharmacokinetics — The second-generation cephalosporins are cleared primarily by the kidney. They have half-lives that range from 0.8 to 3.5 hours, and they penetrate all body cavities.

Spectrum of Activity and Treatment Recommendations — The second-generation cephalosporins possess increased activity against some gram-negative strains, and they effectively treat MSSA and non-enterococcal streptococci. Given the availability of the first-, third-, and fourth-generation cephalosporins and the newer penicillins, second-generation cephalosporins are rarely recommended as primary therapy.

Because cefoxitin and cefotetan demonstrate increased anaerobic coverage, including many strains of B. fragilis, and also cover gonococcus, these two agents are used as part of first-line therapy in pelvic inflammatory disease. They are also used for the treatment of moderately severe intra-abdominal infections and mixed aerobic-anaerobic soft-tissue infections, including diabetic foot infections. The oral preparation cefuroxime achieves serum levels that are approximately one tenth that of intravenous preparations, and this agent is recommended for the outpatient treatment of uncomplicated urinary tract infections and otitis media. Other less costly oral antibiotics effectively cover the same pathogens.

Cefaclor, the other second-generation oral preparation, is inactivated by β-lactamases produced by H. influenzae and M. catarrhalis. Although cefaclor has been recommended for otitis media, other oral antibiotics are generally preferred.

Key Points

About Second-Generation Cephalosporins

1.  Improved activity against Haemophilus influenzae, Neisseria species,and Moraxella catarrhalis.

2.  Cefoxitin and cefotetan have anaerobic activity and are used in mixed soft-tissue infections and pelvic inflammatory disease.

3.  Cefotetan and cefamandole have a methylth-iotetrazole ring that decreases prothrombin production. Vitamin К prophylaxis is recommended in malnourished patients.

4.  Cefuroxime-axetil is a popular oral cephalo-sporin; less expensive alternative oral antibiotics are available, however.

5.  Overall, this generation is of limited usefulness.

Third-Generation Cephalosporins

Pharmacokinetics — With the exception of ceftriaxone, the third-generation cephalosporins are excreted by the kidneys . Ceftriaxone is cleared primarily by the liver, but high concentrations of the drug are also excreted in the biliary system. The half-lives of these agents vary, being as short as 1.5 hours (cefotaxime) and as long as 8 hours (ceftriaxone). They penetrate most body sites effectively.

Spectrum of Activity and Treatment Recommendations — As compared with the first- and second-generation, third-generation cephalosporins have enhanced activity against many aerobic gram-negative bacilli, but they do not cover Serratia marcescens, Acineto-bacter, and Enterobacter cloacae. With the exceptions of ceftazidime and cefoperazone, third-generation cephalosporins are ineffective against P. aeruginosa.

These agents have excellent cidal activity against S. pneumoniae (including moderately penicillin-resistant strains), S. pyogenes, and other streptococci. All members of this generation are ineffective for treating Enterococcus, methicillin-resistant Staphylococcus aureus, highly penicillin-resistant pneumococcus, and L. monocytogenes.

The ESBLs are increasing in frequency, and they promise to reduce the effectiveness of the third- and fourth-generation cephalosporins. A large number of third-generation cephalosporins are available, all with similar indications. Small deficiencies in coverage and less-desirable pharmacokinetics have affected the popularity of a number of these drugs.

Ceftriaxone and cefotaxime are recommended for empiric treatment of community-acquired pneumonia and community-acquired bacterial meningitis. Third-generation cephalosporins can be used in combination with other antibiotics to empirically treat the septic patient. Ceftriaxone is recommended for treatment of N. gonorrhoeae. Cefotaxime is cleared renally and does not form sludge in the gallbladder. For this reason, this agent is preferred over ceftriaxone by some pediatricians, particularly for the treatment of bacterial meningitis in children — where high-dose therapy has been associated with symptomatic biliary sludging. Ceftazidime is the only third-generation cephalosporin that has excellent activity against P. aeruginosa; however, the fourth-generation cephalosporin cefepime (and the monobactam aztreonam) are now more commonly utilized for anti-Pseudomonas therapy in many institutions.

The oral third-generation cephalosporin cefrxime has a long half-life, allowing for once-daily dosing. Cefrxime provides effective coverage for S. pneumoniae (penicillin-sensitive), S. pyogenes, H. inflnenzae,M. catarrhalis, Neisseria species, and many gram-negative bacilli, but it is ineffective against S. aureus. Its absorption is not affected by food. This agent is a potential second-line therapy for community-acquired pneumonia, and it is an alternative to penicillin for the treatment of bacterial pharyngitis. The other oral preparation, cefpodoxime proxetil, has an antimicrobial spectrum similar to that of cefrxime. In addition, it has moderate activity against S. aureus. The indications for use are similar to those for cefrxime, and cefpodoxime proxetil has also been recommended as an alternative treatment for acute sinusitis.

Key Points

About the Third-Generation Cephalosporins

1.  Improved gram-negative coverage.

2.  Excellent activity against Neisseria gonorrhoeae, N. meningitidis, Haemophilus influen-zae, and Moraxella catarrhalis.

3.  Ceftriaxone has a long half-life that allows for once-daily dosing. In children,acalculous cholecystitis can occur with large doses.

4.  Cefotaxime has a shorter half-life but activity identical to that of ceftriaxone; does not cause biliary sludging.

5.  Ceftazidime has excellent activity against most Pseudomonas aeruginosa strains, but reduced activity against Staphylococcus aureus.

6.  Extended spectrum p-lactamases are increasing in frequency and endangering the effectiveness of third-generation cephalosporins.

7.  Recommended for community-acquired pneumonia and bacterial meningitis

Fourth-Generation Cephalosporins

Pharmacokinetics — Clearance of the fourth-generation cephalosporins is renal, and the half-lives of these agents are similar to the renally cleared third-generation cephalosporins. The R₂ substitution of the fourth-generation cephalosporins contains both a positively and negatively charged group that, together, have zwitterionic properties that permit these antibiotics to penetrate the outer wall of gram-negative bacteria and concentrate in the periplasmic space. This characteristic also allows for excellent penetration of all body compartments, including the cerebrospinal fluid.

Spectrum of Activity and Treatment Recommendations — The fourth-generation cephalosporins are resistant to most β-lactamases, and they only weakly induce β-lactamase activity. These agents also bind gram-positive penicillin-binding proteins with high affinity.

The only agent currently available in the United States is cefepime. In addition to having broad antimicrobial activity against gram-negative bacilli, including P. aeruginosa, cefepime provides excellent coverage for S. pneumoniae (including strains moderately resistant to penicillin), S. pyogenes, and MSSA. Cefepime and ceftazidime provide comparable coverage for P. aeruginosa. To maximize the likelihood of cure of serious P. aeruginosa infection, more frequent dosing (q8h) has been recommended.

Cefepime is not effective against L. monocytogenes, methicillin-resistant Staphylococcus aureus, or B. fragilis. As compared with third-generation cephalosporins, cefepime is more resistant to β-lactamases, including the ESBLs. It has been effectively used to treat gram-negative meningitis. Cefepime is effective as a single agent in the febrile neutropenic patient, and it is an excellent agent for initial empiric coverage of nosocomial infections.

Cefpirome is available in Europe. It has an antimicrobial spectrum similar to that of cefepime, although it is somewhat less active against P. aeruginosa.

Key Points

About Fourth-Generation Cephalosporins

1.  Zwiterionic properties allow for excellent penetration of the bacterial cell wall and of human tissues and fluids.

2.  Weakly induce β-lactamases.

3.  More resistant to extended-spectrum β-lactamases and chromosomal β-lactamases.

4.  Excellent gram-positive (including methicillin-sensitive Staphylococcus aureus) and gram-negative coverage (including Pseudomonas aeruginosa).

5.  Excellent broad-spectrum empiric therapy. Useful in nosocomial infections.

Monobactams

Aztreonam

Chemistry and Pharmacokinetics — Aztreonam was originally isolated from Chromobacterium violaceum and subsequently modified. This antibiotic has a distinctly different structure from the cephalosporins, and it is the only available antibiotic in its class. Rather than a central double ring, aztreonam has a single ring (“monocyclic β-lactam structure”), and has been classified as a monobactam.

Because of its unique structure, aztreonam exhibits no cross-reactivity with other β-lactam antibiotics. It can be used safely in the penicillin-allergic patient. The drug penetrates body tissue well and crosses the blood-brain barrier of inflamed meninges. Aztreonam is renally cleared and has a half-life similar to to that of the renally cleared third-and fourth-generation cephalosporins.

Spectrum of Activity and Treatment Recommendations — Aztreonam does not bind to the penicillin-binding proteins of gram-positive organisms or anaerobes; rather, it binds with high affinity to penicillin-binding proteins, particularly penicillin-binding protein-3 (responsible for septum formation during bacterial division), of gram-negative bacilli including P. aeruginosa. Gram-negative organisms exposed to aztreonam form long filamentous structures and are killed.

Key Points

About Aztreonam

1. A distinctly different structure than that of the cephalosporins.

2.  No cross-reactivity with penicillin,

3.  Binds the penicillin-binding proteins of gram-negative, but not of gram-positive bacteria.

4.  Narrow spectrum, with excellent activity against aerobic gram-negative rods.

5.  Marketed as a non-nephrotoxic replacement for aminoglycosides. However, as compared with aminoglycosides, it

a)  has no synergy with penicillins in enterococ-cal infections.

b)  is not helpful for treating Streptococcus viri-dans endocarditis.

6.  Excellent empiric antibiotic when combined with an antibiotic with good gram-positive activity. Useful for the treatment of pyelonephritis.

Aztreonam is effective against most gram-negative bacilli, and this agent has been marketed as a non-nephrotoxic replacement for aminoglycosides. However, unlike aminoglycosides, aztreonam does not provide synergy with penicillins for Enterococcus. A major advantage of aztreonam is its restricted antimicrobial spectrum, which allows for survival of the normal gram-positive and anaerobic flora that can compete with more resistant pathogens. Aztreonam can be used for the treatment of most infections attributable to gram-negative bacilli. It has been used effectively in pyelonephritis, nosocomial gram-negative pneumonia, gram-negative bacteremia, and gram-negative intra-abdominal infections. Importantly, though, aztreonam provides no gram-positive or anaerobic coverage. Therefore, when it is used for empiric treatment of potential gram-positive pathogens in the seriously ill patient, aztreonam should be combined with vancomycin, clindamycin, erythromycin, or a penicillin.

Table Carbapenems: Half-Life, Dosing, Renal Dosing, Cost, and Spectrum

Carbapenems

Chemistry and Pharmacokinetics

The carbapenems have both a modified thiazolidine ring and a change in the configuration of the side chain that renders the β-lactam ring highly resistant to cleavage. Their hydroxyethyl side chain is in a trans rather than cis conformation, and this configuration is thought to be responsible for the group’s remarkable resistance to β-lactamase breakdown. At physiologic pH, these agents have zwitterionic characteristics that allow them to readily penetrate tissues. The carbapenems bind with high affinity to the high molecular weight penicillin-binding proteins of both gram-positive and gram-negative bacteria.

Imipenem is combined in a 1:1 ratio with cilastatin to block rapid breakdown by renal dehydropeptidase I. Meropenem and ertapenem are not significantly degraded by this enzyme and do not require co-administration with cilastatin. These drugs are all primarily cleared by the kidneys.

Key Points

About the Carbapenems

1. β-Lactam ring is highly resistant to cleavage.

2.  Have zwitterionic characteristics, and penetrate all tissues.

3.  Frequent cross-reactivity in penicillin-allergic patients (7%).

4.  Imipenem causes seizures at high doses; be cautious in renal failure patients.Meropenem is less epileptogenic.

5.  Bind penicillin binding proteins of all bacteria with high affinity.

6.  Very broad cidal activity for aerobic and anaerobic gram-positive and gram-negative bacteria. Also covers Listeria monocytogenes and Nocardia.

7.  Imipenem and meropenem are useful for empiric therapy of suspected mixed aerobic and anaerobic infection or a severe nosocomial infection, pending culture results. Reserve for the severely ill patient.

8.  Ertapenem can be given once daily. Lacks Pseudomonas aeruginosa coverage.

9.  Treatment markedly alters the normal bacterial flora.

Spectrum of Activity and Treatment Recommendations

The carbapenems have a very broad spectrum of activity, effectively killing most strains of gram-positive and gram-negative bacteria, including anaerobes. Overall, imipenem has slightly better activity against gram-positive organisms. Meropenem and ertapenem have somewhat better activity against gram-negative pathogens (except Pseudomonas, as described later in this subsection).

These agents are cidal not only against S. pneumoniae, S. pyogenes, and MSSA, but also against organisms that are not covered by the cephalosporins, including Listeria, Nocardia, Legionella, and Mycobacterium avium intracellulare (MAI). They have static activity against penicillin-sensitive enterococci; however, many penicillin-resistant strains are also resistant to carbapenems. methicillin-resistant Staphylococcus aureus, some penicillin-resistant strains of S. pneumoniae, С difficile, Stenotrophomonas maltophilia, and Burkholderia cepacia are also resistant. Resistance in gram-negative bacilli is most often secondary to loss of an outer membrane protein called D2 that is required for intracellular penetration of the carbapenems. Increasing numbers of gram-negative strains can also produce β-lactamases called carbapene-mases that can hydrolyze these drugs.

Imipenem and meropenem can be used as empiric therapy for sepsis, and they are particularly useful if polymicrobial bacteremia is a strong possibility. They can also be used to treat severe intra-abdominal infections and complicated pyelonephritis. Infections attributable to gram-negative bacilli resistant to cephalosporins and aminoglycosides may be sensitive to imipenem or meropenem. Imipenem or meropenem are recommended as primary therapy for Serratia. Meropenem can be used for meningitis, achieving therapeutic levels in the cere-brospinal fluid. Imipenem is not recommended for this purpose because of its propensity to cause seizures. In general, imipenem and meropenem should be reserved for the seriously ill patient or the patient infected with a highly resistant bacterium that is sensitive only to this antibiotic.

Ertapenem has a longer half-life and can be given just once daily, making it a useful agent for home intravenous therapy. This agent is not effective against P. aeruginosa, but otherwise it has a spectrum similar to that of meropenem. It is recommended for complicated intra-abdominal infections, postpartum and postoperative acute pelvic infections, and complicated soft-tissue infections.

Because the carbapenems are extremely broad-spectrum agents, they kill nearly all normal flora. The loss of normal flora increases the risk of nosocomial infections with resistant pathogens including methicillin-resistant Staphylococcus aureus, Pseudomonas, and Candida.

Aminoglycosides

Chemistry and Mechanism of Action

Aminoglycosides were originally derived from Streptomyces species. These agents have a characteristic 6-member ring with amino-group substitutions, and they are highly soluble in water. At neutral pH, they are positively charged, and this positive charge contributes to their antibacterial activity. At a low pH, the charge is reduced, impairing antimicrobial activity. Their positive charge also causes aminoglycosides to bind to and become inactivated by β-lactam antibiotics. Therefore aminoglycosides should never be in the same solution with β-lactam antibiotics.

Upon entering the bacterium, the antibiotic molecules interact with and precipitate Deoxyribonucleic acid and other anionic components. Aminoglycosides also bind to the 30S sub-unit of bacterial 16S ribosomal RNA and interfere with translation. These combined effects are bactericidal.

Toxicity

The aminoglycosides have a narrow ratio of therapeutic effect to toxic side effect, and monitoring serum levels is generally required to prevent toxicity. These agents are among the most toxic drugs prescribed today, and they should be avoided whenever safer alternative antibiotics are available .

Two major toxicities are observed:

1. Nephrotoxicity. Injury to the proximal convoluted tubules of the kidney leads to a reduction in creatinine clearance. The brush border cells of the proximal tubule take up aminoglycosides by endocytosis, and intracellular entry is associated with cell necrosis. Aminoglycosides cause significant reductions of glomerular filtration in 5% to 25% of patients. Patient characteristics associated with an increased risk of nephrotoxicity include older age, pre-existing renal disease, hepatic dysfunction, volume depletion, and hypotension. Re-exposure to aminoglycosides increases risk, as do the use of larger doses, more frequent dosing intervals, and treatment for more than 3 days. The risk of renal failure is also associated with co-administration of vancomycin, ampho-tericin B, clindamycin, piperacillin, cephalosporins, foscarnet, or furosemide. Because renal tubular cells have regenerative power, renal dysfunction usually reverses on discontinuation of the aminoglycoside. Because aminoglycosides are primarily renally cleared, aminoglycoside serum levels are useful for detecting worsening renal function. Trough aminoglycoside serum levels often rise before a significant rise in serum creatinine can be detected.

2.   Ototoxicity. Aminoglycosides enter the inner ear fluid and damage outer hair cells important to the detection of high-frequency sound. Loss of high-frequency  hearing  occurs   in   3%   to   14%   of patients treated with aminoglycosides. The risk of hearing loss is greater after prolonged treatment, with most cases developing after 9 or more days of therapy. Hearing loss is irreversible and can occur weeks after therapy has been discontinued. A genetic predisposition has been observed, with certain families having a high incidence of deafness after receiving aminoglycosides. The risk of hearing loss depends on the specific aminoglycoside. Neomycin has the highest risk of toxicity, followed in order of decreasing frequency by gen-tamicin, tobramycin, amikacin, and netilmicin. Concomitant use of furosemide or vancomycin, and exposure to loud noises increase the risk. As compared with dosing at 8-hour intervals, once-daily dosing reduces the toxic risk. Less commonly, aminoglycosides can cause neuromuscular blockade; they should be avoided in myasthenia gravis. Given the high risk of toxicity, aminoglycosides  should  be  used  only when  alternative antibiotics are unavailable. When aminoglycosides are required, the duration of therapy should be as brief as possible. Pretreatment and periodic testing of high-frequency hearing should be performed, and serum creatinine and aminoglycoside serum levels should be monitored.

Pharmacokinetics

Following intravenous infusion, aminoglycosides take 15 to 30 minutes to distribute throughout the body. Therefore, to determine peak serum level, blood samples should be drawn 30 minutes after completion of the intravenous infusion. The half-life of aminoglycosides is 2 to 5 hours, and these agents are cleared by the kidneys.

Proper dosing of aminoglycosides is more complicated than for most other antibiotics, and these agents require close monitoring. In many hospitals, a pharmacist is consulted to assist in dose management. For daily multiple-dose therapy, a loading dose is first given to rapidly achieve a therapeutic serum level; maintenance doses are then administered. Doses are calculated based on ideal body weight. In the setting of renal dysfunction, dosing must be carefully adjusted, and peak and trough serum levels monitored. As renal impairment worsens, the dosage interval should be extended.

Once-daily aminoglycoside dosing is now the preferred therapy in nearly all instances. As compared with multidose therapy, once-daily administration reduces the concentration of the aminoglycoside that accumulates in the renal cortex and lowers the incidence of nephrotoxicity.

Table. Aminoglycosides: Half-Life, Dosing, Renal Dosing, Cost, and Spectrum

Table. Organisms That May Be Susceptible to Aminoglycosides

Because aminoglycosides demonstrate concentration-dependent killing, the high peak levels achieved with this regimen increase the bactericidal rate and prolong the post-antibiotic effect. In addition, a once-daily regimen is simpler and less expensive to administer. This regimen has not been associated with a higher incidence of neuromuscular dysfunction. To adjust for renal impairment, the daily dose should be reduced.

Monitoring of serum levels is recommended for both multidose and once-daily regimens. With multi-dose therapy, blood for a peak level determination should be drawn 30 minutes after intravenous infusion is complete, and for a trough level, 30 minutes before the next dose. Blood for peak and trough determinations should be drawn after the third dose of antibiotic to assure full equilibration within the distribution volume. In the critically ill patient, blood for a peak level determination should be drawn after the first dose to assure achievement of an adequate therapeutic level.

Key Points

About Aminoglycoside Toxicity

1.  Very low ratio of therapeutic benefit to toxic side effect.

2.  Monitoring of serum levels usually required.

3.  Nephrotoxicity commonly occurs (usually reversible). Incidence is higher in

a)  elderly individuals,

b)  patients with pre-existing renal disease,

c)   patients with volume depletion and hypotension, and

d)  patients with liver disease.

4.  Higher incidence with co-administration of vancomycin, cephalosporins, clindamycin, pipe-racillin, foscarnet, or furosemide.

5.  The loss of high-frequency hearing and vestibular dysfunction resulting from ototoxicity is often devastating for elderly individuals.

6.  Neuromuscular blockade is rare.

7.  Once-daily therapy may be less toxic.

For once-daily dosing, trough levels need to be monitored to assure adequate clearance. Serum level at 18 hours should be <1 µg/mL. Alternatively, blood for a level determination can be drawn between 6 and 14 hours, and the value applied to a nomogram to help decide on subsequent doses. In the seriously ill patient, blood for a peak level determination should also be drawn 30 minutes after completion of the infusion to assure that a therapeutic level is being achieved (for gentamicin-tobramycin, a target concentration of 16 to 24 µg/mL should be achieved). Once-daily dosing is not recommended for the treatment of enterococcal endocarditis and has not been sufficiently studied in pregnancy or in patients with osteomyelitis or cystic fibrosis.

Spectrum of Activity and Treatment Recommendations

The aminoglycosides are cidal for most aerobic gram-negative bacilli, including Pseudomonas species. These agents kill rapidly, and the killing is concentration-dependent — that is, the rate increases as the concentration of the antibiotic increases. Once-daily dosing takes advantage of this characteristic. Aminoglycosides also demonstrate persistent suppression of bacterial growth for 1 to 3 hours after the antibiotic is no longer present. The higher the concentration of the aminoglycoside, the longer the post-antibiotic effect. Aminoglycosides also demonstrate synergy with antibiotics that act on the cell wall (β-lactam antibiotics and glycopeptides). The effect of these combinations is greater than the sum of the anti-microbial effects of each individual agent. Synergy has been achieved in the treatment of enterococci, S. viridans, S. aureus, coagulase-negative staphylococci, P. aeruginosa, L. monocytogenes, and JK corynebacteria.

An aminoglycoside in combination with other antibiotics is generally recommended for treatment of the severely ill patients with sepsis syndrome to assure broad coverage for gram-negative bacilli. An aminoglycoside combined with penicillin is recommended for empiric coverage of bacterial endocarditis. Tobramycin combined with an anti-pseudomonal penicillin or an anti-pseudomonal cephalosporin is recommended as primary treatment of P. aeruginosa. Streptomycin or gentamicin is the treatment of choice for tularemia and Yersinia pestis, and either agent can also be used to treat Brucella. Gentamicin combined with penicillin is the treatment of choice for both S. viridans and Enterococcus faecalis.

Key Points

About Dosing and Serum Monitoring of Aminoglycosides

1.  Aminoglycosides take 15 to 30 minutes to equilibrate in the body.

2.   For multidose therapy, blood for a peak serum level determination should be drawn 30 minutes after infusion.

3.   Blood for trough serum level determinations should be drawn just before the next dose.

4.  Conventionally, aminoglycosides are given 3 times daily. Dosing should be based on lean body weight.

5.  Once-daily dosing takes advantage of concentration-dependent killing and the post-antibiotic effects of aminoglycosides.

6.  Once-daily dosing reduces, but does not eliminate, nephrotoxicity.

7.   In most cases, trough serum levels need to be monitored only during once-daily dosing.Toxicity correlates with high trough levels.

8.  Once-daily dosing is not recommended for enterococcal endocarditis or pregnant women.

Key Points

About Aminoglycoside Antibacterial Activity

1.  6-Member ring, soluble in water, positively charged; never with cephalosporins or acidic solutions.

2.  Cause temporary holes in bacterial membranes, bind to ribosomal RNA,and interfere with translation.

3.   Killing is concentration-dependent.

4.  The higher the concentration, the longer the post-antibiotic effect.

5.   Excellent gram-negative coverage; streptomycin for tularemia and plague.

6.  Synergy with penicillins in S. viridans, Enterococcus, and Pseudomonas aeruginosa infections.

Glycopeptide Antibiotics

Chemistry and Mechanism of Action

Vancomycin and teicoplanin are complex glycopeptides of approximately 1500 Da molecular weight. These agents act primarily at the cell wall of gram-positive organisms by binding to the D-alanine-D-alanine precursor and preventing it from being incorporated into the peptidoglycan. The binding of vancomycin to this cell wall precursor blocks the transpeptidase and transglycolase enzymes, interfering with cell wall formation and increasing permeability of the cell. These agents may also interfere with RNA synthesis. They bind rapidly and tightly to bacteria and rapidly kill actively growing organisms. They also have a 2-hour post-antibiotic effect.

Toxicity

The most common side effect of the glycopeptide antibiotics is “red man syndrome,” which occurs most often when vancomycin is infused rapidly. The patient experiences flushing of the face, neck, and upper thorax. This reaction is thought to be caused by sudden histamine release secondary to local hyperosmolality and not to be a true hypersensitivity reaction. Infusing vancomycin over a 1-hour period usually prevents this reaction. There is less experience with teicoplanin; however, this agent does not cause significant thrombophlebitis, and skin flushing after rapid infusion is uncommon. Ototoxicity has been reported.

Key Points

About Glycopeptide Antibacterial Activity

1. Act on the cell wall of gram-positive bacteria by binding to the D-alanine-D-alanine peptidoglycan precursor.

2.   Require active bacterial growth.

3.  Also interfere with RNA synthesis.

4.   Have a 2-hour post-antibiotic effect.

Pharmacokinetics

The half-lives of vancomycin (4 to 6 hours) and teicoplanin (40 to 70 hours). Both drugs are excreted primarily by the kidneys, and in the anuric patient, the half-life of vancomycin increases to 7 to 9 days. For vancomycin, peak levels should reach 20 to 50 µg/mL, with trough levels being maintained at 10 to 12 µg/mL. Vancomycin penetrates most tissue spaces, but does not cross the blood-brain barrier in the absence of inflammation. Therapeutic cerebrospinal levels are achieved in patients with meningitis. Unlike vancomycin, which is minimally bound to protein, teicoplanin is 90% protein-bound, accounting for its slow renal clearance. Tissue penetration has not been extensively studied, and little data are available on penetration of bone, peritoneal, or cerebrospinal fluid.

Key Points

About Vancomycin Toxicity

1.   Rapid infusion associated with “red man syndrome.”

2.   Phlebitis is common.

3.  Ototoxicity leading to deafness uncommon, preceeded by tinnitus

4.   Rarely nephrotoxic, potentiates aminoglycoside nephrotoxicity

Table Glycopeptides, Macrolides, Clindamycin,Tetracyclines,and Chloramphenicol: Half-Life, Dosing, Renal Dosing, Cost, and Spectrum

Antimicrobial Spectrum and Treatment Recommendations

Vancomycin and teicoplanin both cover methicillin-resistant Staphylococcus aureus and MSSA, and they are the recommended treatment for methicillin-resistant Staphylococcus aureus. These agents also kill most strains of coagulase-negative staphylococci (S. epidermidis), which are usually methicillin-resistant. They are recommended for the treatment of coagulase-negative staphylococcal line sepsis and bacterial endocarditis. For the latter infection, the glycopeptide antibiotic should be combined with one or more additional antibiotics. Vancomycin-intermediately-resistant strains of S. aureus were first discovered in Japan and have also been identified in Europe and the United States. These strains have minimum inhibitory concentrations of 8 to 16 µg/mL and are cross-resistant to teicoplanin. The increasing use of vancomycin has selected for these strains and warns us that the indiscriminant use of the glycopeptide antibiotics must be avoided.

Vancomycin and teicoplanin not only have excellent activity against Staphylococcus, but also against penicillin-resistant and susceptible strains of S. pneumoniae, and they are recommended for empiric treatment of the seriously ill patient with pneumococcal meningitis to cover for highly penicillin-resistant strains. The glycopeptide antibiotics also effectively treat S. pyogenes, GpB streptococci, S. viridans, and S. bovis, and they are recommended for treatment of these infections in the penicillin-allergic patient. Corynebacterium jeikeium (previously called JK diphtheroids) is sensitive to vancomycin, and that antibiotic is recommended for its treatment. Oral vancomycin clears С difficile from the bowel, and in the past it was recommended for C. difficile toxin-associated diarrhea. However, because of the increased risk of developing vancomycin-resistant Enterococcus following oral vancomycin, this regimen is recommended only for cases that are refractory to metronidazole or for patients who are very seriously ill.

Vancomycin is frequently used to treat Enterococcus faecalis and faecium; however, an increasing number of strains have become resistant. Three gene complexes transfer resistance. The van A gene cluster directs peptido-glycan cell wall synthesis and coverts D-alanine-D-alanine (the site of vancomycin action) to D-alanine-D-lactate, markedly reducing vancomycin and teicoplanin binding. The other two resistance gene clusters, van В and van C, result in vancomycin resistance, but do not impair teicoplanin activity.

Macrolides and Ketolides

Key Points

About the Treatment Recommendations for Vancomycin

1.  Treatment of choice for methicillin-resistant Staphylococcus aureus; vancomycin-tolerant strains have been reported.

2.  Treatment of choice for coagulase-negative staphylococci.

3.   Excellent activity against high-level penicillin-resistant Streptococcus pneumoniae.

4.   In the penicillin-allergic patient, vancomycin is recommended for Strep.pyogenes, Gp В streptococci, Strep, viridans, and Strep, bovis.

5.   Excellent activity against some strains of Enterococcus; however,van A gene-mediated vancomycin-resistant enterococci are increasing in frequency.

6.  Vancomycin use must be restricted to reduce the likelihood of selecting for vancomycin-resistant Enterococcus and vancomycin-tolerant Staph. aureus.

Chemistry and Mechanism of Action

The founding member of the macrolide family, erythromycin, was originally purified from a soil bacterium. It has a complex 14-member macrocyclic lactone ring (which gives rise to the class name “macrolides”) attached to two sugars. Azithromycin has a 15-member lactone ring and a nitrogen substitution. Clarithromycin has a methoxy group modification at carbon 6 of the erythromycin molecule. These modifications enhance oral absorption and broaden the antimicrobial spectrum.

The newest class of macrolide-like agents are the semisynthetic derivatives of erythromycin called ketolides. The ketolides, represented by talithromycin, have a 14-member macrolactone ring with a keto group at position 3, with the hydroxyls at positions 11 and 12 replaced by a cyclic carbamate. These agents all inhibit protein biosynthesis by blocking the passage of nascent proteins through the ribosome exit tunnel. In the case of conventional macrolides, inhibition is accomplished by binding to a single domain of the 5OS ribosomal subunit (domain V of the 23 rRNA molecule). As compared with the macrolides, talithromycin binds to the 50S subunit with higher affinity, binding to two regions of the 23S rRNA molecule (domains II and V) rather than one region. This unique binding mode explains the enhanced antimicrobial activity of ketolides against macrolide-resistant pathogens.

Table Organisms That May Be Susceptible to Macrolides and Ketolides

Toxicity

Macrolides and ketolides are among the safer classes of antibiotics. The primary adverse reactions are related to these agents’ ability to stimulate bowel motility. In fact, erythromycin can be used to treat gastric paresis. Particularly in younger patients, abdominal cramps, nausea, vomiting, diarrhea, and gas are common with erythromycin. These symptoms are dose-related and are more common with oral preparations, but can also occur with intravenous administration. Gastrointestinal toxicity can be debilitating, forcing the drug to be discontinued. Azithromycin and clarithromycin at the usual recommended doses are much less likely to cause these adverse reactions.

Talithromycin administration has been accompanied by difficulty with accommodation, resulting in blurred vision. Patients have also experienced diplopia following administration of this agent. Talithromycin treatment has also resulted in the sudden onset of severe and occasionally fatal hepatitis. All patients receiving this agent should therefore be warned of this potential side effect, and the drug should be prescribed only for cases of pneumonia in which the incidence of penicillin-resistant S. pneumoniae is high. Under these circumstance a fluoroquinolone with gram-positive coverage may be preferred.

Macrolides and ketolides may exacerbate myasthenia gravis and should be avoided in patients with that illness. Macrolides prolong the QT interval, and erythromycin administration has, on rare occasions, been associated with ventricular tachycardia.

These agents are metabolized by the cytochrome P450 3A4 system, and they cause an increase in serum levels of other drugs metabolized by that system, including many of the statins, short-acting benzodiazepines, such as midazolam (Versed), cisapride (Propulsid), ritonavir (Norvir), and tacrolimus (Prograf).

Pharmacokinetics

The stearate, ethylsuccinate, and estolate forms of erythromycin are reasonably well absorbed on an empty stomach, reaching peak serum levels 3 hours after inges-tion. Clarithromycin, azithromycin, and talithromycin are better absorbed orally than erythromycin is, resulting in peak concentrations within 1 hour. Erythromycin and azithromycin should be taken on an empty stomach.  If cost is not a primary issue, the improved absorption and lower incidence of gastrointestinal toxicity make the three newer agents preferable to erythromycin in most instances.

Key Points

About Macrolide Chemistry, Mechanism of Action, and Toxicity

1.  Complex 14- to 15-member lactone ring structure.

2.  Inhibit RNA-dependent protein synthesis, bind to 50S ribosomal subunit; talithromycin binds with higher affinity, binding to two sites rather than just one,

3.  Can be bacteriostatic or cidal.

4.  Gastrointestinal irritation, particularly with ery-thromycin, is the major toxicity.

5.  Hypersensitivity reactions can occur.

6.  Transient hearing loss with high doses, mainly in elderly individuals.

7.  Talithromycin can cause blurred vision and diplopia. Also can result in fatal hepatitis.

8.  Can exacerbate myasthenia gravis.

9.  Prolonged QT interval; occasionally causes ventricular tachycardia.

10.Metabolized by the cytochrome P450 3A4 system; increase serum concentrations of other drugs metabolized by that system.

Most of the macrolides and ketolides are metabolized and cleared primarily by the liver. Azithromycin is not metabolized, being excreted unchanged in the bile. Small percentages of these drugs are also excreted in the urine. These agents are widely distributed in tissues, achieving concentrations that are several times the peak concentration achieved in serum in most areas the body, including the prostate and middle ear. Clarithromycin levels in middle ear fluid have been shown to be nearly 10 times serum levels. Azithromycin concentrations in tissue exceed serum levels by a factor of 10 to 100, and its average half-life in tissues is 2 to 4 days. Therapeutic levels of azithromycin have been estimated to persist for 5 days after the completion of a 5-day treatment course. With the exception of intravenous erythromycin, these agents fail to achieve significant levels in the cerebrospinal fluid.

Spectrum of Activity and Treatment Recommendations

Macrolides demonstrate excellent activity against most gram-positive organisms and some gram-negative bacteria. Erythromycin can be bacteriostatic or bactericidal. Cidal activity increases when antibiotic concentrations are high and bacteria are growing rapidly.

These drugs are recommended for the treatment of community-acquired pneumonia. However S. pneumoniae resistance to macrolides has steadily increased and now ranges between 10% and 15%. Resistance is more likely in intermediately penicillin-resistant strains (40% macrolide resistant) and highly penicillin-resistant strains (60% macrolide resistance). Multiresistant S. pneumoniae can be treated with talithromycin as a consequence of that agent’s different ribosomal binding sites.

In most countries, including the United States, 95% of S. pyogenes are sensitive to macrolides. However, in Japan, where macrolides are commonly used, 60% are resistant. Because S. aureus can develop resistance after a single mutation, macrolides are generally not recommended in their treatment. The macrolides and ketolides are effective against mouth flora, including anaerobes, but they do not cover the bowel anaerobe B. fragilis. The macrolides are also the treatment of choice for Legionella pneumophilia, with talithromycin, azithromycin, and clarithromycin being more potent than erythromycin.

Macrolides are the primary antibiotics used to treat the two major pathogens associated with atypical pneumonia: Mycoplasma pneumoniae and Chlamydophila pneumoniae. Talithromycin is also approved for acute bacterial sinusitis. In many instances the erythromycins can be used as an alternative to penicillin in the penicillin-allergic patient.

Clarithromycin is one of the primary antibiotics used for the treatment of atypical mycobacterial infections, particularly MAI complex. Azithromycin in combination with other antibiotics is also recommended for the treatment of MAI complex, and it can be used alone for MAI prophylaxis in HIV-infected patients with CD4 cell counts below 100 cells/mL.

In combination with antacid therapy, effective regimens for curing peptic ulcer disease caused by Helicobacter pylori include azithromycin or clarithromycin combined with bismuth salts and either amoxicillin, metronidazole, or tetracycline. Single high-dose azithromycin (1 g) effectively treats chancroid, as well as Chlamydia trachomatis urethritis and cervicitis. Single-dose therapy also cures male Ureaplasma urealyticum urethritis.

Clindamycin

Chemistry and Mechanism of Action

Although clindamycin is structurally different from erythromycin, many of its biologic characteristics are similar. Clindamycin consists of an amino acid linked to an amino sugar, and it was derived by modifying lincomycin. It binds to the same 5 OS ribosomal binding site used by the macrolides, blocking bacterial protein synthesis.

Key Points

About the Spectrum and Treatment Indications for Macrolides and Ketolides

1.  Gram-positive coverage, plus mouth anaerobes.

2.  Recommended for treatment of community-acquired pneumonia.

Increased use of macrolides selects for resistant strains of Streptococcus pyogenes and S. pneu-moniae. Penicillin-resistant strains of S.pneumo-niae are often resistant to macrolides.

4.  Talithromycin is effective against multi-resistant S. pneumoniae.

5.  Recommended for treatment of Legionella pneumophilia.

6.  Recommended for Mycoplasma, Ureaplasma, and Chlamydia.

7.  Clarithromycin or azithromycin can used for treatment of Helicobacter pylori.

8.  Clarithromycin is a primary drug for treatment of Mycobacterium avium intracellulare (MAI), and azithromycin is useful for MAI prophylaxis in HIV patients with low CD4 cell counts.

Toxicity

Diarrhea is a major problem seen in 20% of patients taking clindamycin. The incidence is highest with oral administration. In up to half of the affected patients, the cause of diarrhea is pseudomembranous colitis, a disease caused by overgrowth of the anaerobic bacteria C. difficile.

Pharmacokinetics

Clindamycin is well absorbed orally; however, the drug can also be administered intravenously and the intravenous route can achieve higher peak serum levels. Clindamycin penetrates most tissues, but it does not enter the cerebrospinal fluid. Clindamycin is metabolized primarily by the liver and is excreted in the bile. Therapeutic concentrations of clindamycin persist in the stool for 5 or more days after the antibiotic is discontinued, and the reduction of clindamycin-sensitive flora persists for up to 14 days. Small percentages of clindamycin metabolites are also excreted in the urine.

Antimicrobial Spectrum and Treatment Recommendations

Clindamycin is similar to erythromycin in its activity against streptococci and staphylococci. Moderately penicillin-resistant S. pneumoniae are often sensitive to clindamycin. In the penicillin-allergic patient, clindamycin is a reasonable alternative for S. pyogenes pharyngitis. Because its activity against H. influenzae is limited, clindamycin is not recommended for the treatment of otitis media.

Clindamycin distinguishes itself from the macrolides by possessing excellent activity against most anaerobic bacteria. It is used effectively in combination with an aminoglycoside, aztreonam, or a third-generation cephalosporin to treat fecal soilage of the peritoneum. However, other less-toxic regimens have proved to be equally effective. Clindamycin in combination with a first-generation cephalosporin can be used to block toxin production in severe cellulitis and necrotizing fasciitis caused by MSSA or S. pyogenes. It is also effective for the treatment of anaerobic pulmonary and pleural infections. Clindamycin also has significant activity against Toxoplasma gondii and is recommended as alternative therapy in the sulfa-allergic patient.

Tetracyclines

Chemistry and Mechanisms of Action

The tetracyclines consist of four 6-member rings with substitutions at the 4, 5, 6, and 7 positions that alter the pharmacokinetics of the various preparations; however, with the exception of tigecycline, these changes have no effect on the antimicrobial spectrum.

Key Points

About Clindamycin

Binds to the 50S ribosomal binding site used by the macrolides.

2.  Diarrhea is a common side effect, with Clostrid-ium difficile toxin found in half of cases.

3.  Pseudomembranous colitis can lead to toxic megacolon and death. If С difficile toxin is detected, clindamycin should be discontinued.

4.  Active against most gram-positive organisms including MSSA; covers many intermediate penicillin-resistant Streptococcus pneumoniae, but is not a first-line therapy.

5.  Excellent anaerobic coverage, including Bac-teroides frag His.

6.  Used to reduce toxin production by S. pyogenes and Staphylococcus aureus.

7.  Used to treat anaerobic lung abscesses and toxoplasmosis in the sulfa-allergic patient.

The tetracyclines enter gram-negative bacteria by passively diffusing through porins. They bind to the 30S ribosomal subunit and block tRNA binding to the mRNA ribosome complex. This blockade primarily inhibits protein synthesis in bacteria, but to a lesser extent, it also affects mammalian cell protein synthesis, particularly mitochondria. The inhibition of bacterial protein synthesis stops bacterial growth, but does not kill the bacterium. Therefore, tetracycline is termed a bacteriostatic agent.

Toxicity

Photosensitivity reactions consisting of a red rash over sun-exposed areas can develop. Hypersensitivity reactions are less common than with the penicillins, but they do occur. Tetracyclines interfere with enamel formation, and in children, teeth often become permanently discolored. Therefore these agents are not recommended for children 8 years of age or younger, or for pregnant women. Because the tetracyclines inhibit protein synthesis, they increase azotemia in renal failure patients. Minocycline can cause vertigo, and that side effect has limited its use. Benign intracranial hypertension (pseudo-tumor cerebri) is another rare neurologic side effect.

Pharmacokinetics

Tetracycline is reasonably well absorbed (70% to 80%) by the gastrointestinal tract. Food interferes with its absorption. Doxycycline is nearly completely absorbed in the gastrointestinal tract. Calcium- or magnesium-containing antacids, milk, or multivitamins markedly impair absorption of all tetracycline preparations, and simultaneous ingestion of these products should be avoided. Tigecycline can be administered only intravenously. Tetracycline is cleared primarily by the kidneys; other agents, including doxycycline and tigecycline are cleared primarily by the liver.

Antimicrobial Spectrum and Treatment Recommendations

The tetracyclines are able to inhibit the growth of a broad spectrum of bacteria. However, for most conventional pathogens, other agents are more effective. High concentrations of tetracycline are achieved in the urine, and this agent can be used for uncomplicated urinary tract infections. Doxycycline combined with gentamicin is the treatment of choice for brucellosis. Tetracyclines are also recommended for the treatment of Lyme disease (Borrelia burgdorferi), and chlamydia infections (including Chlamydia pneumonia, psittacosis, epididymitis, ure-thritis, and endocervical infections). Tetracyclines are the treatment of choice for rickettsial infections (including Rocky Mountain spotted fever, ehrlichiosis, Q fever, and typhus fever). They are also often used in combination with other antibiotics for the treatment of pelvic inflammatory disease.

The most recently developed member of this family, tigecycline, was derived from minocycline. Tigecycline has a broader spectrum of activity. It effectively inhibits the growth of many resistant gram-positive bacteria . This agent also demonstrates improved activity against many highly resistant nosocomial gram-negative bacteria, but it does not effectively cover P. aeruginosa or Proteus species. Tigecycline is approved for complicated intra-abdominal and soft-tissue infections.

Table Organisms That May Be Susceptible to the Tetracyclines

Key Points

About the Tetracyclines

1.  Bind to the 30S subunit of the ribosome, blocking tRNA binding and inhibiting protein synthesis. Bacteriostatic for most gram-positive and gram-negative bacteria.

2.  Toxicities include photosensitivity, interference with dental enamel formation in children, gastrointestinal discomfort, fatty liver changes, exacerbation of azotemia, vertigo (minocy-cline), and pseudotumor cerebri.

3.  Tetracycline can be used for uncomplicated urinary tract infections.

4.  Recommended for brucellosis, Lyme disease, chlamydia, and rickettsial infections

5.  Recommended, in combination with other antibiotics, for pelvic inflammatory disease.

6.  Oral absorption blocked by calcium- and magnesium-containing antacids, milk, and multivitamins.

7.  Tigecycline has improved gram-positive and gram-negative coverage, with the exception of Pseudomonas aeruginosa and Proteus. It is approved for complicated intra-abdominal and soft-tissue infections.

Chloramphenicol

Chemistry and Mechanisms of Action

Chloramphenicol consists of a nitro group on a benzene ring and a side chain containing five carbons. Chloramphenicol uses an energy-dependent mechanism to enter bacteria, and once in the cell, binds to the larger 50S subunit of the 70S ribosome, blocking attachment of tRNA. It inhibits bacterial protein synthesis, making it bacteriostatic for most bacteria; however, chloramphenicol is cidal for H. influenzae, S. pneumoniae, and N. meningitidis.

Toxicity

Probably as result of its binding to human mitochondrial ribosomes, this agent has significant bone marrow toxicity . Two forms are observed.

The first form is dose-related and is commonly observed in patients receiving chloramphenicol 4 g or more daily. The reticulocyte count decreases, and anemia develops in association with elevated serum iron. Leukopenia and thrombocytopenia are also commonly encountered. These changes reverse when the antibiotic is discontinued. The second form of marrow toxicity, irreversible aplastic anemia, is rare, but usually fatal. This complication can occur weeks or months after the antibiotic is discontinued. Any patient receiving chloramphenicol requires twice-weekly monitoring of peripheral blood counts. If the white blood cell drops below 2500/mm³, the drug should be discontinued.

Pharmacokinetics

As a result of the much higher incidence of idiosyncratic aplastic anemia associated with oral administration as compared with intravenous administration, oral preparations of chloramphenicol are no longer available in the United States. The drug is well absorbed, and therapeutic serum levels can be achieved orally. Chloramphenicol is metabolized by the liver. It diffuses well into tissues and crosses the blood-brain barrier in uninfiamed as well as inflamed meninges. A serum assay is available, and serum levels should be monitored in patients with hepatic disease, maintaining the serum concentration between 10 and 25 µg/mL.

Antimicrobial Spectrum and Treatment Recommendations

Chloramphenicol has excellent activity against most gram-positive organisms with the exception of enterococci and S. aureus, as well as many gram-negative pathogens.

Key Points

About Chloramphenicol

1.   Binds to 50S subunit of the ribosome, blocking protein synthesis; is bacteriostatic.

2.   Idiosyncratic aplastic anemia has limited the use of chloramphenicol; dose-related bone marrow suppression is another concern.

3.   Broad spectrum of activity, including Salmonella, Brucella, Bordetella, anaerobes, Rick-ettsiae, Chlamydiae, Mycoplasma, and spiro-chetes.

4.  Can be used as alternative therapy in the penicillin-allergic patient.

Chloramphenicol also is very active against spirochetes, as well as Rickettsiae, Chlamydiae, and mycoplasmas.

Because of its bone marrow toxicity, chloramphenicol is not considered the treatment of choice for any infection. Alternative, less-toxic agents are available for each indication. For the penicillin-allergic patient, chloramphenicol can be used for bacterial meningitis. Chloramphenicol can also be used as alternative therapy for brain abscess, C. perfringens, psittacosis, rick-ettsial infections including Rocky Mountain spotted fever, Vibrio vulnificus, and typhoid fever.

Quinolones

Chemical Structure and Mechanisms of Action

The quinolones all contain two 6-member rings with a nitrogen at position 1, a carbonyl group at position 4, and a carboxyl group attached to the carbon at position 3. Potency of the quinolones is greatly enhanced by adding fluorine at position 6, and gram-negative activity is enhanced by addition of a nitrogen-containing piperazine ring at position 7.

The quinolones inhibit two enzymes critical for Deoxyribonucleic acid synthesis: Deoxyribonucleic acid gyrase, which is important for regulating the superhelical twists of bacterial Deoxyribonucleic acid, and topoiso-merase IV, which is responsible for segregating newly formed Deoxyribonucleic acid into daughter cells. The loss of these activities blocks Deoxyribonucleic acid synthesis and results in rapid bacterial death. Killing is concentration-dependent.

Key Points

About the Chemistry, Mechanisms of Action, and Toxicity of Quinolones

1. Inhibit bacterial Deoxyribonucleic acid gyrase (important for coiling Deoxyribonucleic acid) and topoisomerase (required to segregate Deoxyribonucleic acid to daughter cells). Rapidly cidal, with concentration-dependent killing.

2.  Main side effects are

a)  nausea and anorexia.

b)  allergic reactions (most common with gemifloxacin; less common with other quinolones).

c)  Arthropathy and tendonitis. May damage cartilage. Not routinely recommended in children.

d)  Gatifloxacin can cause hypo- or hyperglycemia.

e)  Moxifloxacin prolongs the QT interval.

Toxicity

The most common side effects are mild anorexia, nausea, vomiting, and abdominal discomfort. Quinolones can result in arthropathy because of cartilage damage and tendonitis. Although rare, this complication can be debilitating, but it usually reverses weeks to months after the quinolone is discontinued. Because of concerns about cartilage damage in children, quinolones are not recommended for routine administration in pediatric patients. Gatifloxacin administration can be associated with severe dysregulation of glucose homeostasis and can result in either severe hypo- or hyperglycemia. Fluoroquinolones are associated with a concentration-dependent delay in cardiac repolarization, causing a prolongation of the QT interval — a condition that can predispose to ventricular tachycardia. In combination with other agents that effect repolarization, moxifloxacin has occasionally been associated with life-threatening cardiac arrhythmias.

Pharmacokinetics

The quinolones are readily absorbed orally, but can also be given intravenously. Ciprofloxacin, levofloxacin, and gatifloxacin are cleared primarily by the kidneys. Moxifloxacin is also partially metabolized by the liver, and gemifloxacin is metabolized primarily by the liver. All quinolones demonstrate similar tissue penetration, being concentrated in prostate tissue, feces, bile, and lung tissue. These drugs tend to be very highly concentrated in macrophages and neutrophils.

Spectrum of Activity and Treatment Recommendations

Ciprofloxacin — Ciprofloxacin is the most potent quinolone for P. aeruginosa. As a result of an excellent gram-negative spectrum, ciprofloxacin is one of the primary antibiotics recommended for treatment of urinary tract infections.

Table Quinolones, Linezolid, Quinupristin/Dalfopristin, Daptomycin, Metronidazole, and Sulfanomides: Half-Life, Dosing, Renal Dosing, Cost, and Spectrum

Table Organisms That May Be Susceptible to the Quinolones

It concentrates in the prostate and is recommended for treatment of prostatitis. For gonococcal urethritis, it is a useful alternative to ceftriaxone. Ciprofloxacin has been used effectively for traveler’s diarrhea most commonly caused by enterotoxigenic E. coli and Shigella. It is the drug of choice for Salmonella typhi (typhoid fever), and it also is recommended for treatment of Salmonella gastroenteritis when antibiotic treatment is necessary. Ciprofloxacin is the recommended treatment for cat scratch disease caused by Bartonella henselae.

Levofloxacin, Moxifloxacin, Gatifloxacin, and Gemifloxacin — These agents all demonstrate improved gram-positive coverage and have been recommended as one of the first-line treatments for community-acquired pneumonia in the otherwise healthy adult who does not require hospitalization. With the exception of gemifloxacin, these agents can also be used in soft-tissue infection in which a combination of gram-positive and gram-negative organisms is suspected. Given the worse toxicity profiles of the three newer agents (moxifloxacin, gatifloxacin, and gemifloxacin), levofloxacin should probably be the fluoroquinolone of choice for those infections. Gatifloxacin and moxifloxacin demonstrate moderate in vitro activity against anaerobes and may be considered for the treatment of mixed infections thought to include anaerobes. The exact indications for these agents are currently evolving. Fear of selecting for resistant pathogens has led to their use being restricted in some hospitals.

Oxazolidones (Linezolid)

Chemistry and Mechanisms of Action

The oxazolidones have a unique ring structure consisting of a 5-member ring containing an oxygen and a nitrogen. The nitrogen connects to a 6-member ring, and each specific compound has side chains added to both rings at positions A and В. These agents bind to the 50S ribosome at a site similar to that used by chloramphenicol. However, unlike chloramphenicol, they do not inhibit the attachment of tRNA, but instead block the initiation of protein synthesis by preventing the nearby 30S subunit from forming the 70S initiation complex. The oxazolidones are bacteriostatic against staphylococcal species and enterococci.

Key Points

About the Specific Quinolones

1.  Ciprofloxacin:

a)  Excellent coverage of Pseudomonas. Also covers many other gram-negative organisms including Esch. coli, Salmonella,Shigella, Neisseria, and Legionella.

b)  Kills Mycoplasma, Chlamydia, and Ure-aplasma.

c)   Recommended for urinary tract infections and prostatitis, gonococcal urethritis, traveler’s diarrhea,typhoid fever, and Salmonella gastroenteritis; used for cat scratch disease.

2.  Levofloxacin, gatifloxacin, moxifloxacin, gemi-floxacin

a)  Greater activity against Streptococcus pneumoniae, covers highly penicillin-resistant strains.

b)  Also cover methicillin-sensitive Staphylococcus aureus.

c)   Recommended for community-acquired pneumonia (levofloxacin preferred).

d)  Levofloxacin, gatifloxacin, and moxifloxacin recommended for mixed skin infections.

e)  Gatifloxacin and moxifloxacin have somewhat improved anaerobic coverage.

f)   Gatifloxacin and moxifloxacin recommended for mixed skin infections.

Toxicity

Linezolid is the only agent in this class released for use. Reversible thrombocytopenia has been reported in association with prolonged therapy, and monitoring of platelet count is recommended for patients receiving two or more weeks of linezolid. Leukopenia and hepatic enzyme elevations have also been reported. Because this agent is a weak inhibitor of monoamine oxidase, hypertension has been reported in association with ingestion of large amounts of tyramine. Pseudoephedrine and selective serotonin reuptake inhibitors should be prescribed with caution.

Pharmacokinetics

Linezolid is well-absorbed orally and peak serum levels are achieved in 1 to 2 hours. Food slows absorption, but does not lower peak levels. An intravenous preparation is also available. Linezolid achieves excellent penetration of all tissue spaces, including the cerebrospinal fluid. The drug is partly metabolized by the liver and excreted in the urine.

Key Points

About Linezolid

1.   Like chloramphenicol, binds to the 50S ribo-some subunit; inhibits the initiation of protein synthesis.

2.  Thrombocytopenia common with treatment exceeding 2 weeks; inhibitor of monoamine oxidase; avoid tyramine, pseudoephedrine, serotonin uptake inhibitors.

3.  Strictly gram-positive activity; bacteriostatic activity for vancomycin-resistant enterococci (vancomycin-resistant Enterococcus), and methicillin-resistant Staphylococcus aureus. Also has activity against penicillin-resistant Streptococcus pneumoniae.

4.   Recommended for the treatment of vancomycin-resistant Enterococcus.

Antimicrobial Activity and Treatment Recommendations

Linezolid demonstrates activity only against gram-positive organisms. It has bacteriostatic activity against both vancomycin-resistant Enterococcus faecium and Enterococcus faecalis (vancomycin-resistant Enterococcus). This agent is also active against MSSA and methicillin-resistant Staphylococcus aureus, and has activity against penicillin-resistant S. pneumoniae. Linezolid is recommended primarily for the treatment of vancomycin-resistant Enterococcus.

Streptogramins

Chemical Structure and Mechanism of Action

The streptogramins belong to the macrolide family. They are derived from pristinamycin. Quinupristin is a peptide derived from pristinamycin IA and dalfo-pristin is derived from pristinamycin IIB. A combination of 30:70 quinupristin:dalfopristin has synergistic activity and has been named Synercid. These two agents inhibit bacterial protein synthesis by binding to the 50S bacterial ribosome. Quinupristin inhibits peptide chain elongation, and dalfopristin interferes with peptidyl transferase activity.

Toxicity

Myalgias and arthralgias are the most common and severe adverse reaction, and they can force discontinuation of the drug. Administration has also been associated with hyperbilirubinemia.

Pharmacokinetics

The streptogramins are administered intravenously, and they are metabolized primarily in the live.

Antimicrobial Activity and Treatment Indications

Synercid is active primarily against gram-positive organisms. It has proved to be efficacious in the treatment of vancomycin-resistant Enterococcus and MRS A. Synercid or linezolid are the treatments of choice for vancomycin-resistant Enterococcus.

Key Points

About Synercid

1. Combination of two pristinamycin derivatives: quinupristin and dalfopristin. Together, they synergistically block protein synthesis. Both bind to the 50S ribosomal subunit.

2.  Myalgias and arthralgias can force discontinuation of the drug. Nausea, vomiting,and diarrhea also occur.

3.  Spectrum of activity: covers primarily gram-positive bacteria. Active against vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus.

4.  Recommended for the treatment of vancomycin-resistant Enterococcus.

Daptomycin

Chemical Structure and Mechanism of Action

Daptomycin is a large cyclic lipopeptide (С₇₂Н₁₀₁N₁₇О₂₆) with a molecular weight of 1620 that was derived from Streptomyces roseosporus. Daptomycin has a mechanism of action that is distinctly different from that of other antibiotics. It binds to bacterial membranes and causes rapid depolarization of the membrane potential. As a result, protein, Deoxyribonucleic acid, and RNA synthesis is inhibited. This antibiotic is cidal and causes rapid concentration-dependent killing, but it does not result in the systemic release of cell membrane or cell wall contents. It also demonstrates significant post-antibiotic effect. Synergy with aminoglycosides, β-lactam antibiotics, and rifampin has been observed.

Toxicity

Muscle pain and weakness are reported in less than 5% of patients. This drug is also associated with a rise in creatine phosphokinase. The patient’s creatine phosphokinase levels should be monitored weekly, and the drug should be discontinued if creatine phosphokinase exceeds 1000 in association with symptoms of myopathy, or if creatine phosphokinase exceeds 2000 in the absence of symptoms. Other drugs associated with rhabdomyolysis, specifically HMG-CoA reductase inhibitors (statins), should not be administered with daptomycin. Less commonly, daptomycin administration has resulted in neuropathy associated with a slowing of nerve conduction velocity. The peripheral or cranial nerves can be affected. Patients may experience paresthesia or Bell’s palsy. This rare toxicity has also been observed in animal studies.

Pharmacokinetics

Daptomycin is given intravenously, and a 4-mg/kg dose achieves peak serum levels of 58 µg/mL. Daptomycin is 92% protein-bound and is excreted by the kidneys. Its ability penetrate various tissue compartments including the cerebrospinal fluid has not been extensively studied.

Spectrum of Activity and Treatment Recommendations

Daptomycin kills aerobic and facultative gram-positive organisms, including Enterococcus faecium and faecalis (including VREs), S. aureus (including MRS A), S. epidermidis (including methicillin-resistant strains), S. pyogenes, and Corynebacterium jeikeium. It is approved for the treatment of complicated skin and soft tissue infections by susceptible strains and for S. aureus (including methicillin-resistant Staphylococcus aureus) bacteremia and right-sided endocarditis. It is not currently approved for vancomycin-resistant Enterococcus, because of insufficient clinical data. Daptomycin is inactivated by surfactant and should not be used for the treatment of pneumonia.

Key Points

About Daptomycin

1.   Large, cyclic lipopeptide that binds to and depolarizes bacterial membranes.

2.   Rapidly cidal, concentration-dependent killing; post-antibiotic effect.

3.  Toxicities include muscle pain and weakness associated with creatine phosphokinase leak; no co-administration of statins. Less common: peripheral or cranial nerve neuropathy.

4.   Kills enterococci (including vancomycin-resistant Enterococcus), Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus), Staphylcoccus epidermidis, Streptococcus pyogenes, and corynebacteria.

5.  Approved to treat complicated skin and soft-tissue infections, and S. aureus (including methicillin-resistant Staphylococcus aureus) bacteremia and right-sided endocarditis.

6.   Inactivated by surfactant; should not be used to treat pneumonia.

Metronidazole

Chemical Structure and Mechanism of Action

Metronidazole is a nitroimidazole with a low molecular weight that allows it to readily diffuse into tissues. Within a bacterium, this antibiotic acts as an electron acceptor and is quickly reduced. The resulting free radicals are toxic to the bacterium, producing damage to Deoxyribonucleic acid and to other macromolecules. Metronidazole has significant activity against anaerobes.

Toxicity

Metronidazole is usually well tolerated, but it can result in a disulfiram (Antabuse-like) reaction with alcohol consumption. Concern about the muta-genic potential of this agent has resulted in multiple mammalian studies that, overall, have failed to demonstrate significant Deoxyribonucleic acid abnormalities. Metronidazole is not recommended in pregnancy, and it should usually be avoided in patients on Coumadin, because it impairs metabolism of that drug.

Key Points

About Metronidazole

1.  Electron acceptor; produces free radicals that damage bacterial Deoxyribonucleic acid.

2.  Antabuse-like reaction can occur; mutagenic effects not proven in mammals, but the drug should be avoided in pregnancy. Impairs Coumadin metabolism.

3.  Excellent activity against anaerobes, amoebae, Giardia, and Trichomonas. Penetrates tissues well, including abscesses.

4.  Indicated in combination with other antibiotics for mixed bacterial infections. Has no activity against aerobic bacteria.

5.  Treatment of choice for Clostridium difficile-induced diarrhea. Used as part of combination treatment for Helicobacterpylori.

Pharmacokinetics

This agent is rapidly and completely absorbed orally, but it can also be given intravenously. Therapeutic levels are achieved in all body fluids, including the cerebrospinal fluid and brain abscess contents. Metronidazole is metabolized primarily in the liver.

Spectrum of Activity and Treatment Recommendations

Metronidazole was originally used primarily for Trichomonas vaginitis, being effective both topically and orally. It is also effective for treating amoebic abscesses and giardiasis. Metronidazole is cidal for most anaerobic bacteria, and it is the antibiotic of choice for covering anaerobes. Because metronidazole has no significant activity against aerobes, it is usually administered in combination with a cephalosporin for aerobic coverage. Metronidazole is the drug of choice for treatment of pseudomembranous colitis attributable to overgrowth of C. difficile. Metronidazole is also recommended as part of the regime for Helicobacter pylori gastric and duodenal infection.

Sulfonamides and Trimethoprim

Chemical Structure and Mechanisms of Action

The sulfonamides all have a structure similar to paraaminobenzoic acid, a substrate required for bacterial folic acid synthesis. All sulfonamides inhibit bacterial folic acid synthesis by competitively inhibiting paraaminobenzoic acid incorporation into tetrahydropteroic acid. These agents are bacteriostatic.

A sulfonyl radical is attached to carbon 1 of the 6-member ring, increasing paraaminobenzoic acid inhibition. Alterations in the sulfonyl radical determine many of the pharmacokinetic properties of the compounds. Trimethoprim consists of two 6-member rings, one of which has two nitrogens and two amino groups, the other having three methoxybenzyl groups. This agent strongly inhibits dihydrofolate reductase and complements sulfonamide inhibition of folate metabolism. Inhibition of bacterial dihydrofolate reductase by trimethoprim is 100,000 times that of the agent’s inhibition of the mammalian enzyme, minimizing toxicity to the patient.

Table. Organisms That May Be Susceptible to Trimethoprim/Sulfa

Toxicity

Hypersensitivity reactions represent the most severe toxicity. Maculopapular drug rashes, erythema multiforme, Steven-Johnson syndrome, vasculitis (including drug-induced lupus), serum sickness-like syndrome, and anaphylaxis have been reported. Hemolytic anemia can be associated with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Sulfonamides should be avoided in the last month of pregnancy because they displace bilirubin bound to plasma albumin and increase fetal blood levels of unconjugated bilirubin.

Pharmacokinetics

Sulfonamides are classified as short-, medium-, or long?acting, depending on half-life. Sulfisoxazole is in the short-acting class, having a half-life of 5 to 6 hours. Sulfamethoxazole and sulfadiazine are medium-acting. All of these agents are generally well absorbed orally. Intravenous preparations are available for some agents. All are metabolized by the liver, undergoing acetylation and glucuronidation, with the metabolites being excreted in the urine. Trimethoprim is excreted primarily by the renal tubules, and very high concentrations of active drug are found in the urine. Some trimethoprim is also excreted in bile. The half-life of trimethoprim is 9 to 11 hours matching the half-life of sulfamethoxazole. The ratio of trimethoprim to sulfamethoxazole supplied is 1:5.

Spectrum of Activity and Treatment Recommendations

The sulfonamides demonstrate activity against gram-positive and gram-negative organisms; however, resistance in both community and nosocomial strains is widespread . Sulfonamides have proved to be effective for the empiric treatment of uncomplicated urinary tract infections; however, because of widespread resistance, they are seldom used as empiric therapy in other infections. Sulfonamides are the treatment of choice for Nocardia asteroides, and are useful in combination with other agents for the treatment of M. kansasii.

Trimethoprim is generally administered in combination with sulfamethoxazole. This combination often results in significantly improved activity. Trimetho-prim-sulfamethoxazole (TMP-SMX) demonstrates excellent activity against Listeria monocytogenes, and it is the antibiotic of choice in the penicillin-allergic patient with listeriosis.

Key Points

About Sulfonamides

1. Competitively inhibit para-aminobenzoic acid incorporation, blocking folic acid synthesis; trimethoprim inhibits dihydrofolate reductase, potentiating sulfonamide activity.

2.  Hypersensitivity reactions (including Steven-Johnson syndrome) are common; hemolytic anemia seen in G6PD-deficient patients. Agran-ulocytosis and thrombocytopenia are less common.

3.  Broad spectrum of activity for gram-positive and gram-negative organisms, but resistance is common.

4.  Used for initial therapy of uncomplicated urinary tract infections. Treatment of choice for Nocardia.

5.  Trimethoprim-sulfamethoxazole combination is the drug of choice for Pneumocystis prophylaxis and treatment.

It can be used to treat a number of other gram-positive and gram-negative pathogens. However, plasmid-mediated resistance is common, and treatment for most pathogens should be initiated only after sensitivity is confirmed by microbiologic testing. This combination is highly effective for killing Pneumocystis carinii, and TMP-SMX is the drug of choice for treatment or prophylaxis of that infection in immunocompromised hosts, including patients with AIDS.