http://www.uic.edu/pharmacy/courses/pmpr342/0contents/menu_l.html#Quinolones PENICILLINS Gail Itokazu, Pharm.D. Goals and Objectives.

By the end of the lecture the student should be able to discuss the following about penicillin antibiotics: 1. Describe their mechanism of action and pharmacologic properties. 2. Describe their spectrum of activity. 3. Describe their major side effects. 4. Discuss their use in the clinical setting. Required readings. The goal of these readings is to reinforce the clinical application of penicillins. Lower Respiratory Tract Infections, Chapter 100, pages 1995-2016. Pharmacotherapy:A Pathophysiologic Approach, 3rd Edition. Upper Respiratory Tract Infections, Chapter 101, pages 2017-2035. Pharmacotherapy:A Pathophysiologic Approach, 3rd Edition. DRUG NATURAL PENCILLINS Aqueous penicillin G Penicillin G Pencillin VK DOSE ROUTE DOSING INTERVAL 4-6 6 6

1-4 million units IV 250-500 mg PO 250-500 mg PO

PENICILLINASE-RESISTANT PENICILLINS Methicillin 1-2 gm Oxacillin Naficllin Dicloxacillin Cloxacillin 1-2 gm 500 mg 1-2 gm 250-500 mg 250-500 mg 250-500 mg

IV/IM 4-6 IV/IM PO IVIM PO PO PO 4-6 4-6 4-6 4-6 6 6

AMINOPENICILLINS Ampicillin Amoxicillin CARBOXY-PENICILLINS Carcenicillin Ticarcillin UREIDO-PENICILLIN Mezlocillin 1-2 gm 250-500 mg 250-500 mg 382-764 mg 3 gm 3 gm 4 gm 3-4 gm IV/IM 4-6 PO 6 PO 8 PO 8 IV/IM 4-6 4 6 IV/IM 4-6 IV/IM 6 4-6 4-6 4 8 6-8 6 8 12-24

Piperacillin PENICILLIN/INHIBITOR COMBINATIONS Ampicillin/sulbactam 3 gm IV/IM Ticarcillin/clavulanate 3.1 gm IV 3.75 gm IV Piperacillin/tazobactam 4.5 gm IV Amoxicillin/clavulanate 250-500 mg PO MONOBACTAM Aztreonam 1-2 gm IV/IM CARBAPENEM Imipenem 500 mg IV/IM Meropenem 1 gm IV GLYCOPEPTIDE Vancomycin 1 gm IV PENICILLINS Gail Itokazu, Pharm.D. I. BACKGROUND

Penicillins are beta-lactam compounds which have a 4 membered beta-lactam ring that is fused to a 5-membered thiazolidine ring. Side chain modifications of this structure confers: 1) an improved spectrum of activity, and 2) pharmacokinetic advantages. Six classes of penicillins are now available. II. MECHANISM OF ACTION & PHARMACOLOGIC PROPERTIES 1. Prevents cell wall synthesis by binding to enzymes called penicillin binding proteins (PBPs). These enzymes are essential for the synthesis of the bacterial cell wall. 2. Bactericidal. 3. Concentration-independent bactericidal activity.

III. MECHANISMS OF BACTERIAL RESISTANCE TO PENICILLIN It is not uncommon for more than one of these resistance mechanism to be operating simultaneously. 1. destruction of beta-lactam ring by beta-lactamases; an intact beta-lactam ring is essential for antibacterial activity. 2. altered affinity of penicillins for their target site, the penicillin binding proteins. 3. decreased penetration of antibiotic to the target site, the PBPs. This is only applicable to gram-negative bacteria since gram-positive bacteria lack an outer cell membrane. It is the outer cell membrane that reduces permeability of drug to the target site. IV. MAJOR CLASSIFICATIONS OF PENICILLINS 1. PENICILLIN G (BENZYLPENICILLIN) SPECTRUM OF ACTIVITY. Gram-positive aerobic cocci: Streptococci pyogenes (Group A strep), Streptococcus agalactiae (Group B strep), viridans streptococci, Enterococci. Staphylococci are usually resistant. Penicillin resistant S. pneumoniae with variable degrees of resistance (intermediately resistant, highly resistant) to penicillin is becoming a worldwide problem. Potential therapies for these resistant isolates include cefotaxime, ceftriaxone, vancomycin, imipenem. Gram-negative aerobes: Neisseria meningitidis, Pasteurella multocida. Anaerobes: Clostridium species, Fusobacterium species, Actinomyces israelii. Other: Treponema pallidum, Listeria monocytogenes. PHARMACOKINETICS: Distributes well into the urine; synovial, pleural, and pericardial fluids; cerebral spinal fluid (CSF). Elimination is primarily via the kidneys and dosage adjustment is necessary to minimize the potential for seizures. GENERAL CLINICAL USES: Useful for skin and soft tissue infections caused by Streptocccus pyogenes, meningitis caused by susceptible N. meningitidis and Streptococcus pneumoniae, oral or dental infections which frequently involve anaerobic streptococci, and syphilis which is caused by Treponema pallidum.

GENERAL SIDE EFFECTS/PRECAUTIONS: A. Hypersensitivity reactions manifested by rashes, eosinophilia, fever, interstitial nephritis. B. Central nervous stimulation including myoclonic twitching and seizures. Risk factors include high doses, particularly when doses are not modified for renal dysfunction, lowered seizure threshold as may occur with meningitis. MISCELLANEOUS: A. Probenecid (usual dose of 500mg four times daily) blocks renal tubular transport of penicillin resulting in usually a 2-fold increase in penicillin blood levels. Useful in alternative regimens for syphilis in combination with amoxicillin; or in circumstances when higher blood levels of penicillin are desired. SPECIFIC AGENTS: A. Aqueous penicillin G. This formulation is usually used in patients who require intravenous penicillin for more severe or complicated infections (eg: meningitis, pneumonia). 3.4 meq of K+ accompany each 1 million unit (1MU) of penicillin G and hyperkalemia may occur particularly when high doses are give to patients with renal dysfunction. B. Procaine penicillin G. Repository, intramuscular formulation that provides prolonged blood levels of penicillin. May be used for treatment of uncomplicated pneumonia caused by penicillin-susceptible Streptococcus pneumoniae; syphilis. "Procaine reaction" characterized by dizziness, palpitations, auditory or visual disturbances, fear of impending death. Symptoms usually resolve within 5-10 minutes. C. Benzathine penicillin G. Long acting intramuscular formulation that provides low, blood levels for 3-4 weeks. Used for syphilis (primary, secondary, latent); rheumatic fever prophylaxis; Streptococcal pharyngitis. D. Penicillin G/Penicillin VK. Oral forms of penicillin. Penicillin G is susceptible to breakdown by gastric acid which is why it has been largely replaced bypenicillin VK which is stable in the acid environment of the stomach.

2. PENICILLINASE-RESISTANT PENICILLINS Side chain modification prevents destruction of beta-lactam ring by beta-lactamases produced by Staphylococci. Thus, unlike penicillin G, penicillinase-resistant penicillins are useful for Staphylococcal infections.

SPECTRUM OF ACTIVITY. Gram-positive aerobic cocci: Methicillin-susceptible Staphylococcus aureus (MSSA); viridans streptococci; less potent than penicillin against Streptococcus pyogenes (Group A strep) and Streptococcus pneumoniae; not active against Enterococci. Gram-negative aerobes: Not active. Anaerobes: Compared to penicillin, less active or inactive against penicillin-susceptible anaerobes. GENERAL CLINICAL USES: Primarily used to treat infections involving MSSA such as bacteremia associated with: 1) indwelling devices, 2) injection drug use, and 3) skin and soft tissue infections; and endocarditis which may be a complication of bacteremia. Sometimes used in combination with an aminoglycoside (usually gentamicin) for their synergistic effect against Staphylococci. GENERAL SIDE EFFECTS/PRECAUTIONS: A. Hypersensitivity reactions manifested by rashes, eosinophilia, fever, interstitial nephritis. SPECIFIC AGENTS: A. Nafcillin. IV/IM/PO formulations . Phlebitis, neutropenia. B. Methicillin. IV/IM formulations. Less commonly used because of increased risk of interstitial nephritis; signs and symptoms which include eosinophilia, rash, renal failure, proteinuria, fever. C. Oxacillin. IV/IM/PO. Hepatitis occurs more frequently than with nafcillin. D. Dicloxacillin and Cloxacillin. PO formulations. These oral formulations are preferred over oral forms of nafcillin or oxacillin because their blood levels are higher. 3. AMINO-PENICILLINS Side chain modification (addition of amino group) to basic benzylpenicillin molecule increases spectrum of activity to include aerobic gram-negative bacilli. SPECTRUM OF ACTIVITY. Gram-positive aerobic cocci: Same activity as for penicillin G but is more active than penicillin against Enterococci. Like penicillin G, Staphylococci are usually resistant to ampicillin.

Gram-negative aerobes: Active against most beta-lactamase negative Hemophilus influenzae; Escherichia coli and Proteus mirabilis, particularly if involved with community-acquired infections; Salmonella and Shigella species. Usually not active against aerobic gram-negative bacteria causing hospital-acquired infections. Anaerobes: See penicillin G. Other: Listeria monocytogenes. GENERAL CLINICAL USES: Used as empiric therapy in many community-acquired infections involving the respiratory tract (eg: bronchitis, sinusitis, otitis media) where frequent pathogens include Streptococcus pneumoniae, Hemophilus influenzae; urinary tract infections caused by susceptible Escherichia coli. A high prevalence of betalactamase producing aerobic gram-negative bacteria may preclude the empiric use of amino-penicillins for these community-acquired infections. GENERAL SIDE EFFECTS/PRECAUTIONS: A. Hypersensitivity reactions manifested by rashes, eosinophilia, fever, interstitial nephritis. B. Ampicillin rash is a generalized erythematous, maculopapular rash that occurs in patients taking ampicillin and who have a concurrent viral illness (eg: mononucleosis, cytomegalovirus, viral respiratory tract infection). MISCELLANEOUS: 1. Probenecid increases blood levels (see "Miscellaneous" section under penicillin G). SPECIFIC AGENTS: A. Ampicillin. IV/IM/PO formulations. More effective than amoxicillin against Shigella. B. Amoxicillin. PO formulation. More active than ampicillin against Salmonella. Favored over ampicillin because: 1) better absorption, 2) food does not interfere with absorption, 3) less frequent dosing (Q8 vs Q6 hours for ampicillin). 4. CARBOXY-PENICILLINS Side chain modification (substitution of amino group with a carboxy group and others) increases spectrum of activity to include other aerobic gram-negative bacilli. SPECTRUM OF ACTIVITY. Gram-positive aerobic cocci: Less active than ampicillin against Enterococci, Streptococcus pneumoniae, Streptococcus pyogenes. Not active against methicillin-susceptible Staphylococcus aureus (MSSA).

Gram-negative aerobes: Active against many hospital-acquired pathogens such as Pseudomonas aeruginosa, Enterobacteriaceae (indole positive Proteus, Enterobacter, Morganella). Similar activity to ampicillin against Hemophilus species, Escherichia coli, Proteus mirabilis. Inactive against Klebsiella. Anaerobes: Bacteroides fragilis (at high concentrations). GENERAL CLINICAL USES: Usually in combination with another antibiotic (generally an aminoglycoside) for aerobic gram-negative infections(especially P. aeruginosa). GENERAL SIDE EFFECTS/PRECAUTIONS: A. Hypersensitivity reactions manifested by rashes, eosinophilia, fever, interstitial nephritis. SPECIFIC AGENTS: A. Carbenicillin indanyl sodium. PO formulation. An indanyl ester which releases active carbenicillin after breakdown in the liver. Low blood levels preclude its use for infections outside the urinary tract. B. Ticarcillin. IV/IM formulations. Similar spectrum to carbenicillin except that it is 2-4 times more active than carbenicillin against Pseudomonas aeruginosa. Side effects include occasional bleeding due to platelet dysfunction. Each gram of ticarcillin is accompanied by 5.2meq of sodium.Ureidopenicillins have a lower sodium load (see section on Ureidopenicillins). 5. UREIDO-PENICILLINS Further side chain modifications increased the spectrum of activity to include additional aerobic gram-negative bacilli. SPECTRUM OF ACTIVITY. Gram-positive aerobic cocci: More active than carboxy-penicillins against Enterococci, Streptococcus pneumoniae, Streptococcus pyogenes. Gram-negative aerobes: Active against many hospital-acquired pathogens such as Pseudomonas aeruginosa (more active than carboxy-penicillins); Enterobacteriaceae (eg: Klebsiella, indole positive Proteus, Enterobacter, Morganella). More active than ticarcillin against Hemophilus influenzae. PHARMACOKINETICS: Has dose-dependent, non-linear kinetics. GENERAL CLINICAL USES: Similar to carboxy-penicillins.

GENERAL SIDE EFFECTS/PRECAUTIONS: A. Hypersensitivity reactions manifested by rashes, eosinophilia, fever, interstitial nephritis.

SPECIFIC AGENTS: A. Mezlocillin (MezlinR). IV/IM formulations. Similar spectrum of activity to ticarcillin including comparable activity against Pseudomonas aeruginosa; invitro may be more active against Klebsiella pneumoniae. Each gram contains 1.85meq of sodium. B. Piperacillin (PipracilR). IV/IM formulations. It is 4-fold more active than mezlocillin against Pseudomonas aeruginosa. Each gram contains 1.98meq of sodium. 6. PENICILLIN/INHIBITOR COMBINATIONS In order to overcome resistance due to beta-lactamase enzymes, various penicillins have been combined with beta-lactamase inhibitors that irreversibly inhibits betalactamases.Unfortunately, not all beta-lactamase enzymes can be neutralized by the currently available beta-lactamase inhibitors. These inhibitors generally do not have any clinically useful antibacterial activity. Currently available products combine ampicillin, amoxicillin, ticarcillin, or piperacillin with a beta-lactamase inhibitor. The intrinsic antibacterial activity of the penicillin is an important factor in the effectiveness of the penicillin/inhibitor combinations. Differences Between Inhibitors. Sulbactam: Little activity against Class I beta-lactamases. Clavulanate: Strongest inducer of type I chromosomal beta-lactamases. Tazobactam: Weakest inducer of type I chromosomal beta-lactamases; most potent inhibitor. PHARMACOKINETICS: Pharmacokinetics of inhibitors are similar to their respective penicillins. GENERAL CLINICAL USES: As monotherapy for mixed aerobic/anaerobic infections caused by susceptible bacteria (eg: intraabdominal/gynecologic infections, skin and soft tissue infections such as diabetic ulcers). For serious infections or infections in which resistant gram-negative bacteria are suspected a second agent (eg: aminoglycoside) can be added.

GENERAL SIDE EFFECTS/PRECAUTIONS: A. Hypersensitivity reactions manifested by rashes, eosinophilia, fever, interstitial nephritis.

SPECIFIC AGENTS: A. Ampicillin/sulbactam (UnasynR). IV/IM formulations. Has the spectrum of ampicillin plus beta-lactamase producing organisms such as Hemophilus influenzae, Moraxella catarrhalis, Bacteroides fragilis, Escherichia coli (although susceptibilities to Escherchia coli is variable), Proteus species, Klebsiella species,Enterobacter aerogenes, Acinetobacter calcoaceticus, methicillin-susceptible Staphylococcus aureus (MSSA). Useful for infections due to these beta-lactamase producing bacteria (sinusitis, otitis); mixed aerobic/anaerobic infections, bite wounds. B. Amoxicillin/clavulanate (AugmentinR). PO formulation. Similar to ampicillin/sulbactam with respect to spectrum of activity and clinical usefulness. Side effects include nausea, vomiting, anddiarrhea which can sometimes be minimized if taken with meals. C. Ticarcillin/clavulanate (TimentinR). IV/IM formulations. Has the spectrum of ticarcillin plus beta-lactamase producing bacteria such as Staphylococcus aureus, Escherichia coli, Klebsiella species, Proteus, Hemophilus species, Bacteroides fragilis. Clavulante does not increase the activity of ticarcillin against gram-negative bacteria that produce Class 1 Richmond-Sykes beta-lactamases (eg: Pseudomonas, Serratia, Citrobacter, Enterobacter). D. Piperacillin/tazobactam (ZosynR). IV/IM formulations. Has the spectrum of piperacillin plus beta-lactamase producing bacteria such as Escherichia coli, Enterobacter, Citrobacter, Providencia, methicillin-susceptible Staphylococcus aureus, Bacteroides fragilis, Hemophilus species. http://www.uic.edu/pharmacy/courses/pmpr342/itokazu/penicillins.html

CEPHALOSPORINS Gail Itokazu, Pharm.D Goals and Objectives.

By the end of the lecture the student should be able to discuss the following about cephalosporin antibiotics: 1. Describe their mechanism of action and pharmacologic properties. 2. Describe their spectrum of activity. 3. Describe their major side effects. 4. Discuss their use in the clinical setting.

Required readings. The goal of this reading is to reinforce the clinical application of cephalosporins.

Gram-negative Sepsis and Septic Shock. Chapter 112, pages 2237-2250. Cephalosporin 1st Cefazolin Cephalothin Cephapirin Cephalexin Cefadroxil Cephradine 2nd Cefamandole Cefuroxime Cefoxitin Cefotetan 1-2gm 0.75-1.5gm 250-500mg 1-2gm 1-2gm IV/IM IV/IM PO IV/IM IV/IM 4-6 8 12 4-6 12 yes yes yes yes 1-2gm 1-2gm 0.5-1gm 250-500mg 500mg 250mg <500mg> IV/IM IV/IM IV/IM PO PO PO PO 8 4-6 4-6 6 12 6 12 yes yes yes yes yes yes Dose Route Dosing Interval Renal

Cefmetazole Cefaclor Cefprozil Cefpodoxime Loracarbef 3rd Cefotaxime Ceftriaxone Ceftizoxime Ceftazidime Cefoperazone Cefixime 4th Cefipime I. BACKGROUND

2gm 250-500mg 250-500mg 200-400mg 200-400mg 1-2gm 1-2gm 1-2gm 1-2gm 1-2gm 400mg 200mg

IV PO PO PO PO IV/IM IV/IM IV/IM IV/IM IV/IM PO PO

6-12 8 12-24 12 12 6-8 12-24 8-12 8 12 24 12

yes yes yes yes yes yes yes yes

yes

yes

Cephalosporins are beta-lactam compounds in which the beta-lactam ring is fused to a 6membered dihydrothiazine ring, thus forming the cephem nucleus. Side chain modifications to the cephem nucleus confers 1) an improved spectrum of antibacterial activity, 2) pharmacokinetic advantages, and 3) additional side effects. Based on their spectrum of activity, cephalosporins can be broadly categorized into four generations. II. MECHANISM OF ACTION & PHARMACOLOGIC PROPERTIES 1. Prevents cell wall synthesis by binding to enzymes called penicillin binding proteins (PBPs). These enzymes are essential for the synthesis of the bacterial cell wall. 2. Bactericidal. 3. Concentration-independent bactericidal activity, with maximal killing at 4-5 times the MIC of the organism. 4. Clinically significant post-antibiotic effect is not observed. Given these pharmacodynamic properties (concentration-independent bactericidal activity and lack of a post-antibiotic effect, optimal dosing regimens should be designed to continuously maintain drug levels above the MIC of pathogens. III. SPECTRUM OF ACTIVITY

In general, 1st generation cephalosporins have better activity against gram-positive bacteria and less gram-negative activity, while 3rd generation agents, with a few exceptions, have better gram-negative activity and less gram-positive activity. The only fourth generation agent has both gram-positive and gram-negative activity. IV. MECHANISMS OF BACTERIAL RESISTANCE It is not uncommon for several resistance mechanisms to be operating simultaneously. 1. destruction of beta-lactam ring by beta-lactamases; an intact beta-lactam ring is essential for antibacterial activity 2. altered affinity of cephalosporins for their target site, the penicillin binding proteins 3. decreased penetration of antibiotic to the target site, the PBPs. This is only applicable to gram-negative bacteria because gram-positive bacteria lack an outer cell membrane, and therefore penetration to the target site is not a problem. V. GENERAL INFORMATION FOR CEPHALOSPORINS 1. SPECTRUM OF ACTIVITY. PHARMACOKINETICS: Generally distributes well into the lung; kidney; urine; synovial, pleural, and pericardial fluids. Penetration into the cerebral spinal fluid(CSF) of some 3rd generation cephalosporins (cefotaxime, ceftriaxone, and ceftazidime) is adequate to effectively treat bacterial meningitis. Elimination is primarily via the kidneys, though a few exceptions include cefoperazone and ceftriaxone which have significant biliary elimination. GENERAL CLINICAL USES: Their broad spectrum of activity and safety profile make the cephalosporins one of the most widely prescribed class of antimicrobials. The earlier generation cephalosporins are commonly used for community-acquired infections, while the later generation agents, with their better spectrum of activity against gram-negative bacteria make them useful for hospital-acquired infections or complicated communityacquired infections. GENERAL SIDE EFFECTS/PRECAUTIONS: A. Hypersensitivity reactions manifested by rashes, eosinophilia, fever (1-3%); interstitial nephritis. Given the structural similarity of cephalosporins and penicillins, an estimated 1-7% of patients with penicillin allergies will also be hypersensitive to cephalosporins. Cephalosporins should be avoided in patients with immediate allergic reactions to penicillins (eg: anaphylaxis, bronchospasm, hypotension, etc.). Cephalosporins may be tried with caution in patients with delayed or mild reactions to penicillin. B. Thrombophlebitis (1-5%).

VI. FIRST GENERATION CEPHALOSPORINS SPECTRUM OF ACTIVITY. Gram-positive aerobic cocci: Very active against Streptococci pyogenes (Group A strep), Streptococcus agalactiae (Group B strep), viridans streptococci. Methicillin-resistant Staphylococci, Enterococci, penicillin-resistant Streptococcus pneumoniae are resistant. Gram-negative aerobes: Commonly active against Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae, though susceptibilities may vary. Inadequate activity against Moraxella catarrhalis and Hemophilus influenzae. Anaerobes: Active against most penicillin-susceptible anaerobes found in the oral cavity, except those belonging to the Bacteroides fragilis group. GENERAL CLINICAL USES. Uncomplicated, community-acquired infections of the skin and soft tissue and urinary tract. Useful for respiratory tract infections caused by pencillin-sensitive Streptococcus pneumoniae but not for Hemophilus influenzae and Moraxella catarrhalis. While effective for these infections, other less expensive alternatives should be used when appropriate because of their efficacy and narrower spectrum of activity (eg: penicillins, trimethoprim/sulfamethoxazole). Parenteral 1st generation agents are used for surgical wound prophylaxis. SPECIFIC AGENTS: A. Cefazolin (Ancef , Kefzol, Cephalothin (Keflin , Vantage, Cephpirin (Cefadyl). IV/IM formulations. Spectrum of cephalothin and cefazolin are similar except that cefazolin is slightly more active against Escherichia coli and Klebsiella species. The longer half-life of cefazolin allows less frequent dosing. B. Cephalexin (Keflex, Keftab, Biocef), Cephradine (Anspor, Velosef), Cefadroxil (Duricef, Ultracef). PO formulations. Less frequent dosing with cefadroxil. VI. SECOND GENERATION CEPHALOSPORINS There are 2 groups within the 2nd generation agents that differ in their: 1) spectrum of activity and 2) adverse reaction profile. These groups are the "true" second generation cephalosporins (cefamandole, cefuroxime) and the cephamycins (cefoxitin, cefotetan, cefmetazole). SPECTRUM OF ACTIVITY. Gram-positive aerobic cocci: In general, true 2nd generation agents are comparable to 1st generation agents against nonenterococcal streptococci; are less active invitro, but still have adequate activity against MSSA. Compared to the 1st generation agents, thecephamycins are less active against gram-positive cocci. Both groups of cephalosporins are inactive against methicillin-resistant Staphylococci and Enterococci.

Gram-negative aerobes. The "true" cephalosporins are more active than 1sts for Hemophilus influenzae, Moraxella catarrhalis, Neisseria meningitidis, and some Enterobacteriaceae. The cephamycins in some instances (eg: cefotetan) have improved activity against Enterobacteriaceae. Anaerobes: Cephamycins are active against most anaerobes found in the mouth as well as colon (eg: Bacteroides species, including Bacteroides fragilis). GENERAL CLINICAL USES. The "true" 2nd generation agents are useful for community-acquired infections of the respiratory tract (Hemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae) and uncomplicated urinary tract infections (Escherichia coli). The cephamycin group is useful formixed aerobic/anaerobic infections of the skin and soft tissues, intraabdominal, and gynecologic infections, and surgical prophylaxis. SIDE EFFECTS/PRECAUTIONS. The cephamycin agents have a side chain called the methylthiotetrazole (MTT) group which predisposes patients to: 1) hypoprothrombinemia and bleeding by disturbing synthesis of vitamin-k dependent clotting factors. Risk factors are renal or hepatic disease, poor nutrition, the elderly, and cancer. 2) alcohol intolerance by causing a disulfiram-like reaction, avoid alcohol products for several days after antibiotics have stopped. SPECIFIC AGENTS: A. Cefamandole (MandolR). (IV/IM) formulations. Better activity against selected methicillinsusceptible Staphylococcus aureus than cefazolin. May not be reliable therapy for Hemophilus influenzae. Although not a cephamycin, it contains an NMTT side chain. B. Cefurxoime (Zinacef, Kefurox). IV/IM/PO formulations. Somewhat less potent against Staphylococcus aureus, but more potent against Streptococcus pneumoniae and Streptococcus pyogenes than 1st generation cephalosporins. Active against Hemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Proteus mirabilis, Klebsiella species. Although cefuroxime has been used for the treatment of bacterial meningitis caused by H. influenzae, it is not recommended because studies show neurologic deficits are more frequent in children treated with cefuroxime versus selected 3rd generation cephalosporins (cefotaxime, ceftriaxone). This finding is related to delayed sterilization of cerebral spinal fluid. C. Cefonicid (MonocidR). IV/IM formulation. Similar to cefamandole and cefuroxime, though less active against gram-positive cocci (methicillin-susceptible Staphylococcus aureus, Group A strep, Streptococcus pneumoniae). Long half-life allows once daily dosing.

D. Cefoxitin (MefoxinR). IV/IM formulations. A cephamycin, which is less active than 1st generation agents against gram-positive bacteria. Active against Neisseria gonorrhea, but less active than "true" second generation cephalosporins against Hemophilus influenzae. E. Cefotetan (CefotanR). IV/IM formulations. A cephamycin with similar activity to cefoxitin. Compared to second generation cephalosporins and cefoxitin, has improved activity against Enterobacteriaceae including Enterobacter. Also active against Hemophilus influenzae, Neisseria gonorrhea, Neisseria meningitidis. Generally 2-4 fold less active than cefoxitin against gram-positive cocci. For Bacteroides fragilis, is comparable to cefoxitin; but less active than cefoxitin against non-Bacteroides fragilis species within the Bacteroides fragilis group; the clinical significance of which is unknown. Used insurgical wound prophylaxis when activity against Bacteroides fragilisis needed. F. Cefmetazole (ZefazoneR). IV/IM formulations. A cephamycin, similar to cefoxitin and cefotetan. Similar to cefoxitin and more active than cefotetan against methicillin-susceptible Staphylococcus aureus. 2-4 fold more active than cefoxitin against Enterobacteriaceae (eg: Escherichia coli, Klebsiella sp, Proteus mirabilis). Also active against Hemophilus influenzae and Moraxella catarrhalis. Bacteroides fragilis is similar to cefoxitin, against other Bacteroides species, is similar or slightly less active than cefoxitin. Used in surgical wound prophylaxis when activity against Bacteroides fragilis is needed, repeat dose would be necessary in procedures lasting more than 4 hours.

G. Cefaclor (Ceclor), Cefprozil (Cefzil), Loracarbef(Lorabid), Cefpodoxime proxetil (Vantin). PO formulations. Cefaclor is more commonly associated with a serum sickness like illness. Loracarbef is a new category of compounds called the carbacephems, which are analogues of cephalosporins. Loracarbef is the carbacephem analogue of cefaclor. H. Cefuroxime axetil (CeftinR). PO formulation of cefuroxime. Is the oral ester of cefuroxime that is hydrolyzed to cefuroxime during absorption. VI. THIRD GENERATION CEPHALOSPORINS Improved activity against Enterobacteriaceae associated with hospital-acquired infections; some agents are also active against Pseudomonas aeruginosa which is a frequent cause of hospital-acquired pneumonia. SPECTRUM OF ACTIVITY. Gram-positive aerobic cocci: Cefotaxime, ceftriaxone, and ceftizoxime are active against methicillin-susceptible Staphylococcus aureus (though less than 1st and some 2nd generation agents), very active against Groups A and B streptococci, and viridans streptococci. Cefotaxime and ceftriaxone are more active than ceftizoxime against Streptococcus pneumoniae, particularly intermediately-penicillin resistant Streptococcus pneumoniae. None are active against methicillin-resistant Staphylococci, Enterococci, and Listeria monocytogenes.

Gram-negative aerobes: Very active against Hemophilus influenzae, Moraxella catarrhalis, Neisseria meningitidis, and Enterobacteriaceae (eg: Escherichia coli, Klebsiella species, Proteus mirabilis, Providencia)found in hospital and community-acquired infections. Some Enterobacter species have a tendency to become resistant during cephalosporin therapy, and thus cephalosporins are not the drugs of choice for Enterobacter infections. Only and ceftazidime and cefoperazone are active against Pseudomonas aeruginosa, and ceftazidime is preferred because it is more potent than cefoperazone against gramnegative bacteria. Anaerobes: Cefotaxime, ceftriaxone, and ceftizoxime are adequate for oral anaerobes. GENERAL CLINICAL USES. For infections involving gram-negative bacteria, particularly hospitalacquired infections or complicatedcommunity-acquired infections of the respiratory tract, blood, intra-abdominal, skin and soft tissue, and urinary tract. Because of their activity includes the aerobic gram negative bacteria covered by aminoglycosides, they may be an alternative to aminoglycosides in some patients with renal dysfunction. The clinical situations requiring use of 3rd generation cephalosporins are likely to be encountered in patients who are hospitalized, have recently received antibiotics, or are immunocompromised. SPECIFIC AGENTS: A. Cefotaxime (Claforan), Ceftriaxone (Rocephin), Ceftizoxime (cefizox) . IV/IM formulations. Activity against Enterobacteriaceae (eg: Escherchia coli, Klebsiella pneumoniae) are similar. None are active against Pseudomonas aeruginosa. Only cefotaxime and ceftriaxoneachieve adequate drug levels in the cerebral spinal fluid to constitute reliable empiric therapy for bacterial meningitis.Ceftriaxone is eliminated to a significant degree by the biliary system, and as a result, biliary pseudo-lithiasis has been reported as a side effect of this agent. B. Ceftazidime (Fortaz, Tazidime, Tazicef), Cefoperazone (Cefobid). IV/IM formulations. Spectrum includes Pseudomonas aeruginosa (against which ceftazidime is more active) and Enterobacteriaceae covered by the 3rd generation agents in item A above. Disadvantages of cefoperazone are: 1) the least active 3rd generation agent against Enterobacteriaceae and 2) contains MTT side chain (see SIDE EFFECTS/PRECAUTIONS under 2nd generation agents). C. Cefixime (Suprax), Ceftibuten (Cedax) .PO formulations administered once or twice daily. Inactive against methicillin-susceptible Staphylococcus aureus, thus not good choices for skin and soft tissue infections. Generally very active against gram-negative bacteria causing community-acquired infections(Hemophilus influenzae, Moraxella catarrhalis). Cefixime is effective as a single dose therapy for uncomplicated Neisseria gonorrhea infection. While used in otitis media, cefixime may not routinely eradicate Streptococcus pneumoniae.

VII. FOURTH GENERATION CEPHALOSPORIN Has the excellent activity against Enterobacteriaceae and Pseudomonas aeruginosa which is similar to ceftazidime. In addition, it also has better gram-positive activity than ceftazidime. SPECTRUM OF ACTIVITY. Gram-positive aerobic cocci: Active against Streptococcus pneumoniae, and Groups A and B streptococci. Though active against methicillin-susceptible Staphylococcus aureus, it is less potent than the 1st and 2nd generation agents. Gram-negative aerobes: Similar to ceftazidime. Anaerobes: Not active against Bacteroides fragilis. GENERAL CLINICAL USES. Similar to 3rd generation agents. SPECIFIC AGENT: A. Cefepime (MaxipimeR). IV/IM formulations. http://www.uic.edu/pharmacy/courses/pmpr342/itokazu/cephalosporins.html

MONOBACTAM Gail Itokazu, Pharm.D Goals and Objectives.

By the end of the lecture the student should be able to discuss the following about monobactam antibiotics: 1. Describe their mechanism of action and pharmacologic properties. 2. Describe their spectrum of activity. 3. Describe their major side effects. 4. Discuss their use in the clinical setting. I. BACKGROUND Aztreonam is a monocyclic beta-lactam. Its spectrum is limited to only aerobic-gram negative bacteria. It is frequently used in patients unable to tolerate beta-lactams. II. MECHANISM OF ACTION & PHARMACOLOGIC PROPERTIES 1. Interferes bacterial cell wall synthesis by binding to penicillin-binding protein 3 (PBP 3) of aerobic gram-negative bacilli such as enterobacteriaceae and Pseudomonas. 2. Bactericidal. 3. Concentration-independent bactericidal activity, which means that optimal dosing regimens should maintain antibiotic levels above the MIC of the organism. III. PHARMACOKINETICS 1. Absorption. Poor oral absorption. Rapid and complete absorption after intramuscular injection. 2. Distribution. Urine, kidney, prostate, pericardial fluid, peritoneal fluid, synovial fluid, pleural fluid, bone, liver, lung, adipose tissue. Penetration into the cerebral spinal fluid has been documented, however, 3rd generation cephalosporins are the drugs of choice for meningitis caused by susceptible pathogens. 3. Elimination. Primarily via the kidneys which accounts for two-thirds of the elimination of unchanged drug. Appropriate references should be consulted for specific dosage reductions for various degrees of renal dysfunction.

V. SPECTRUM OF ACTIVITY Limited to only aerobic-gram negative bacteria. Active against Hemophilus influenzae, Pseudomonas aeruginosa, Enterobacteriaceae (eg: Escherichia coli, Klebsiella pneumoniae), Neisseria meningitidis, Neisseria gonorrhea. This spectrum of activity is similar to the 3rd generation cephalosporins and the aminoglycosides. VI. RESISTANCE Resistance to Enterobacteriaceae and Pseudomonas does occur, its frequency may vary between institutions. 1. Mechanisms of resistance a. failure to penetrate outer membrane of aerobic gram-negative bacteria b. destruction by beta-lactamases c. failure to bind to penicillin binding proteins (PBPs) SIDE EFFECTS/PRECAUTIONS Generally well tolerated. Is weakly immunogenic and has been used in patients with penicillin allergies unable to tolerated penicillins or cephalosporins. VII. CLINICAL USES In settings when therapy is directed against aerobic gram-negative bacteria. If coverage for gram-positive bacteria and/or anaerobes is needed, then the appropriate additional agent(s) should be used in combination with aztreonam. Patients who have allergic reactions to penicillin, cephalosporins, or carbapenems may be treated with aztreonam. Use is similar to 3rd generation cephalosporins, major exceptions would be meningitis. 1. Intra-abdominal infections. Because aztreonam lacks activity against anaerobes, it must be combined with anti-anaerobic drugs. 2. Obstetric/gynecologic infections. Same as for intra-abdominal infections. 3. Respiratory tract infections. a. Hospital-acquired pneumonia. Like the 3rd generation cephalosporins, aztreonam is active against many of the aerobic gram-negative bacteria that cause these pneumonias. If aspiration pneumonia is suspected, an agent such as clindamycin should be added.

b. Community-acquired (pneumonia, bronchitis). Lack of activity against gram-positive cocci (eg: Streptococcus pneumoniae) which are major causes of these infections makes it a poor choice for empiric monotherapy. 4. Bacteremia. 5. Skin and soft tissue, in combination with appropriate antimicrobials. 6. Bone and joint.

VIII.SPECIFIC AGENTS 1. Aztreonam (AzactamR). IV/IM formulations. http://www.uic.edu/pharmacy/courses/pmpr342/itokazu/monobactam.html#top

CARBAPENEMS Gail Itokazu, Pharm.D

Goals and Objectives.

By the end of the lecture the student should be able to discuss the following about carbapenem antibiotics: 1. Describe their mechanism of action and pharmacologic properties. 2. Describe their spectrum of activity. 3. Describe their major side effects. 4. Discuss their use in the clinical setting. I. BACKGROUND Carbapenems differ from penicillin and cephalosporins by a methylene replacement for the sulfur in the 5-membered ring structure. They are very active against gram-negative, grampositive, and anaerobes.

II. MECHANISM OF ACTION & PHARMACOLOGIC PROPERTIES 1. Interferes bacterial cell wall synthesis by binding to penicillin-binding protein (PBPs), enzymes which are essential for cell wall synthesis. 2. Bactericidal. 3. It is only available in combination with cilastatin which inhibits dehydropeptidasse-I, an enzyme in the brush border of the kidney that degrades imipenem. Thus, inhibition prevents inactivation of imipenem and it also has a nephro-protective effect. Cilastatin has no antibacterial activity. III. PHARMACOKINETICS 1. Absorption. Poor oral absorption. 2. Distribution. Urine, sputum, synovial fluid, pleural fluid, bone. Variable penetration into the cerebral spinal fluid has been documented, however, 3rd generation cephalosporins are the drugs of choice for meningitis for susceptible pathogens. Its potential to cause seizures also precludes it from being a drug of choice for meningitis.

3. Elimination. Primarily via the kidneys by glomerular filtration. Appropriate references should be consulted for specific dosage reductions for various degrees of renal dysfunction.

V. SPECTRUM OF ACTIVITY Because of its binding to PBPs of both gram-negative and gram-positive bacteria, and its stability to many beta-lactamases, it has a very broad spectrum of activity. 1. Aerobic gram-negative bacteria. Active against Escherichia coli, Klebsiella, Enterobacter, Pseudomonas aeruginosa, Neisseria meningitidis. 2. Gram-positive cocci. Streptococcus pneumoniae (including penicillin-resistant), methicillin-susceptible Staphylococcus, streptococci. Enterococcus faecalis are moderately susceptible. 3. Anaerobes. Very active, including Bacteroides, Fusobacterium, anaerobic gram-positive cocci. Bacteria that are resistant to imipenem are methicillin-resistant Staphylococci, Corynebacterium JK, Enterococcus faecium, Xanthamonas maltophilia, Pseudomonas cepacia. Cross-resistance with aminoglycosides, ceftazidime, piperacillin usually does not occur. Because of induction of beta-lactamases, resistance to cephalosporins and expanded spectrum penicillins may occur (antagonism). VI. RESISTANCE 1. Mechanisms of resistance a. loss of an outer membrane protein (D2) which is necessary for imipenem to reach its PBP target site b. destruction by beta-lactamases

VII. CLINICAL USES Carbapenems are excellent choices for infections due to resistant pathogens or for infections with multiple organisms involved (eg: mixed, aerobic/anaerobic bacteria) for which more than 1 antibiotic is required. Carbapenems are considered one of the drugs of choice for hospitalacquired Enterobacter.

These situations are likely to be encountered in patients who are hospitalized (or recently hospitalized), have recently received antibiotics, or who are immunocompromised.

1. Intra abdominal infections. 2. Obstetric/gynecologic infections. 3. Respiratory tract infections. a. Hospital-acquired pneumonia (including aspiration). 4. Bacteremia. 5. Serious skin and soft tissue infections. 6. Bone and joint. 7. Complicated UTI. Carbapenems should not be used for infections in which an antibiotic with a more narrow spectrum of activity would suffice. VIII.SPECIFIC AGENTS 1. Imipenem/cilastatin (PrimaxinR). IV/IM formulations. Allergic reactions (<3%). Drug fever, pruritus, rash, urticaria. There is cross-reactivity with penicillins. Seizures (0.4-1.5%). Risk factors include underlying central nervous system disorders (stroke, seizures), renal dysfunction in patients in whom the dose was not modified. Nausea/vomiting (1%) particularly with rapid infusions.

2. Meropenem (MerremR). IV formulation. May also be administered as bolus (over 5 minutes) or as a 15-30 minute infusion. Compared to imipenem, has the potential for fewer seizures when given to children with meningitis. http://www.uic.edu/pharmacy/courses/pmpr342/itokazu/carbapenems.html

AMINOGLYCOSIDES Gail Itokazu, Pharm.D

Goals and Objectives.

By the end of the lecture the student should be able to discuss the following about aminoglycoside antibiotics: 1. Describe their mechanism of action and pharmacologic properties. 2. Describe their spectrum of activity. 3. Describe their major side effects and drug interactions. 4. Discuss their use in the clinical setting. I. BACKGROUND Aminoglycoside antibiotics have an essential six-membered ring with amino-group substitutions, thus the name aminocyclitol. They have excellent activity against aerobic gramnegative bacteria frequently seen in hospital-acquired infections. However, their two major toxicities are nephrotoxicity and ototoxicity. II. MECHANISM OF ACTION & PHARMACOLOGIC PROPERTIES 1. Interferes with bacterial protein synthesis by binding to the 30S ribosomal subunit. An oxygen-dependent transport system is necessary for aminoglycosides to reach their target site; the transport system is inhibited by divalent cations (Ca++, Mg++), low pH, anaerobiasis, and hyperosmolarity. 2. Rapidly bactericidal. 3. Concentration-dependent bactericidal activity, which means that the rate and extent of bacterial killing increases as drug concentrations increase. 4. Post-antibiotic effect (ie): continued killing of bacteria despite antibiotic levels below the MIC of the organism. These pharmacodynamic properties (concentration-dependent killing and post-antibiotic effect is the rationale for once daily dosing of aminoglycosides.

III. PHARMACOKINETICS

1. Absorption. Poor oral absorption. Intramuscular absorption is good. Peak blood levels are achieved within 0.5-1.5 hours. 2. Distribution. Urine, kidney, endolymph, and perilymph of the inner ear. Reasonable concentrations are achieved in bone, synovial fluid, and peritoneal fluid. Penetration into the central nervous system is poor, thus although controversial, intrathecal or intraventricular administration is sometimes tried. Low concentrations achieved in bronchial secretions. 3. Elimination. Glomerular filtration by the kidneys accounts for almost all (99%) of the elimination. Aminoglycosides are removed by peritoneal and hemodialysis. Appropriate references should can be consulted for specific dosage reductions for various degrees of renal dysfunction. DOSE 1. Conventional. The goal of conventional dosing of aminoglycosides is to achieve peak drug levels between 4-10mcg/ml and trough concentrations less than 2.0mcg/ml. Higher levels are used for serious infections or infections caused by resistant bacteria, while lower levels were generally used for less serious infections, infections at sites where aminoglycosides are highly concentrated (eg: urinary tract) or when used in combination with other antibiotics for synergy. Dose: (gentamicin, tobramycin, netilmicin) 1-2mg/kg (lean body weight) hours in patients with normal renal function. Amikacin: 5-7.5mg/kg (lean body weight) Q8-12 hours in adults with normal renal function. Dosage adjustments are necessary in patients with renal dysfunction and who are obese. 2. Once daily dosing. A single daily dose (4-7mg/kg of gentamicin, tobramycin) is administered once daily. Since aminoglycosides display concentration dependent bactericidal activity and a post-antibiotic effect, these traits would theoretically provide for a more effective and less toxic regimen. Various nomograms are available for oncedaily dosing of aminoglycosides. There is a lack of data on the efficacy and safety of once-daily dosing of aminoglycosides in certain patient populations and certain types of infections. V. SPECTRUM OF ACTIVITY

Aminoglycosides are useful for infections caused by aerobic gram-negative bacilli, particularly the more resistant bacteria associated with hospital-acquired infections. While aminoglycosides are also active against aerobic gram-negative bacilli that cause community-acquired infections, their toxicities and the availability of other less toxic antimicrobials would not make them the drugs of choice for these infections.

1. Aerobic gram-negative bacilli. Very active, including Enterobacteriaceae (Escherichia coli, Klebsiella, Proteus), Pseudomonas aeruginosa, Acinetobacter, Providencia. Minimally active against Hemophilus. 2. Gram-positive aerobes. Though active against Staphylococci, Streptococci (eg: Enterococci, Group B streptococci, viridans streptococci) aminoglycosides are not the preferred agents. Aminoglycosides (particularly gentamicin, streptomycin) may be used in combination with cell-wall active drugs such as beta-lactams and vancomycin forsynergy against Staphylococci and Streptococci. (see gram-positive bacteria listed above). Importantly, only low levels of aminoglycoside (peak levels of 3-4mcg/ml and trough levels less than 1mcg/ml) are generally recommended when used for synergy. 3. Anaerobes are not susceptible because they lack the necessary system that transports aminoglycosides to their target site. 4. Other. Mycobacterium tuberculosis (amikacin, streptomycin) and Mycobacterium-avium intracellulare (amikacin). VI. RESISTANCE Resistant aerobic gram-negative bacilli to aminoglycosides are problematic in some areas. Cross-resistance between aminoglycosides is not always complete. 1. Mechanisms of resistance a. aminoglycoside modifying enzymes that inactivate the aminoglycoside 1. adenyltransferase --> adenylation of a hydroxyl group 2. acetyltramsferase --> acetylation of an amino group 3. phosphotransferase --> phosphorylation of a hydroxyl group Amikacin is less susceptible to aminoglycoside-modifying enzymes because of protective side chains, and therefore may still be useful when resistance to gentamicin or tobramycin develops. b. altered ribosome binding sites

c. altered aminoglycoside uptake, cross resistance to all aminoglycosides occurs. SIDE EFFECTS/PRECAUTIONS 1. Nephrotoxicity is a major toxicity (5-10%). Risk factors for nephrotoxicity include prolonged duration of therapy, increased age, preexisting renal insufficiency, recent aminoglycoside therapy, concurrent use of other nephrotoxins (eg: amphotericin b, vancomycin, others), volume depletion, liver disease. Toxicity is due to accumulation of aminoglycosides in proximal tubular cells of the kidney, and is usually reversible since proximal tubular cells can regenerate. Some studies have suggested than netilmicin and tobramycin are less nephrotoxic than gentamicin; however, other studies have been unable to find a difference between aminoglycosides. 2. Ototoxicity, including vestibular (1-3%) and auditory (2-14%) is a major toxicity and is usually irreversible, and can occur after the end of treatment. Risk factors for ototoxicity include dose and duration of therapy, repeated exposure to aminoglycosides, loop diuretics, vancomycin, hypovolemia, liver dysfunction, increased age, higher blood levels, renal impairment. Clinical symptoms of cochlear toxicity include tinnitus; and of vestibular toxicity, headache, nausea, and vomiting. 3. Neuromuscular blockade may be problematic particularly in situations where neuromuscular transmission is already compromised (eg: myasthenia gravis, administration of D-tubocuare, succinylcholine) is eversed by intravenous calcium gluconate.

IV. DRUG INTERACTIONS 1. Penicillins. Coadministration of aminoglycosides with penicillin result in inactivation of the aminoglycoside. This interaction may be minimized by not drawing aminoglycoside blood levels immediately after administration of the penicillin. 2. Heparin Heparin will also decrease the measured aminoglycoside blood levels. Management includes proper flushing of intravenous lines containing heparin before drawing aminoglycoside blood levels. VII. CLINICAL USES Aminoglycosides are excellent agents for infections due to aerobic gram-negative bacteria, particularly those associated with hospital-acquired infections. They are commonly used in

combination with cell-wall active antibiotics (eg: beta-lactams) because combinations such as these are generally synergistic against aerobic gram-negative bacilli (eg: Pseudomonas aeruginosa, Enterobacteriaceae). 1. Empiric therapy for serious or life-threatening infection, or infection that is presumed to be due to resistant aerobic gram-negative bacilli. These circumstances are likely to be encountered in patients who are hospitalized patients, have recently been hospitalized, have recently received antibiotics, or are immunocompromised.

Septicemia. Intraabdominal infections. In combination with other antibiotics active against anaerobes. Activity of aminoglycoside may be limited by: 1) anaerobic environment and low pH in an abscess, 2) necrotic tissue that may contain divalent cations (see section on mechanism of action. Complicated urinary tract infections. Complicated, skin and soft tissue infections (in combination with other appropriate antibiotics (eg:diabetic ulcer). Endocarditis. When used in combination with a cell-wall active drug (eg: beta-lactam, vancomycin) for endocarditis due to gram-positive cocci (Staphylococci, Enterococci, Viridans streptococci), low levels (peak 3-4mcg/ml, and trough <1.0 mcg/ml) are generally recommended. Osteomyelitis/septic arthritis. Lower respiratory tract. (eg: pneumonia), although the low pH of bronchial secretions may inhibit the activity of aminoglycosides.

VIII.SPECIFIC AGENTS 1. Streptomycin. IM formulation. Streptomycin may be obtained by calling the pharmaceutical company Roerig, a division of Pfizer Incorporated. Uses include part of a combination regimen for Mycobacterium tuberculosis (TB), in combination with a cellwall active antibiotic (eg: penicillin) for Enterococcal infection, tularemia, and brucellosis. Nephrotoxicity is less common compared to other aminoglycosides. 2. Gentamicin (GaramycinR). IV/IM formulation. 2-4 times the bactericidal activity of tobramycin against Serratia marcescens. 3. Tobramycin (NebcinR). IV/IM formulation. Generally 2-4 times more active than gentamicin against Pseudomonas aeruginosa. 4. Netilmicin (NetromycinR). Less active against either tobramycin or gentamicin against Pseudomonas aeruginosa. It is not clear if netilmicin is associated with less ototoxicity. 5. Neomycin sulfate (Mycifradin, Myciguent). PO/topical formulations. Oral neomycin (plus oral erythromycin) is used for bowel decontamination prior to abdominal surgery. 6. Paromomycin (HumatinR). PO formulation. Used for parasitic infections and Cryptosporridiosis in HIV patients.

http://www.uic.edu/pharmacy/courses/pmpr342/itokazu/aminoglycosides.html

GLYCOPEPTIDE Gail Itokazu, Pharm.D Goals and Objectives.

By the end of the lecture the student should be able to discuss the following about glycopeptide antibiotics: 1. Describe their mechanism of action and pharmacologic properties. 2. Describe their spectrum of activity. 3. Describe their major side effects and drug interactions. 4. Discuss their use in the clinical setting. 5. Know when it is appropriate to use the intravenous versus the oral preparations of vancomycin.

Required reading. The goal of this reading is to reinforce the clinical application of gylocopeptide antibiotics. Nosocomial and Device-related Infections, Chapter 118, pages 2387-2399. Pharmacotherapy Pathophysiologic Approach, 3rd Edition. Editors: Dipiro JT et al. I. BACKGROUND Introduced in 1956 for the treatment of penicillin-resistant Staphylococci, vancomycin's toxicity as well as the introduction of penicillinase-resistant glycopeptide antibiotics soon made vancomycin a less useful agent. However, the emergence of methicillin-resistant Staphylococci gave vancomycin an important role in the treatment of infectious diseases. II. MECHANISM OF ACTION & PHARMACOLOGIC PROPERTIES 1. Inhibits cell wall synthesis by binding to the D-alanyl-D-alanine terminus of cell wall precursor units. There is no competition between penicillin and vancomycin for binding sites. 2. Bactericidal.

III. PHARMACOKINETICS

1. Absorption. Poor oral absorption and large quantities are found in stool. Detectable blood levels may occur in patients with severe inflammatory bowel disease and renal insufficiency. 2. Distribution. Urine, kidney. Penetration into the cerebral spinal fluid is erratic. 3. Elimination. Renal clearance via glomerular filtration accounts for the majority of elimination. Appropriate references should be consulted for specific dosage reductions for various degrees of renal dysfunction. 1. Though the value of vancomycin blood levels is controversial and being reevaluated, some clinicians may have the following goals: peak levels of 20-40mcg/ml and trough levels less than 10mcg/ml has traditionally been suggested. However, there is a lack of data to support these therapeutic goals.

V. SPECTRUM OF ACTIVITY Vancomycin is active against gram-positive bacteria including Staphylococci, Streptococci (eg: Enterococci, Group B streptococci, Streptococcus pneumoniae, penicillin-resistant Streptococcus pneumoniae, Corynebacterium JK, Bacillus species, Listeria, and Clostridium difficile. VI. RESISTANCE Until the late 1980's, vancomycin could be counted upon to be effective for infections caused by gram-positive bacteria such as Staphylococci and Streptococci (eg: Enterococcus). However, vancomycin-resistant Enterococci is emerging as an important worldwide problem as there are no reliable, alternative antimicrobial therapies for these organisms. 1. Mechanisms of resistance a. altered binding to vancomycin target site

VII. SIDE EFFECTS/PRECAUTIONS The earliest preparations of vancomycin contained impurities which were associated with significant toxicities (eg: nephrotoxicity). The purified preparations available today are much more tolerable, though toxicities still exist. 1. Infusion related reactions referred to as the "red man syndrome" occurs when vancomycin is infused to rapidly. Symptoms of the "red man syndrome" are tingling and flushing of the face, neck, and thorax, and hypotension. The mechanism of this

reaction is thought to be release of histamine. Slowing the infusion rate to over 1 hour is tolerated by most patients. 2. Nephrotoxicity is uncommon with the purified preparations available today; however, toxicity is enhanced when used concomitantly with aminoglycosides. 3. Ototoxicity has been associated with blood levels of 60-100mcg/ml. 4. Neutropenia generally occurs during long term therapies such as for osteomyelitis or endocarditis. IV. DRUG INTERACTIONS 1. Heparin administered concomitantly with vancomycin may inactivate vancomycin, and has been associated with therapeutic failure.

VII. CLINICAL USES Intravenous vancomycin is generally reserved for situations when other antibiotics that are usually used for gram-positive infections cannot be used (eg: 1) beta-lactam-resistant grampositive infections, 2) allergies to beta-lactams). Resistant pathogens are likely to be encountered in hospitalized patients with intravenous catheters, injection drug users. Types of infections include:

endovascular/endocarditis skin and soft tissue infections osteomyelitis/septic arthritis lower respiratory tract (eg: hospital acquired pneumonia) septicemia/bacteremia

2. Specific pathogens. 1. These bacteria are also referred to as methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE), respectively. If infection fails to respond to vancomycin alone, gentamicin, rifampin or both have been used to achieve a synergistic bactericidal activity. However, antagonism may occur with some of these combinations. 2. Penicillin-resistant Streptococcus pneumoniae remain susceptible to vancomycin. 3. Enterococci that are resistant to ampicillin (or penicillin).

III.SPECIFIC AGENT

1. Vancomycin (Vancocin, Vancolid). IV formulation. Intravenous infusion should be over at least 1 hour to minimize the risk for "red man syndrome."Should not be administered via intramuscular injections as this is very irritating.

2. Vancomycin HCL Capsules (Vancocin HCL Pulvules). PO formulation, 125mg capsules. For pseudomembranous colitis. Because of cost and the risk of selecting out for vancomycin-resistant gram-positive bacteria, oral metronidazole is the drug of choice for Clostridium difficile colitis in most circumstances. http://www.uic.edu/pharmacy/courses/pmpr342/itokazu/glycopeptide.html

QUINOLONES Gail Itokazu, Pharm.D Goals and Objectives.

By the end of the lecture the student should be able to discuss the following about quinolone antibiotics: 1. Describe their mechanism of action and pharmacologic properties. 2. Describe their spectrum of activity. 3. Describe their major side effects and drug interactions. 4. Discuss their use in the clinical setting.

I. BACKGROUND Nalidixic acid was the first member of the quinolone class of antimicrobials described in 1962. However, its limited spectrum of activity and the rapid development of resistance limited its usefulness. In the 1980's, modification of the quinolone ring including addition of a fluorine at position 6 (hence the name fluoroquinolone) led to agents with: 1) an increased antibacterial spectrum, and 2) improved pharmacokinetic properties. The terms fluoroquinolone and quinolone will be used interchangeably. II. MECHANISM OF ACTION & PHARMACOLOGIC PROPERTIES 1. Inhibits bacterial DNA synthesis by interfering with DNA gyrase (bacterial topoisomerase II), which is an enzyme necessary for DNA replication. 2. Rapidly bactericidal. 3. Concentration-dependent bactericidal activity, which means that the extent of bacterial killing increases as drug concentrations increase. 4. Post-antibiotic effect is seen for some aerobic gram-positive and negative bacteria; the clinical significance of this finding is unknown. III. PHARMACOKINETICS 1. Absorption. Well absorbed after oral administration (50% to >95%). Absorption of ciprofloxacin and ofloxcin result in blood levels comparable to their intravenous preparations. Thus, oral dosage formulations (and not the parenteral formulations) should be used if the patient is able to take oral medications.

2. Distribution. Urine, kidney, prostate tissue, lung, bone, stool, neutrophils, macrophages. Given this tissue distribution, the fluoroquinolones are very useful for the management of infections in these areas of the body. 3. Elimination. The kidneys are an important route of elimination; however the extent of elimination by the kidneys varies between agents. Appropriate references should be consulted for specific dosage reductions for various degrees of renal dysfunction. Fluoroquinolone Pharmacokinetics Fluoroquinolone(a) Dose(b) F(c) Renal Effect of Food on Oral Absorption Norfloxacin 400mg po Q12 35-70% 27% may decrease(f) 250-750mg po Q12 Ciprofloxacin 70% 29% ---(g) 200-400mg IV Q12(e) 200-400mg po Q12 Ofloxacin 98% 70% slight decrease(h) 200-400mg IV Q12 Enoxacin 200-400mg po Q12 88% 44% decreased Lomefloxacin 400mg po Q24 >95% 66% a=quinolones available in the United States. b=when dosage range is given, the dose will depend in part, on the type and severity of infection. c=bioavailability. d=renal elimination. e=AUCs of the 400mg IV dose and 500mg oral dose are similar. AUCs of 200mg IV dose and 250mg oral dose are similar. f = recommended to take 1 hr before or 2 hr after meals. g=may take without regard to meals, however the manufacturer recommends the ideal time is 2 hrs after meals. h=manufacturer does not recommend taking with food, but since the rate and extent of absorption is only slightly decreased, can usually be taken without regard to meals.

V. SPECTRUM OF ACTIVITY Fluoroquinolones are useful for infections caused by gram-negative bacilli. However currently marketed drugs in this county have only moderate activity against gram-positive bacteria and are therefore not the drugs of choice for infections caused by these bacteria. The currently available quinolones in the United States have no clinically useful anaerobic activity. 1. Gram-positive bacteria. Moderate activity against Streptococci and Staphylococci including some methicillin-resistant Staphylococci, although resistance to methicillinresistant Staphylococci is now more frequent to quinolones. 2. Gram-negative bacilli. Excellent activity against pathogens seen in hospital-acquired infections such as the Enterobacteriaceae (Escherichia coli, Klebsiella species, Enterobacter species); community-acquired respiratory infections (Hemophilus

influenzae and Moraxella catarrhalis);gastrointestinal infections (Salmonella, Shigella, Campylobacter, and Vibrio species) and sexually transmitted diseases (Neisseria gonorrhea and Chlamydia trachomatis). Ciprofloxacin is the most active quinolone against Pseudomonas aeruginosa. Other differences between quinolones for specific organisms exist and will be discussed under the individual agents. 3. Other. Some quinolones are used in combination with other antimycobacterial drugs for the treatment of Mycobacterium tuberculosis andMycobacterium-aviumintracellulare. VI. RESISTANCE Clinically significant resistance to Fluoroquinolones is an increasing problem worldwide. Overuse and exposure to quinolones are important risk factors for the emergence of resistance. Pseudomonas aeruginosa and Staphylococci are pathogens where resistance is becoming more commonplace. 1. Mechanisms of resistance a. alterations in DNA gyrase b. decreased permeability.

SIDE EFFECTS/PRECAUTIONS 1. Safety and efficacy in children <18 years has not been established and animal studies have demonstrated destruction to cartilage tissue. Specific literature should be consulted when the benefit of using quinolones in children outweighs the risk of using these agents. 2. Should not be used in pregnant or nursing women. 3. Tendon rupture, particularly the Achilles tendon has been reported. Quinolones should be discontinued at the first sign of possible tendon rupture (eg: pain, inflammation) and to refrain from exercise until the diagnosis of tendinitis is excluded. 4. Intravenous ciprofloxacin may cause irritation at the infusion site if the drug is infused over less than 60 minutes or a small peripheral vein is used. IV. DRUG INTERACTIONS 1. Cation-containing compounds. Co-administration of fluoroquinolones with cationcontaining compounds (eg: aluminum, magnesium, calcium, zinc, iron, sucralfate, the buffer in DDI ) results in the formation of cation-quinolone complexes which are poorly absorbed. Concurrent administration of nutritional supplements have also been found to decrease the absorption of quinolones because they may contain the divalent cations zinc and iron. Therapeutic failure may result from this significant drug interaction.

*DDI or dideoxyinosine is used to treat HIV infection. Management of Interaction: Separate administration of quinolone and cation-containing compound. Use alternative therapies such as histamine blockers instead of antacids when appropriate. 2. Theophylline/Caffeine. By inhibiting the microsomal P450 enzymes involved in the metabolism of theophylline, increased concentrations of theophylline may occur. The effect on theophylline metabolism varies with the quinolone, enoxacin having the greatest effect (40-65% reduction in theophylline clearance), followed by ciprofloxacin (30% reduction in theophylline clearance), and norfloxacin, ofloxacin, lomefloxacin having the least effect (2-11% increase in theophylline levels). Management of Interaction. Monitor for clinical signs and symptoms of theophylline toxicity (nausea, vomiting, headache, insomnia, restlessness) andmeasure theophylline levels in patients receiving enoxacin or ciprofloxacin. No adjustment should be necessary in patients receiving norfloxacin, ofloxacin, or lomefloxacin. 3. Non-steroids anti-inflammatory drugs (NSAID). Concurrent use of the NSAID fenprofen has resulted in stimulation of the central nervous system (ie:seizures). The mechanism of this interaction may be displacement of the inhibitory neurotransmitter GABA from their receptors in the brain. Management of Interaction: Warn patients of the potential for stimulation of the central nervous system. 4. Warfarin. It is not clear if there is an interaction between warfarin (increase in prothrombin time) or cyclosporine (increase in cyclosporine levels). Close monitoring of prothrombin time and cyclosporine levels should be employed until more conclusive data are available.

VII. CLINICAL USES Fluoroquinolones are effective agents for a variety of infections, including those listed below. However, because of the concern over resistance with indiscriminate use of these agents, in general, fluoroquinolones should be reserved for infections due to bacteria that are resistant to other less expensive antimicrobials or for use in patients unable to tolerate these other antimicrobials. 1. Urinary tract infections. Uncomplicated, complicated urinary tract infections, prostatitis. Only ofloxacin and ciprofloxacin are approved for prostatitis. 2. Sexually transmitted diseases. Neisseria gonorrhea. single doses of ciprofloxacin and ofloxacin can be used for

uncomplicated urethritis, cervicitis, or rectal infections. Reports of fluoroquinoloneresistant gonococci are emerging. Chlamydia trachomatis. Ofloxacin is the only approved quinolone. Chancroid. Ciprofloxacin approved. 3. Gastrointestinal. 4. Respiratory tract. Community-acquired (eg: pneumonia, bronchitis, otitis). Should not be used alone as empiric therapy because of their inadequate activity against Streptococcus pneumoniae, one of the common pathogens in these infections. Quinolones would be effective alternatives when infections are caused by gram-negative bacteria such as Hemophilus influenzae, and Moraxella catarrhalis that are resistant to agents such as amoxicillin, trimethoprim/sulfamethoxazole. Hospital-acquired (eg:pneumonia). Have been effective for gram-negative pneumonia. Aspiration pneumonia. Should not be used because of their lack of activity against anaerobes. Atypical pneumonia (eg: Mycoplasma, Chlamydia, Legionella). Further studies are needed to determine the role of quinolones in these infections. 5. Bone and Joint. Gram-positive bacteria. Although data exists to demonstrate their effectiveness, quinolones are not the drugs of choice because of theirmoderate activity against Staphylococci, and tendency for resistance to develop. Gram-negative bacteria. Convenient alternative for long-term, outpatient therapy. 6. Skin and soft tissue. Not the drugs of choice because of moderate activity against gram-positive bacteria. For mixed infections with gram-positive and gram-negative bacteria, a quinolone can be combined with an agent such as clindamycin. Clindamycin is active against gram-positive bacteria and anaerobes.

VIII.SPECIFIC AGENTS 1. Norfloxacin (NoroxinR). Poorly absorbed, and should not be used for infections outside the urinary tract. 2. Ciprofloxacin (CiproR). Most potent quinolone against Pseudomonas aeruginosa, a common cause of hospital-acquired infections. May be used as part of a combination regimen for Mycobacterium-avium-intracellularae infections in HIV patients. An ophthalmic preparation (Ciloxan(R)) for bacterial keratitis and conjunctivitis is available.

3. Ofloxacin (FloxinR). Similar spectrum of activity to ciprofloxacin, but is at least 4-fold less potent than ciprofloxacin against Pseudomonas aeruginosa. Ofloxacin is the most potent quinolone against Chlamydia trachomatis, a pathogen causing sexually transmitted diseases. An ophthalmic preparation of ofloxacin has been recently marketed. 4. Enoxacin (PenetrexR). Overall is less active against gram-negative aerobes than is ciprofloxacin and ofloxacin. Absorption is decreased in an alkaline environment as may occur with simultaneous administration of drugs that lower gastric acidity. Has the most potential to reduce theophylline clearance. 5. Lomefloxacin (MaxaquinR). Long half-life permits once daily dosing.Postmarketing surveillance has found this quinolone to be a more frequent cause of photosensitivity than was initially suspected. http://www.uic.edu/pharmacy/courses/pmpr342/itokazu/quinolones.html

MACROLIDES, TETRACYCLINES, AND SULFONAMIDES Paula A. Teichner, Pharm.D.

Goals and Objectives: By the end of this lecture, the student should be able to:

1. Describe the mechanism of action for the marcolides, tetracyclines and sulfonamides. 2. List the spectrum of activity for the macrolides, tetracyclines, and sulfonamides. 3. List the pharmacokinetic parameters and the major clinical indications for the macrolides, tetracyclines and sulfonamides. 4. Describe the major adverse effects and drug interactions for the macrolides, tetracyclines and sulfonamides. 5. Describe the differences between erythromycin and the newer macrolides (advantages and disadvantages). 6. Devise a rational treatment plan for use of the macrolides, tetracyclines and sulfonamides based on the clinical indication and patient specific characteristics.

Required Reading: Harrison's Principles of Internal Medicine. 12th Edition. 1991.Chapter 85. Pages 489-492. MACROLIDES ERYTHROMYCIN A. MECHANISM OF ACTION Generally considered bacteriostatic, however may be bactericidal under certain circumstances. Inhibits bacterial RNA-dependent protein synthesis. Macrolides bind to the 50S subunit of the 70S ribosome, which causes dissociation of t-RNA from the ribosome inhibits protein synthesis. B. SPECTRUM OF ACTIVITY Gram positive aerobes - Active against streptococcus pneumoniae and other streptococci, staphylococci, and corynebacterium diphtheriae.

Gram negative aerobes - Active against Legionella pneumophila, Neisseria gonorrhoeae, Moraxella catarrhalis, Bordetella pertussis. Enterobacteriaceae are resistant. Anaerobes - Bacteroides fragilis are usually resistant. Other - Mycoplasma pneumoniae, chlamydia trachomatis/pneumoniae, Treponema pallidum. C. PHARMACOKINETICS Absorption - Erythromycin base is subject to destruction by gastric acid and is poorly soluble in water. Newer oral preparations have acid-resistant coating to prevent drug dissolution until drug reaches the small bowel. Generally better absorption in the fasting state. Several different salt forms available to make drug more soluble and acid stable. Distribution - Penetrates most tissues except the brain and CSF. High concentrations achieved in macrophages and PMNs. Persists in tissue longer than serum. Metabolism/Excretion - Concentrated by the liver, excreted in bile and feces. Dosage reduction not necessary in patients with renal failure.

D. CLINICAL USES FOR ERYTHROMYCIN Most common uses: 1. Community-acquired Pneumonias - where atypical pathogens such as Mycoplasma pneumoniae and Legionella pneumophilia are common. 2. Chlamydial infections (ie. chlamydia pneumoniae pneumonia or chlamydia trachomatis pelvic infections, especially in pregnancy.) 3. Bordetella pertussis Other uses:

1. 2. 3. 4. 5.

Streptococcal infections in patients with PCN allergy Minor staphylococcal skin infections Campylobacter gastroenteritis Syphilis in pregnancy Prophylaxis of bacterial endocarditis

E. ADVERSE DRUG REACTIONS 1. GI upset - nausea, vomiting, diarrhea

2. Thrombophlebitis - with parenteral administration. Can be decreased by diluting in 250 ml of fluid and slowing the rate of infusion. 3. Hypersensitivity reactions - fever, skin rash, eosinophilia 4. Cholestatic Hepatitis - occurs with estolate preparation, mainly in adults. DO NOT USE ESTOLATE IN ADULTS. 5. Ototoxicity - associated with large doses, especially in the elderly or patients with underlying renal insufficiency. F. DRUG INTERACTIONS Erythromycin inhibits cytochrome P450 enzyme system, and can decrease the clearance and increase the toxicity of theophylline, carbamezepine, cyclosporine, terfenadine, triazolam, etc. Erythromycin can also increase the hypoprothrombinemic effect of warfarin. Erythromycin may increase the bioavailability of digoxin which may increase the serum levels and cause toxicity. G. DRUG PREPARATIONS AND DOSING Oral - Several oral preparations are available: base, stearate salt, ethylsuccinate ester and estolate form. Available as capsules and film-coated tablets. Dose is 250-500 mg po q6 hours, 333 mg po q8 hours or 500 mg po q12h depending on the severity of illness and the indication. Parenteral - Available as lactobionate or gluceptate salt. Used for patients with serious infections or patients unable to take oral medications. Dose is 250-1000 mg iv q6h. Must be given as an intravenous infusion. DO NOT give IM secondary to pain upon injection. CLARITHROMYCIN (Biaxin) AND AZITHROMYCIN (Zithromax) A. BACKGROUND Clarithromycin is a 14-member structure (macrolide), similar to erythromycin, while azithromycin is a 15-member lactone ring (azalide). Both drugs were approved for use in 1991. Compared to erythromycin, these agents have better absorption, a longer t1/2, fewer GI side effects, better tissue penetration and a broader spectrum of activity. The disadvantage is the high cost compared to erythromycin. B. SPECTRUM OF ACTIVITY Gram positive aerobes - Clarithromycin is 2-4 times more active in vitro than erythromycin against most streptococci and staphylococci. Azithromycin is 2-4 timesless active against the gram positives compared to erythromycin.

Gram negative aerobes - Azithromycin has greater activity than both erythromycin and clarithromycin against Moraxella catarrhalis and Hemophilus influenzae. The active metabolite of clarithromycin, 14-hydroxyclarithromycin, is slightly more active against M. catarrhalis and H. influenzae than the parent drug, and the combination of the two provides additive or synergistic activity. Other - Both azithromycin and clarithromycin are more active than erythromycin against chlamydia spp. and Legionella pneumophilia. Clarithromycin has good activity against Helicobacter pylori. Both clarithromycin and azithromycin are active against Toxoplasma gondii and atypical mycobacteria such as Mycobacterium avium.

C. PHARMACOKINETICS PHARMACOKINETICS CLARITHROMYCIN Bioavailability (%) 55%. Take with or without food Distribution In tissues In liver, metabolites renally Metabolism eliminated T1/2 (hours) 5-7 hours Dosage Adjustment in CrCl < 30 ml/min RF AZITHROMYCIN 37%. Take on empty stomach Extensively distributed in tissues. Most unmetabolized and excreted in feces 68 hours. T1/2 in tissue is 2-4 days. Not required

D. INDICATIONS FOR USE OF CLARITHROMYCIN & AZITHROMYCIN 1. Upper and lower respiratory tract infections (ie. pharyngitis, sinusitis, bronchitis and pneumonia) - to cover pathogens usually seen in these infections such as S. pneumoniae, H. influenzae, M. pneumoniae, M. catarrhalis, etc. 2. Skin infections - uncomplicated 3. Non-gonococcal urethritis and cervicitis due to Chlamydia trachomatis (Azithromycin only). 4. Mycobacterium Avium Complex in patients with AIDS - Clarithromycin is approved for treatment, and must be used in combination with at least one other drug. Both clarithromycin and azithromycin are approved for MAC prophylaxis. 5. Helicobacter pylori - Clarithromycin E. ADVERSE DRUG REACTIONS 1. GI - occur less frequently than with erythromycin. Most common are nausea, diarrhea, abdominal pain and taste disturbance. GI side effects may be more common in patients with HIV.

2. Hepatotoxicity - abnormalities in liver function tests occur uncommonly. F. DRUG INTERACTIONS Clarithromycin - may increase levels of theophylline (by ~20%) and carbamezepine. May increase the cardiovascular toxicity of terfenadine and astemizole. May increase serum concentrations of rifabutin. Azithromycin - does NOT appear to interact with the cytochrome P450 system, thereby allowing other drugs to be metabolized without inhibition. No known drug interaction with theophylline, carbamezepine or terfenadine. ? effect on warfarin. Food decreases the absorption separate from meals. G. DRUG PREPARATIONS AND DOSING Clarithromycin Only availabe po as 250 mg and 500 mg tablets Dose is 250-500 mg po q12 hours depending on infection being treated. Azithromycin Available po as 250 mg capsules, 600 mg tabs and 1 gram oral suspension dose packet. Dose for respiratory tract infections and skin infections is 500 mg x 1 dose (2 capsules), followed by 250 mg po x 4 more days (Total therapy = 5 days). Can be given as a shorter treatment course due to prolonged tissue half-life. For treatment of non-gonococcal urethritis/cervicitis, given as a single 1 gram oral dose. H. COST (Cost per treatment course in retail setting) Erythromycin (500 qid) Clarithromycin (500 bid) Azithromycin (250 qd) $12.29/10 day course $62.29/10 day course $39.29/5 day course I. Comparison Between Newer Macrolides and Erythromycin Advantages of Clarithro and Azithro over Erythromycin

Decrease GI side effects Increase Spectrum of activity Fewer drug interactions (azithromycin) Less frequent dosing (may increase compliance) Better tissue penetration

Disadvantages Increase COST! DIRITHROMYCIN (Dynabac) New macrolide with spectrum of activity similar to that of erythromycin. Approved in October 1995 for once-daily dosing (500 mg po qd). Take with food. Available as 250 mg tablets. Not recommended for use in fections where H. influenzae is suspected. TETRACYCLINES A. MECHANISM OF ACTION Tetracyclines are primarily bacteriostatic. They enter the bacteria by diffusion and once inside, bind reversibly to the 30S ribosomal unit >> block addition of amino acids to the growing peptide chain. B. SPECTRUM OF ACTIVITY Gram positive aerobes - Many gram (+) cocci are susceptible, but many strains of staphylococci, streptococci, and pneumococci are developing resistance. Therefore, the tetracyclines are NOT the drugs of choice for most gram positive aerobes. Gram negative aerobes - Pseudomonads and many Enterobacteriaceae are resistant. Urinary concentrations are adequate for community-acquired E. coliinfections. Anaerobes - Increased incidence of Bacteroides fragilis resistance to the tetracyclines. Therefore they are not the drugs of choice for suspected or documented B. fragilis infections. Other - Active against Mycoplasma pneumoniae, Chlamydia trachomatis, Borellia burgdorferi, and Rickettsiae.

C. CLASSIFICATION

CLASSIFICATION

SERUM T1/2 GI ABSORPTION (%) 9 hours 58 Short Acting (oxytetracycline, tetracycline) 8 hours 77 Intermediate (demeclocycline) 12 hours 66 18 hours 93 Long Acting (doxycycline, minocycline) 16 hours 95

D. PHARMACOKINETICS Absorption occurs primarily in the proximal small bowel. Improved when taken in the fasting state (less important for doxycycline and minocycline). Peak levels 1-3 hours post- dose. Absorption is impaired when taken concurrently with other divalent and trivalent cations such as calcium and magnesium (antacids, milk). Distribution into the lungs, liver, kidney, sputum. All tetracyclines are concentrated in the liver and excreted into bile. Long-acting TCNs have enhanced lipid solubility better tissue penetration. Excretion - primarily via the kidneys. T1/2 prolonged in renal failure except for doxycycline. The TCNs are not recommended for use in renal failure (except doxycycline).

E. CLINICAL USES FOR THE TETRACYCLINES Drugs of Choice For: 1. Rickettsial Infections (Rocky Mountain spotted fever, etc). 2. Sexually Transmitted Diseases (STDs)/ Pelvic Inflammatory Disease (PID) - Chlamydia trachomatis is common pathogen in these infections and tetracycline is drug of choice. 3. Atypical Pneumonias Caused by organisms such as Mycoplasma pneumoniae and Chlamydia pneumoniae. 4. Lyme Disease (early) - caused by Borrelia burgdoferi. Other Common Uses: 1. Brucellosis 2. Helicobacter pylori 3. Acne 4. Traveller's diarrhea

F. ADVERSE EFFECTS 1. Teeth and Bone - May cause a grey-brown discoloration of the teeth (which is permanent) and enamel hypoplasia. Also may cause depression of skeletal bone growth in the human fetus and children. Not for use in pregnant or lactating women or in children under 8 years of age. 2. Hypersensitivity Reactions - urticaria, morbilliform rashes 3. Photosensitivity 4. Gastrointestinal irritation - Nausea, vomiting, diarrhea

5. Esophageal Ulceration - Can be avoided by taking medication with full glass of water and not prior to bed. 6. Renal Dysfunction - Tetracyclines aggravate pre-existing renal failure by inhibiting protein synthesis. 7. Vestibular Toxicity - Consists of tinnitus, dizziness, light-headedness. Occurs only with minocycline. Reversible after d/c of drug. G. DRUG INTERACTIONS Food decreases absorption of tetracycline. Calcium, magnesium, aluminum, iron- containing products and milk form complexes with the tetracyclines and decrease absorption>>Separate administation time by 2 hours. H. DRUG PREPARATIONS AND DOSING

DRUG HOW AVAILABLE USUAL ADULT DOSE Tetracycline 250, 500 mg caps/tablets 250-500 mg po q6 hours 50, 100 mg caps/tablets Doxycycline 200 mg x 1, 100 mg po/IV q12-24 hours INJ - 100, 200 mg vial 50, 100 mg caps/tablets Minocycline 200 mg x 1, 100 mg po q12 hours INJ - 100 mg vial SULFONAMIDES A. MECHANISM OF ACTION The sulfonamides were the first systemic antibacterial drugs used in humans. Sulfonamides are primarily bacteriostatic, and work by interfering with folic acid synthesis. Sulfonamides competitively inhibit incorporation of PABA (para-aminobenzoic acid) into dihydrofolic acid (an intermediate in the process of folate metabolism)>> inhibit formation of folate which is essential for microorganism cell division. B. SPECTRUM OF ACTIVITY Gram positive aerobes - Are active against Streptococcus pyogenes. Gram negative aerobes - E. coli are usually susceptible, especially at concentrations achieved in the urine. Active against some strains of Neisseria meningitidis. Other - Active against Chlamydia, Toxoplasma and Nocardia species. C. CLASSIFICATION OF SULFONAMIDES

1. Short Acting (sulfisoxazole, sulfadiazine) - soluble in urine. 2. Intermediate Acting - Sulfamethoxazole (Gantanol) Less soluble and excreted more slowly than short acting sulfonamides >> provides higher blood levels. Increased chance of crystalluria >> need to ensure good urine output. 3. Long Acting - No longer recommended secondary to hypersensitivity reactions. D. PHARMACOKINETICS Rapidly absorbed (short and intermediate acting), well-distributed in body. Drug metabolized in the liver and excreted renally via glomerular filtration and tubular secretion. Dosage reduction necessary in renal failure. E. CLINICAL USE OF SULFONAMIDES 1. Uncomplicated UTI - problems with increasing resistance. 2. Toxoplasma gondii - sulfadiazine used in combination with pyrimethamine. 3. Nocardia asteroides F. ADVERSE EFFECTS 1. Hematologic - avoid in patients with glucose 6-phosphate dehydrogenase deficiency >>hemolysis. Can also cause bone marrow suppression >> leucopenia, anemia, or thrombocytopenia. 2. Hypersensitivity reactions - rash, fever, vasculitis, erythema multiforme, Stevens- Johnson syndrome. 3. Kernicterus - Avoid in neonates and during the last trimester of pregnancy. Sulfonamides compete for bilirubin-binding sites and increase levels of unconjugated bilirubin. G. DRUG INTERACTIONS Sulfonamides can increase the activity of warfarin need to decrease dose of oral anticoagulants. Hypoglycemic effect of tolbutamide and chlorpropamide may be increased by sulfonamides.

TRIMETHOPRIM A. MECHANISM OF ACTION

Inhibits the enzyme dihydrofolate reductase, thereby interfering with the conversion of dihydrofolate to tetrahydrofolate, the precursor of folinic acid. B. SPECTRUM OF ACTIVITY See TMP/SMX below C. PHARMACOKINETICS Well absorbed from the GI tract, widely distributed in tissues, primarily excreted unchanged by the kidneys (60-80%). Serum t1/2 9-11 hours and prolonged in renal failure. Dosage adjustment required in renal failure. D. CLINICAL USE 1. Uncomplicated UTIs 2. Pneumocystis carinii pneumonia - in combination with dapsone. E. AVAILABILITY 100, 200 mg tablets. TRIMETHOPRIM-SULFAMETHOXAZOLE [TMP/SMX], (Bactrim, Septra) A. BACKGROUND This compound is also known as co-trimoxazole. This combination inhibits 2 sequential steps of bacterial metabolism (see below). Has 2 theoretical advantages: 1. Decreases chance of developing resistance, and 2. May be synergistic. Available in oral and intravenous formulations. Combination provides ideal blood ratio of 1: 20 for optimal synergy.

B. MECHANISM OF ACTION Sequential inhibition of synthesis of folic acid inhibit DNA production. Folate production is essential for nearly all microorganisms because they cannot extract exogenous folate from their diet, which is in contrast to mammalian cells.

The combination product TMP/SMX is bactericidal and synergistic against many gram positive and gram negative bacteria. C. SPECTRUM OF ACTIVITY

Gram Positive Cocci - Active against Staphylococcus aureus (including some MRSA), S. epidermidis, Streptococcus pneumoniae, and viridans streptococci. Not active against enterococci. Gram Negative Aerobes - Active against most Enterobacteriaceae including E. coli, Enterobacter spp. Hemophilus influenzae, Moraxella catarrhalis, Salmonellaand Shigella spp, Xanthomonas maltophilia. Not active against Pseudomonas aeruginosa. Anaerobes - Not active against anaerobes. Other - Listeria monocytogenes, Pneumocystis carinii and most Nocardia species. D. PHARMACOKINETICS Absorption - Well absorbed from the GI tract. Distribution - Distributes into most tissues; penetrates CSF (~40% of serum levels), pleural and peritoneal fluids. Achieves high concentrations in the prostatic fluid. Elimination - Primarily excreted by the kidneys. When CrCl < 30 ml/minute, needs dosage adjustment. F. CLINICAL USES FOR TMP/SMX (DOSING) 1. Urinary Tract Infections - Acute (1 DS po q12 hours) - Recurrent 2. Pneumocystis carinii pneumonia - treatment and prophylaxis (15 mg/kg/day TMP in doses q6-8 hours. 1 DS po qd or qM,W,F for prophylaxis). 3. Prostatitis (1 DS po q12 hours) 4. Acute exacerbations of chronic bronchitis (1 DS po q12 hours) 5. Sinusitis/Otitis media - good for ampicillin-resistant strains of H. influenzae and M. catarrhalis (1 DS po q12 hours). 6. Salmonella/Shigella 7. Nocardia infections (10-15 mg/kg/day TMP)

G. ADVERSE EFFECTS 1. GI - nausea, vomiting, diarrhea 2. Hypersensitivity reactions - rash more common in AIDS patients (ie. in up to 50% of patients). 3. Hematologic - as above.

4. Teratogenesis and Kernicterus - Avoid in pregnant or lactating women, or infants < 2 months of age. 5. Hepatitis - rare. H. DRUG INTERACTIONS As mentioned above. TMP/SMX may increase levels of phenytoin, methotrexate. Use cautiously in patients receiving other bone marrow suppressive agents, especially in patients with HIV (ex. AZT). I. DRUG PREPARATIONS http://www.uic.edu/pharmacy/courses/pmpr342/teichner/erythro.html