Antiinfective Agents

CHAPTER 9 Antiinfective Agents



I. Diagnosis
A. Identify the organism
1. Gram stain differentiates bacteria based on structure and composition of the layers of the cell wall.
a) Gram positive = purple stain

b) Gram negative = pink stain

2. Culture and sensitivity; serologic testing

B. Laboratory tests
1. Nonspecific tests: white blood cell count with differential

II. Initial treatment strategies
A. Empiric
1. Empiric therapy must be initiated without delay.

2. Empiric therapy is based on likely pathogens suspected but not specifically known.

3. Empiric therapy is altered to more specific therapies based on culture and sensitivity and patient’s disease state.

B. Definitive
1. Microbiologic or serologic diagnosis with susceptibilities known

C. Prophylaxis
1. Before surgery or procedure

2. Immunocompromised patients

III. Common infections
A. Bacteria
• Classification
image Gram-positive cocci (spherical)
image Staphylococcus aureus

image Streptococcus pneumoniae

image Enterococcus faecalis, Enterococcus faecium

image Gram-positive bacilli (rods)
image Clostridium perfringens, Clostridium difficile

image Gram-negative cocci (spherical)
image Neisseria meningitides, Neisseria gonorrhoeae

image Moraxella catarrhalis

image Gram-negative bacilli (rods)
image Escherichia coli

image Klebsiella spp.

image Enterobacter spp.

image Pseudomonas aeruginosa

image Bacteroides fragilis

image Atypical bacteria
image Chlamydia pneumonia

image Mycobacteria pneumoniae

image Legionella spp.

image Spirochetes (spiral)
image Syphilis (Borrelia burgdorferi)

image Lyme disease (Treponema pallidum)

B. Fungal
1. Superficial
• Vulvovaginal candidiasis
image Major pathogen: Candida albicans

• Oropharyngeal and esophageal candidiasis
image Major pathogen: Candida albicans

• Mycotic infections of hair, skin, and nails
image Tinea pedis (“athlete’s foot”)

image Tinea cruris (“jock itch”)

image Tinea corporis (“ring worm”)

image Tinea capitis

image Pityriasis versicolor

image Onychomycosis

2. Invasive
• Candida
image Caused by Candida spp. (C. albicans, C. glabrata, C. tropicalis, C. krusei)

• Aspergillosis
image Caused by Aspergillus spp.

• Histoplasmosis
image Caused by H.capsulatum

• Cryptococcus
image Caused by C. neoformans

• Blastomycosis
image Caused by B. dermatitidis

• Coccidiomycosis
image Caused by C. immitis

C. Virus
• Types of virus that cause human infection:
image Influenza virus

image Cytomegalovirus (CMV)

image Varicella zoster virus (chickenpox, shingles)

image SARS coronavirus (severe acute respiratory syndrome [SARS])

image Herpes simplex (HSV-1 and HSV-2)

image Respiratory syncytial virus (RSV)

image Adenovirus

image Epstein-Barr virus (EBV)

image Human immunodeficiency virus (HIV)

image Hepatitis A, B, C, or others

IV. Antimicrobial treatment (Table 9-1)
A. Penicillins
1. Mechanism of action (MOA): inhibits synthesis of bacterial cell walls; bactericidal

2. Penicillins are classified as β-lactam antibiotics because their structure consists of a β-lactam ring that joins to a thiazolidine ring

3. Highly active against gram-positive cocci (e.g., Streptococcus), gram-positive rods (e.g., Listeria), and gram-negative cocci (e.g., Neisseria)
a) Antistaphylococcal penicillins: nafcillin, oxacillin, cloxacillin, dicloxacillin

b) Broad-spectrum penicillins
(1) Second-generation (amoxicillin, ampicillin): active against most strains of Escherichia coli, Proteus mirabilis, Salmonella sp, Shigella sp, and Haemophilus influenzae

(2) Third- and fourth-generation (carbenicilin, ticarcillin, piperacillin, mezlocillin, azlocillin): Pseudomonas aeruginosa and indole-positive Proteus spp, Enterobacter spp

4. Adverse effects: anaphylaxis, interstitial nephritis, anemia, leukopenia, hepatitis (oxacillin and nafcillin)

B. β-lactamase inhibitors
1. Exhibit no or minimal antibacterial activity of their own

2. Used in combination products with certain penicillins to allow coverage of β-lactamase–producing organisms that would ordinarily not be covered by the particular penicillin (extends antimicrobial spectrum)

3. All agents are irreversible inhibitors of β-lactamases

4. Examples: clavulanic acid, sulbactam, tazobactam
a) Amoxicillin/clavulanic acid (Augmentin®)

b) Ticarcillin/clavulanic acid (Timentin®)

c) Ampicillin/sulbactam (Unasyn®)

d) Piperacillin/tazobactam (Zosyn®)

C. Cephalosporins (Table 9-2)
1. Mechanism of action (MOA): same as penicillins

2. Also β-lactam antibiotics, but composed of a dihydrothiazine and a β-lactam ring

3. In general, each successive generation has broader gram-negative coverage.

4. First generation (cefazolin, cephadrine, cefadroxil, cephalexin, cephapirin): activity against staphylococci, streptococci, and community-acquired Escherichia coli, Klebsiella, and Proteus spp

5. Second generation (cefuroxime, cefoxitin, cefotetan, cefprozil, cefaclor, loracarbef): expanded coverage against enteric gram-negative rods
a) cefuroxime: useful against Haemophilus influenzae

b) cefoxitin, cefotetan: useful against Bacteroides spp

6. Third generation (ceftriaxone, cefotaxime, cefdinir, ceftizoxime, cefoperazone, cefixime, ceftazidime): broadest coverage for enteric, aerobic gram-negative rods, and retain good activity against streptococci other than enterococci; moderate anaerobic activity (not B. fragilis)
a) ceftazidime: useful against Psuedomonas aeruginosa

7. Fourth generation (cefepime): excellent aerobic gram-negative rod coverage including P.aeruginosa; aerobic and gram-positive coverage is similar to third generation
a) Used as empiric therapy for febrile patients with neutropenia

8. Adverse effects: anaphylaxis, interstitial nephritis, anemia, leukopenia
a) Patients should be asked about allergy to penicillins

D. Carbapenems
1. Mechanism of action (MOA): interferes with cell-wall synthesis similar to penicillins and cephalosporins; bactericidal

2. Active against most gram-positive and gram-negative bacteria including anaerobes
a) Unlike imipenem and meropenem, ertrapenem is not effective against Pseudomonas and Enterobacter

3. Useful for Fournier’s gangrene, intra-abdominal infection
a) Do not use for CNS infections due to seizure risk

4. Examples: imipenem, meropenem (Merrem®), ertropenem (Invanz®), doripenem (Doribax®)
a) Imipenem/cilastatin (Primaxin®): used IV and IM only; combined with cilastatin because the action of dehydropeptidase enzymes on imipenem rapidly produces a nephrotoxic and inactive metabolite; cilastatin prevents dehydropeptidase degradation

5. Adverse effects: precipitate seizure activity or confusion particularly in elderly patients or those with seizure disorders; adjust dose in patients with renal impairment because risk is higher with high-dose exposure
a) Meropenem has a lower risk of seizures than imipenem

E. Monobactams (Aztreonam)
1. Mechanism of action (MOA): interacts with penicillin binding proteins; induces formation of long filamentous bacteria; β-lactam ring is isolated; bacteriocidal

2. Excellent activity against gram-negative aerobes including Pseudomonas aeurginosa; no activity against gram-positive aerobes; inactive against all anaerobes

3. Should be reserved for serious gram-negative infections in the lung, bone, urinary tract, or blood

4. Rarely exhibits cross-sensitivity with agents from other classes of β-lactam antibiotics

5. Adverse effects: injection site reactions, nausea, vomiting, diarrhea, rash

F. Gram-positive antibiotics
1. Vancomycin (Vancocin®, Vancoled®)
a) Mechanism of action (MOA): glycopeptides; binds a D-alanyl-D-alanine precursor that is critical for peptidoglycan crosslinking in most gram-positive bacterial cell walls; bacteriostatic for enterococci; bactericidal against other susceptible isolates

b) Active against staphylococci including methicillin-resistant staphylococcus aureus(MRSA), enterococci, streptococci, and Clostridium including C. difficile (when given orally)
(1) Drug of choice for MRSA/MRSE

(2) Enterococci may be vancomycin–resistant (e.g., vancomycin-resistant enterococci, also known as VRE)

c) Acts synergistically with aminoglycosides against susceptible enterococci

d) Usual adult intravenous dose: 1 g over 60 minutes every 12 hours
(1) Give by slow IV infusion

(2) Adjust dose for patients with renal impairment and in patients older than 65 years

(3) Monitor serum levels and adjust dose accordingly
(a) Therapeutic concentrations: peak 20–40 mg/L; trough 5–15 mg/L

e) Adverse effects
(1) Red man syndrome (flushing of the upper body) if given at infusion rates greater than 10 mg/min. Slow infusion over at least 1 hour is recommended to avoid this side effect.

(2) Nephrotoxicity and ototoxicity (often permanent): may be increased when used in combination with aminoglycosides

2. Linezolid (Zyvox®)
a) Mechanism of action (MOA): interrupts bacterial growth by inhibiting the initiation of protein synthesis

b) Activity against gram-positive infections including certain drug-resistant enterococcus, staphylococcus (MRSA), and pneumococcus strains

c) IV and PO forms available

d) Adverse effects: myelosuppression (infrequent), thrombocytopenia, and hypertension (particularly with tyramine-containing foods)

e) Drug interactions: Avoid use with SSRIs due to risk of serotonin syndrome

3. Quinupristin-dalfopristin (Synercid®)
a) Mechanism of action (MOA): dalfopristin blocks early step in protein synthesis; quinupristin blocks a later step; combination is synergistic; bactericidal

b) Active against antibiotic-resistant gram-positive organisms, particularly vancomycin-resistant Enterococcus faecium (VRE)

c) Adverse effects: reversible arthralgias, myalgias, and peripheral venous irritation

d) Drug interactions: significantly inhibits the cytochrome P-450 (CYP) 3A4 enzyme system

4. Others: Daptomycin (Cubicin®)

G. Fluoroquinolones
1. Mechanism of action (MOA): inhibit bacterial DNA gyrase and topoisomerase, which are critical for DNA replication; bactericidal

2. Variable gram-positive activity; extensive gram-negative activity; poor anaerobic coverage; variable atypical activity; all have high activity against Legionella; some are effective against anthrax
a) First generation (quinolones, naldixic acid [NegGram®]): useful for UTI caused by gram-negative rods

b) Second generation (fluoroquinolones, ciprofloxacin [Cipro®], norfloxacin [Noroxin®], enoxacin [Penetrex®]*, ofloxacin [Floxin®]): active against gram-negative aerobes; ciprofloxacin most active against P. aeruginosa
(1) Poor activity against gram-positive cocci and anaerobes

c) Third generation (levofloxacin [Levaquin®], sparfloxacin [Zagam®]*, gatifloxacin [Tequin®]*, grepafloxacin [Raxar®]*): improved coverage of aerobic gram-positive bacteria including streptococci, staphylococci, and enterococci; less activity against gram-negative bacteria than ciprofloxacin; expanded activity against atypical pathogens

d) Fourth generation (trovafloxacin [Trovan®]*, moxifloxacin [Avelox®]): same as third generation plus broad anaerobic coverage

3. Adverse effects: nausea, CNS disturbances, rash, phototoxicity, QTc prolongation
a) Increased risk of developing tendinitis and tendon rupture (class effect)

b) A longer course of treatment (more than 7 days) of gemifloxacin (Factive®) associated with serious rash, especially in post-menopausal women on hormone replacement therapy and in patients younger than 40 years.

c) Many drugs in class no longer available*:
(1) Grepafloxacin* withdrawn from the United States market by the manufacturer due to adverse cardiovascular events (QT prolongation)

(2) Sparfloxacin* withdrawn due to lack of sales

(3) Trovafloxacin* withdrawn due to risk of hepatic toxicity

(4) Gatifloxacin* withdrawn because of an increased incidence of hypoglycemia and hyperglycemia

4. Drug interactions
a) Antacids, calcium, mineral supplements (divalent cations), sucralfate, and select foods may impair the absorption of oral quinolones.

b) Cimetidine and probenecid can inhibit renal tubular secretion of fluoroquinolones that are primarily eliminated through renal excretion (except trovafloxacin).

c) Fluorquinolones can inhibit clearance of xanthine derivatives (e.g., theophylline).

d) Some fluoroquinolones can raise cyclosporine levels (e.g., ciprofloxacin)

e) Increase effect of warfarin

H. Macrolides
1. Mechanism of action (MOA): inhibits protein by binding to 50S subunit of the bacterial ribosome; bacteriostatic

2. Examples: erythromycin (E-Mycin®, Ery-Tab®, Eryc®, Erythrocin® stearate, Ilosone®, Eryped®, EES®, Emgel®), dirithromycin (Dynabac®), clarithromycin (Biaxin®), azithromycin (Zithromax®), telithromycin (Ketek®)

3. Extensive gram-positive activity; drugs of choice for treating Legionella, Chlamydia, and Mycoplasma infections
a) Azithromycin: more effective against H. influenzae, Legionella and Toxoplasma gondii than erythromycin; effective against mycobacterium avium- intercellulare complex (MAC); longer half-life than erythromycin

b) Clarithromycin: more effective against H. influenzae than erythromycin; also effective against MAC; used with other drug for Helicobacter pylori; also useful in Lyme disease; renally eliminated

4. Adverse effects: GI disturbances (nausea, abdominal cramping), abnormalities in liver function tests (LFTs)

5. Drug interactions: metabolized by CYP3A4 (exception of azithromycin); erythromycin and clarithromycin are strong inhibitors of CYP3A4.

I. Tetracyclines
1. Mechanism of action (MOA): binds to 30S ribosomal subunit blocking protein synthesis; bacteriostatic

2. May be used to treat Rickettsia (Rocky Mountain spotted fever), Chlamydia, Mycoplasma, and Spirochete infections (Lyme disease, syphilis); may be effective against for anthrax; used for acne and rosacea
a) Minocycline and doxycycline are more lipid soluble than other tetracycline antibiotics

3. Examples: tetracycline (Sumycin®, Panmycin®, Tetracyn®), doxycycline (Vibramycin®, Doryx®), minocycline (Minocin®)

4. Adverse effects: nausea, photosensitivity; tooth enamel discoloration in children, QTc prolongation

5. Drug interactions
a) Concomitant administration of iron supplements or antacids may impair the oral absorption of tetracyclines.

b) Tetracyclines (particularly doxycycline) may be less effective in patients receiving anticonvulsants like phenytoin and carbamazepine due to induction of hepatic microsomal enzymes.

c) Tetracyclines may reduce the efficacy of oral contraceptives.

d) Tetracyclines may enhance the anticoagulant effect of warfarin.

J. Sulfonamides
1. Mechanism of action (MOA): inhibits folic acid metabolism by competitively inhibiting p-aminobenzoic acid (PABA) utilization; bacteriostatic

2. Commonly used for uncomplicated UTI, sinusitis, and otitis media

3. Adverse effects
a) Hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PDH) deficient patients

b) Allergy (ask patient if allergic to sulfa drugs)

c) Rash includes Stevens-Johnson syndrome

d) Kernicterus in newborns

4. Examples
a) Silver sulfadiazine (topical)

b) Sulfadiazine

c) Sulfisoxazole

d) Sulfamethoxazole (SMZ)

e) Sulfacetamide

K. Trimethoprim (TMP; Proloprim®)
1. Mechanism of action (MOA): competes with PABA for incorporation into the pteridine precursor molecule that leads to inhibition of dehydropteroate synthetase enzyme

L. SMZ/TMP (Bactrim®, Septra®)
1. There is an increased risk of resistance when sulfonamide antibiotics are used alone.

2. Used for Nocardia (rare pulmonary infection), Chlamydia trachomatis, uncomplicated UTI, burns, Pneumocystis pneumonia (PCP)

3. Adverse effects
a) Rash includes Stevens-Johnson syndrome

b) Leukopenia

c) Granulocytopenia

d) Megaloblastic anemia

e) Thrombocytopenia

M. Aminoglycosides
1. Mechanism of action (MOA): binds to bacterial ribosome causing misreading during translation of bacterial messenger RNA into proteins; bactericidal

2. Active against aerobic, gram-negative bacteria; also active against staphylococci and certain mycobacteria. Good activity against Pseudomonas spp.

3. Examples: gentamicin (Garamycin®), tobramycin (Nebcin®), amikacin (Amikin®), kanamycin (Kantrex®), neomycin (Mycifradin®), streptomycin

4. Adverse effects: nephrotoxicity, ototoxicity, neuromuscular blockade (rare)

5. Drug interactions: aminoglycosides must be used with extreme caution with other drugs that may cause nephrotoxicity

N. Miscellaneous
1. Chloramphenicol (Chloromycetin®)
a) Mechanism of action (MOA): binds to 50S ribosomal subunit blocking protein synthesis; bacteriostatic

b) Broad activity against aerobic and anaerobic gram-positive and gram-negative bacteria including S aureus, enterococci, and enteric gram-negative rods; also has activity against Rickettsia, Chlamydia, Mycoplasma, and Spirochetes

c) Adverse effects: aplastic anemia and dose-related bone marrow suppression; gray baby syndrome

d) Drug interactions: inhibitory effect on CYP2C19, CYP3A4, and, to a lesser extent, CYP2D6

2. Metronidazole (Flagyl®)
a) Mechanism of action (MOA): inhibits bacterial nucleic acid synthesis; bactericidal

b) Greater activity against gram-negative than gram-positive anerobes but active against Clostridium perfringens and Clostridium difficile; also effective against amebae and protozoa

c) Adverse effects: nausea, headache, restlessness, disulfiram-like reactions to alcohol, seizures (rare), peripheral neuropathy (rare)
(1) To be used cautiously in patients with hepatic function impairment

Table 9-1 General Antibiotic Classes Used for Major Organism Categories


























Gram positive Penicillin, nafcillin or oxacillin
First generation cephalosporins
Macrolides
Vancomycin
Gram negative Extended pencillins or imipenem
Second and third generation cephalosporins
Quinolones
Aminoglycosides
Anaerobes Metronidazole
Clindamycin

Table 9-2 Cephalosporins























Generation Drug name Route
First
Cefazolin (Ancef, Kefzol)

Cephalexin (Keflex, Keftab)

Cefadroxil (Duricef, Ultracef)

Cephradine (Velosef)*

Cephapirin (Cefadyl)*
IM, IV

PO

PO

PO, IM, IV

IM, IV
Second
Cefuroxime (Ceftin, Kefurox, Zinacef)

Cefoxitin (Mefoxin)

Cefotetan (Cefotan)

Cefprozil (Cefzil)

Cefaclor (Ceclor)

Loracarbef (Lorabid)
PO, IM, IV

IM, IV

IM, IV

PO

PO

PO
Third
Cefdinir (Omnicef)

Ceftriaxone (Rocephin)

Cefotaxime (Claforan)

Ceftizoxime (Cefizox)*

Cefoperazone (Cefobid)*

Cefixime (Suprax)

Ceftazidime (Fortaz, Tazicef, Tazidime)
PO

IM, IV

IM, IV

IM, IV

IM, IV

PO

IM, IV
Fourth Cefepime (Maxipime) IM, IV

* Discontinued from US market.


Antifungal agents


1. Amphotericin B desoxycholate (Fungizone®); amphotericin B lipid-based (AmBisome®, Abelcet®, Amphotec®)
a) Mechanism of action (MOA): binds with ergosterol to disrupt the fungal plasma membrane; fungicidal

b) Activity against Aspergillus, Coccidioides, Cryptococcus, Histoplasma, and Candida

c) Lipid complex formulations of amphotericin B (amphotericin B lipid complex, liposomal amphotericin B, and amphotericin B cholesterol sulfate complex) have reduced adverse effects, including less risk of nephrotoxicity, and less common infusion-related reactions (chills, fever, nausea).

d) Adverse effects: nephrotoxicity (more likely with conventional amphotericin B); increased LFT

2. Caspofungin (Cancidas®)
a) Mechanism of action (MOA): irreversibly inhibits the enzyme 1,3–D-glucan synthase, thereby disrupting the integrity of the fungal cell wall; fungicidal

b) Activity against Candida, Aspergillus, and Histoplasma

c) Adverse effects: May increase LFT

3. Flucytosine (Ancobon®)
a) Mechanism of action (MOA): interferes with DNA synthesis

b) Activity against Candida and Cryptococcus

c) Adverse effects: dose-related bone marrow suppression, hepatotoxicity
(1) Use with extreme caution in patients with renal dysfunction

4. Griseofulvin (Frisactin®, Grifulvin V®, Fulvicin®)
a) Activity against Trichophyton, Microsporum, and Epidermophyton

5. Azole antifungal (itraconazole [Sporanox®], ketoconazole [Nizoral®], fluconazole [Diflucan®])
a) Mechanism of action (MOA): inhibits ergosterol synthesis

b) Activity against Candida albicans
(1) Fluconazole is the drug of choice for localized candidal infections (e.g., UTI, thrush).

c) Interactions
(1) Ketoconazole: major substrate of CYP A4; strong inhibitor of CYP 3A4, CYP 1A2, and CYP 2C8, CYP 2C9; moderate inhibitor of CYP 2A6, CYP 2C19, and CYP 2D6

(2) Itraconazole: major substrate of CYP 3A4; major inhibitor of CYP 3A4

(3) Fluconazole: strong inhibitor of CYP 2C19 and 2C9; moderate inhibitor of 3A4

(4) To be avoided with cisapride due to life-threatening arrhythmias

(5) To be used with extreme caution with digoxin (decreased clearance of digoxin)

(6) Oral absorption of itraconazole and ketoconazole is impaired by concomitant antacids, H2 blockers, or proton-pump inhibitors (PPI)
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Related posts:

  1. Immunosuppressants
  2. Oncology
  3. Seizure Disorders
  4. Pharmaceutical Calculations

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Jun 21, 2016 | Posted by in PHARMACY | Comments Off on Antiinfective Agents

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