Week 10 Reflection Discussion

Post your major takeaway from this week’s content (3-4 sentences) by the due date. Include your text as a reference.

Classification of Antibiotics

Drugs work on:

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• Cell wall synthesis
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• Cell membrane permeability
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• Protein synthesis (lethal)
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• Nonlethal inhibitors of protein synthesis
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• Synthesis of nucleic acids
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• Antimetabolites
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• Viral enzyme inhibitors

Acquired Resistance

The mechanisms for acquired resistance are:

• Spontaneous mutation
• Conjugation

The emergence of drug-resistant Microbe

Factors to the emergence of drug-resistant Microbe

• Antibiotic use promotes resistance
• Antibiotics that promote resistance
• The extent of antibiotic use affects resistance
• Nosocomial infections
• Superinfection
• Active against a variety of bacteria
• Direct toxicity: Low
• Principal adverse effect: Allergic reaction
• Structure includes a beta-lactam ring
• Beta-lactam family includes:
• Cephalosporins
• Aztreonam
• Imipenem
• Meropenem
• Ertapenem

Mechanism of action

• Weaken the cell wall, causing bacteria to take up excessive water and rupture.
• Active only against bacteria undergoing growth and division.
• Bactericidal

Bacterial resistance

• Inability of penicillins to reach their target
• Inactivation of penicillins by bacterial enzymes

Staphylococcus aureus & Penicillin

When penicillin was introduced in 1940, all strains of Staphylococcus aureus were sensitive to it. However by 1960, 80% of the Staphylococcus aureus found in hospital settings displayed resistance to penicillin.

As a result, a penicillin derivative, methicillin was developed, which is resistant to actions of beta-lactamases.

Today, a methicillin-resistant Staphylococcus aureus (MSRA) strain exists that have a unique mechanism of resistance. It produces penicillin-binding proteins (PBPs) with a low affinity for penicillins and all other beta-lactam antibiotics.

MRSA developed this ability by acquiring genes that code for low-affinity PBPs from other bacteria.

Medications

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• Penicillin G
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• PenicillinV
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• Antistaphylococcal penicillins
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• Broad spectrum penicillins
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• Extended spectrum penicillins

Drugs That Weaken the Bacterial Cell Wall II: Other Drugs

Cephalosporins

• Most widely used group of antibiotics

1. First generation: Cephalexin
2. Second generation: Cefoxitin
3. Third generation: Cefotaxime
4. Fourth generation: Cefepime
5. Fifth generation: Ceftaroline

Carbapenems

• Beta-lactam antibiotics have an extremely broad antimicrobial spectrum with low toxicity
• Not active against MRSA
• Imipenem
• Meropenem
• Ertapenem
• Doripenem

Others

• Vancomycin
• Telavancin
• Aztreonam
• Fosfomycin

Bacteriostatic Inhibitors of Protein Synthesis

Tetracyclines

Four (4) members of the tetracycline family are available for systemic therapy:

• Tetracycline
• Demeclocycline
• Doxycycline
• Minocycline

Uses:

• Mycoplasma pneumoniae
• Lyme disease
• Anthrax
• Helicobacter pylori

Macrolides

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Others

Aminoglycosides: Bactericidal Inhibitors of Protein Synthesis

Aminoglycosides Use:

Aerobic gram-negative bacilli

Most commonly used agents are: Gentamicin, tobramycin, amikacin.

Aminoglycosides are:

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• Narrow-spectrum antibiotics
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• Bactericidal
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• Not absorbed from GI tract
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• Microbial resistance

Adverse effects of Aminoglycosides are:

• Nephrotoxicity
• Ototoxicity (total cumulative and trough levels)
• Hypersensitivity reactions
• Neuromuscular blockade: Concurrent use with neuromuscular blocking agents, general anesthetics, and in myasthenia gravis
• Treatment of choice: Reversal with IV infusion of a calcium salt (e.g., calcium gluconate)

Other adverse effects include: Hypersensitivity reactions and Blood dyscrasias.

Serum Levels

• Dosing
• Single large dose every day or 2 or 3 smaller doses
• Monitoring of serum levels is common; the same aminoglycoside dose can produce very different plasma levels in different patients
• Peak levels must be high enough to kill bacteria; trough levels must be low enough to minimize toxicity

Peak and Trough Levels

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• 1
• Samples for peak levels should be taken 30 minutes after giving an IM injection or after completing a 30-minute IV infusion
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• 2
• Sampling for trough levels depends on the dosing schedule
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• 3
• Divided doses: Take sample just before the next dose
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• Once-daily doses: Draw a single sample 1 hour before the next dose; value should be very lowpreferably close to zero

Available Aminoglycosides:

Gentamicin [Garamycin]- Used to treat serious infections caused by aerobic gram-negative bacilli:

• Pseudomonas aeruginosa
• Escherichia coli
• Klebsiella
• Serratia
• Proteus mirabilis

Adverse effects:

• Nephrotoxicity
• Ototoxicity

Others:

• Tobramycin
• Amikacin
• Neomycin
• Kanamycin
• Streptomycin
• Paromomycin

First drugs available for systemic treatment of bacterial infection.

Sulfonamides inhibits the synthesis of folic acid (folate). Mammalian cells do not manufacture their own folate, therefore not affected only the bacteria are affected.

Primary use now: Urinary tract infection (UTI)

Other uses: Nocardiosis, Chlamydia trachomatis, conjugation therapy for toxoplasmosis/malaria, ulcerative colitis

Adverse effects:

• Hypersensitivity reactions: Stevens-Johnson syndrome
• Hematologic effects
• Kernicterus
• Renal damage from crystalluria

Drug interactions:

• Metabolism-related interactions
• Cross-hypersensitivity

Microbial resistance:

• Many bacterial species have developed resistance to sulfonamides.
• Especially high among gonococci, meningococci, streptococci, and shigellae .
• Resistance may be acquired by spontaneous mutation or by transfer of plasmids that code for antibiotic resistance (R factors).

Silver sulfadiazine and mafenide

Used to suppress bacterial colonization in patients with second- and third-degree burns. Local application of mafenide frequently is painful. Application of silver sulfadiazine is usually pain free. Systemic absorption.

Trimethoprim

• Inhibits dihydrofolate reductase, the enzyme that converts dihydrofolic acid to its active form, tetrahydrofolic acid, thus suppressing bacterial synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and proteins.
• Uses:
• Acute and uncomplicated UTIs
• Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter, coagulase-negative Staphylococcus
• Adverse effects:
• Hematologic effects
• Hyperkalemia
• Use in pregnancy and lactation

Trimethoprim/Sulfamethoxazole (TMP/SMZ)

• Trimethoprim/sulfamethoxazole (TMP/SMZ) combination: Inhibits sequential steps in bacterial folic acid synthesis, making it much more powerful than TMP or SMZ alone. Plasma drug levels.
• Therapeutic uses:
• UTI, otitis media, bronchitis, shigellosis, pneumonia caused by Pneumocystis jiroveci, Pneumocystis pneumonia, and GI infection
• Adverse effects:
• Gastrointestinal
• Nausea and vomiting
• Rash
• Hyperkalemia
• Hypersensitivity reactions (Stevens-Johnson syndrome)
• Blood dyscrasias
• Kernicterus
• Renal damage: Crystalluria

Urinary Tract Infections (UTIs)

• Second most common infection
• Sexually active young women
• Older adult women in nursing homes
• Less frequent in males
• Occurrence likely associated with complications (e.g., septicemia, pyelonephritis)

Organisms That Cause UTIs and Treatment

• Escherichia coli, Klebsiella, Proteus, Enterobacter, Pseudomonas, staphylococci, enterococci, and E. coli
• Trimethoprim/sulfamethoxazole (TMP/SMZ) and nitrofurantoin:
• Frequently the treatment of choice for oral therapy of UTIs
• First-line and second-line treatments

Urinary Tract Antiseptics

• Nitrofurantoin
• Low concentrations: Bacteriostatic
• High concentrations: Bactericidal
• Uses: Lower UTIs, prophylaxis, recurrent lower UTIs
• Methenamine
• Decomposes into ammonia and formaldehyde, which denature bacterial proteins
• Therapeutic uses: Chronic lower UTIs (TMP/SMZ is the preferred drug)
• Drug interactions:
• Urinary alkalinizers
• Sulfonamides
• Adverse effects:
• Relatively safe and generally well tolerated
• Contraindicated in renal and liver failure

Miscellaneous Antibacterial Drug

Fluoroquinolones

• Broad-spectrum agents with multiple applications
• Disrupt DNA replication and cell division
• All can be administered orally or IV
• Side effects generally mild but can cause tendon rupture (low risk)
• Usually affects Achilles tendon
• Avoid in patients younger than 18 years
• Risk to all patients, especially those older than 60 years, those taking glucocorticoids, and those who have undergone kidney, heart, or lung transplantation

Ciprofloxacin [Cipro]

• Broad-spectrum antibiotic (gram-negative and some gram-positive organisms)
• Inhibits bacterial DNA gyrase and topoisomerase II

Others

• Levofloxacin
• Ofloxacin
• Moxifloxacin
• Gemifloxacin
• Metronidazole
• Daptomycin

In the next lesson, you’ll learn about Drug Therapy of Sexually Transmitted Diseases.

Sexually Transmitted Diseases: Infections or parasitic diseases transmitted primarily through sexual contact.

Types of STDs

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• Gonococcal infections
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• Nongonococcal urethritis
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• Pelvic inflammatory disease (PID)
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• Acute epididymitis
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• Syphilis
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• Trichomoniasis
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• Chancroid
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• Herpes simplex
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• Proctitis
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• Anogenital warts