PHARM 2 Exam 1

Antimicrobials

• Used to treat infectious diseases

• 190 million doses of antibiotics are given in hospitals each day

• Modern antimicrobials: 1930s and 1940s (Flemings) 

• Significantly reduced morbidity and mortality from infection

• Sepsis = infection of whole body that results in hypotension and hypothermia 

Basic Principles of Antimicrobial Therapy

Antibiotic

•A chemical produced by one microbe that can harm other microbes

Antimicrobial agent

•Any agent that can kill or suppress microorganisms (bacterias) 

• Never for viral infections

Selective Toxicity

•Toxic to microbes but harmless to the host

•Differences in the cellular chemistry of mammals and microbes

•Disruption of bacterial protein synthesis and cell wall

•Inhibition of an enzyme unique to bacteria

Classification of Antimicrobial/Antibiotics Drugs

The two used for this textbook:

• Classification by susceptible organism: narrow-spectrum drugs/broad-spectrum drugs

• Classification by mechanism of action

Classification of Antibiotics

Drugs work on:

•Cell wall synthesis = water will come into the bacteria and break down -> destroy the bacteria 

•Cell membrane permeability = look above 

•Protein synthesis (lethal)

•Nonlethal inhibitors of protein synthesis

•Synthesis of nucleic acids

•Antimetabolites

•Viral enzyme inhibitors

Bacteriocidal vs Bacteriostatic

Bacteriocidal

•Drugs are directly lethal to bacteria at clinically achievable concentrations

• Destroy the cell wall 

Bacteriostatic

•Drugs can slow bacterial growth but do not cause cell death

• Limit protein synthesis 

Antimicrobial drugs mechanism of actions

• Drugs that inhibit bacterial cell wall synthesis or activate enzymes that disrupt the cell wall—These drugs (e.g., pen- icillins, cephalosporins) weaken the cell wall and thereby promote bacterial lysis and death.

• Drugs that increase cell membrane permeability—Drugs in this group (e.g., amphotericin B) increase the permeability of cell membranes, causing leakage of intracellular material.

• Drugs that cause lethal inhibition of bacterial protein syn- thesis—The aminoglycosides (e.g., gentamicin) are the only drugs in this group. We do not know why inhibition of protein synthesis by these agents results in cell death.

• Drugs that cause nonlethal inhibition of protein synthe- sis—Like the aminoglycosides, these drugs (e.g., tetra- cyclines) inhibit bacterial protein synthesis. However, in contrast to the aminoglycosides, these agents only slow microbial growth; they do not kill bacteria at clinically achievable concentrations.

• Drugs that inhibit bacterial synthesis of DNA and RNA or disrupt DNA function—These drugs inhibit synthesis of DNA or RNA by binding directly to nucleic acids or by interacting with enzymes required for nucleic acid synthe- sis. They may also bind with DNA and disrupt its function. Members of this group include rifampin, metronidazole, and the fluoroquinolones (e.g., ciprofloxacin).

• Antimetabolites—These drugs disrupt specific biochemi- cal reactions. The result is either a decrease in the synthesis of essential cell constituents or synthesis of nonfunctional analogs of normal metabolites. Examples of antimetabo- lites include trimethoprim and the sulfonamides.

• Drugs that suppress viral replication—Most of these drugs inhibit specific enzymes (DNA polymerase, reverse transcriptase, protease, integrase, or neuraminidase), which are required for viral replication and infectivity

Acquired Resistance to Antimicrobial Drugs

•Over time, organisms develop resistance

• Pt gets put in isolation (some of them), we don't want the resistant bacteria to spread to other pts.

• Pt avoiding/ stopping doses/ not taking the right dose 

• Pt discard leftovers to trash that can reach the water lines/ food sources, which pt will reconsume again in a different form. 

•May have been highly responsive and then became less susceptible to one or more drugs

Organisms with Microbial Drug Resistance:

•Enterococcus faecium, Staphylococcus aureus, Enterobacter

Species, Klebsiella species, Pseudomonas aeruginosa, Acinetobacter baumannii, Clostridium difficile

• “Oh I feel better so I will stop taking the antibiotics, even though I'm supposed to take it for 3 more days” 

Microbial Mechanisms of Drug Resistance

(1) decrease the concentration of a drug at its site of action

• cease active uptake of certain drugs, tetracyclines and gentamicin

• increase active export of certain drugs, tetracy- clines, fluoroquinolones, and macrolides

(2) alter the structure of drug target molecules

(3) produce a drug antagonist

• microbe can synthesize a compound that antagonizes drug actions

(4) cause drug inactivation

• For example, many bacteria are resistant to peni- cillin G because of increased production of penicillinase, an enzyme that inactivates penicillin.

• In addition to penicillins, bacterial enzymes can inactivate other antibiotics, including cephalosporins, carbapenems, and fluoroquinolones

• New Delhi Metallo-β-Lactamase 1 (NDM-1) Gene = resistant to nearly all antibiotics, except for tigecycline and colistin

Mechanisms for Acquired Resistance

•Spontaneous mutation

• Random changes in a microbe’s DNA

• Resistance to one drug

•Conjugation

• Extrachromosomal DNA is transferred from one bacterium to another

•Gram-negative bacteria

•Multiple drug resistance

Antibiotic Use and Drug-Resistant Microbe Emergence

How antibiotic use promotes resistance

•Drugs make conditions favorable for the overgrowth of microbes that have acquired mechanisms for resistance (natural selection, the ones that can adapt will live forward) 

Antibiotics that promote resistance

•Broad-spectrum agents do the most to facilitate the emergence of resistance

The extent of antibiotic use affects resistance

•The more that antibiotics are used, the faster drug-resistant organisms emerge

Nosocomial infections

•Healthcare–associated infections (HAI)

Superinfection

•New infection that appears during the course of treatment for a primary infection

•Because superinfections are caused by drug-resistant microbes, they often are difficult to treat

• Intubation pt/ HAP

• Ex: Yeast infection/ C.Diff due to decrease of normal flor/ gut

Antimicrobial Stewardship 

•Promote adherence to appropriate prescribing guidelines

•Reduce demand for antibiotics among healthy adults and parents of young children

•Emphasize adherence to prescribed antibiotic regimens

Public Health Action Plan to Combat Antimicrobial Resistance

•Focus Area I: Surveillance

•Focus Area II: Prevention and Control

•Focus Area III: Research

•Focus Area IV: Product Development

• Different types of antibiotics new to research 

SELECTION OF ANTIBIOTICS

(1) the identity of the infecting organism; (2) drug sensitivity of the infecting organism; and (3) host factors, such as the site of infection and the status of host defenses

• Conditions that might rule out a first-choice agent include (1) allergy to the drug of choice, (2) inability of the drug of choice to penetrate to the site of infection, and (3) heightened suscepti- bility of the patient to toxicity of the first-choice drug

• drug selection must be based on clini- cal evaluation and knowledge of which microbes are most likely to cause infection at a particular site when drugs are given before test results are available

• *it is essential that samples of exu- dates and body fluids be obtained for culture before initiation of treatment → The first rule of antimicrobial therapy is to match the drug with the bug (Gram-stained preparation, polymerase chain reaction (PCR) test or nucleic acid amplification test)

• *sensitivity testing is not always needed. Rather, testing is indicated only when the infecting organism is one in which resistance is likely → disk diffusion, serial dilu- tion, or gradient diffusion

HOST FACTORS THAT MODIFY DRUG CHOICE, ROUTE OF ADMINISTRATION, OR DOSAGE

• Host defenses = consist primarily of the immune system and phagocytic cells (macrophages, neutrophils)

• Site = antibiotic must be present at the site of infection in a concentration greater than the MIC. At some sites, drug penetration may be hampered, making it difficult to achieve the MIC → When treating meningitis, two approaches may be used: (1) We can select a drug that readily crosses the blood-brain barrier, and (2) we can inject an antibiotic directly into the subarachnoid space

• Foreign materials (e.g., cardiac pacemakers, prosthetic joints and heart valves, synthetic vascular shunts) present a special local problem. Phagocytes react to these objects and attempt to destroy them. Because of this behavior, the phagocytes are less able to attack bacteria, thereby allow- ing microbes to flourish.

• Previous allergic reaction, genetic factors,

DOSAGE, DURATION, AND MONITORING OF TREATMENT

Duration of therapy depends on a number of variables, including the status of host defenses, the site of the infection, and the identity of the infecting organism

• Early discontinuation is a common cause of recurrent infection, and the organisms responsible for relapse are likely to be more drug resistant than those present when treatment began

• Antimicrobial therapy is assessed by monitoring clinical responses and laboratory results.

• The frequency of monitoring is directly proportional to the severity of infection. Important clinical indicators of success are reduction of fever and res- olution of signs and symptoms related to the affected organ system (e.g., improvement of breath sounds in patients with pneumonia).

• Serum drug levels may be monitored for two reasons: to ensure that levels are sufficient for antimicrobial effects and to avoid toxicity from excessive levels.

• Success of therapy is indicated by the disappearance of infectious organisms from posttreatment cultures.

Antimicrobial Effects of Antibiotic Combinations

When two antibiotics are used together, the result may be additive, potentiative, or, in certain cases, antagonistic.

• An additive response is one in which the antimicrobial effect of the combination is equal to the sum of the effects of the two drugs alone.

• A potentiative interaction (also called a synergis- tic interaction) is one in which the effect of the combination is greater than the sum of the effects of the individual agents.

• Antagonism occurs because bactericidal drugs are usually effective only against organisms that are actively growing

Indications for Antibiotic Combinations

most common indication for using multiple antibiotics is initial therapy of a severe infection of unknown etiology, espe- cially in the neutropenic host

• An infection may be caused by more than one microbe. Multiple infectious organisms are common in brain abscesses, pelvic infections, and infections resulting from perforation of abdominal organs

• which drug combinations are employed for the specific purpose of suppressing the emergence of resis- tant bacteria

• an antibiotic combination can reduce tox- icity to the host

• combination of antibiotics can have greater antibacterial action than a single agent. This is true of the combined use of penicillin plus an aminoglycoside in the treatment of enterococcal endocarditis → weakening the cell wall, peni- cillin facilitates penetration of the aminoglycoside to its intra- cellular site of action

use of multiple antibiotics has several drawbacks, includ- ing (1) increased risk of toxic and allergic reactions, (2) pos- sible antagonism of antimicrobial effects, (3) increased risk of superinfection, (4) selection of drug-resistant bacteria, and (5) increased cost

PROPHYLACTIC USE OF ANTIMICROBIAL DRUGS

in certain situations, antimicrobial prophylaxis is both appropriate and effective. Whenever prophylaxis is proposed, the benefits must be weighed against the risks of toxicity, allergic reactions, superinfection, and selection of drug-resistant organisms

• Procedures in which prophylactic efficacy has been documented include cardiac surgery, peripheral vascular surgery, orthopedic surgery, and surgery on the gastrointestinal (GI) tract (stomach, duodenum, colon, rectum, and appendix)

• Prophylaxis is also beneficial for women undergoing a hysterectomy or an emergency cesarean section

• Thus before undergoing such procedures, these patients may need prophylactic antimicrobial medication with Individuals with congenital or valvular heart disease and those with prosthetic heart valves (now not as used)

• Severe neutropenia puts individuals at high risk of infection → prophylaxis may increase the risk of infection with fungi: by killing normal flora, whose presence helps suppress fungal growth, antibiotics can encourage fungal invasion

• For young biological females with recurrent urinary tract infection, prophylaxis with trimethoprim/sulfamethoxazole may be helpful.

• Oseltamivir (an antiviral agent) may be employed for prophylaxis against influenza.

• For individuals who have had severe rheumatic endocarditis, lifelong prophylaxis may be needed.

• Antimicrobial prophylaxis is indicated after exposure to organisms responsible for sexually transmitted diseases (e.g., syphilis, gonorrhea).

MISUSES OF ANTIMICROBIAL DRUGS

• Attempted Treatment of Viral Infection = majority of viral infections, including mumps, chicken- pox, and the common cold, do not respond to currently avail- able drugs

• Treatment of Fever of Unknown Origin = If the fever is not because of an infection, antibiotics would not only be inappropriate, but they would also expose the patient to unnecessary toxicity and delay cor- rect diagnosis of the fever’s cause. → The only situation in which fever, by itself, constitutes a legitimate indication for antibiotic use is when fever occurs in the severely immunocompromised host.

• Improper Dosage = If the dosage is too low, the patient will be exposed to a risk of adverse effects without benefit of antibacterial effects. If the dosage is too high, the risks of superinfection and adverse effects become unnecessarily high

• Treatment in the Absence of Adequate Bacteriologic Information = therapy should not be undertaken in the absence of bacteriologic information. This important guideline is often ignored.

• Omission of Surgical Drainage = Antibiotics may have limited efficacy in the presence of for- eign material, necrotic tissue, or exudate. Hence, when appro- priate, surgical drainage and cleansing should be performed to promote antimicrobial effects.

PENICILLINS

ideal antibiotics because they are active against a variety of bacteria, and their direct toxicity is low.

*very active against gram-positive organisms

*As a result, only certain penicillins (e.g., ampicillin) are able to cross it and thereby reach PBPs on the cytoplasmic membrane

• Allergic reactions are the principal adverse effects.

• have a beta-lactam ring in their structure, the penicillins are known as beta-lactam antibiotics

• weaken the cell wall, causing bacteria to take up excessive amounts of water and rupture. As a result, penicillins are generally bactericidal

• weaken the cell wall by two actions: (1) inhibition of transpeptidases and (2) disinhibition (activation) of autolysins

• (1) disrupt synthesis of the cell wall and (2) promote its active destruction. These combined actions result in cell lysis and death.

• The molecular targets of the penicillins (transpeptidases, autolysins, other bacterial enzymes) are known collectively as penicillin-binding proteins (PBPs) → 1/3

Penicillinases (Beta-Lactamases)

enzymes that cleave the beta-lactam ring and thereby render penicillins and other beta-lactam antibiotics inactive

• synthesized by gram-positive and gram- negative bacteria

• Transfer of resistance is of special importance with Staphylococcus aureus → this ability by acquiring genes that code for low-affinity PBPs from other bacteria

• common nucleus: 6-aminopenicillanic acid. This nucleus contains a beta-lactam ring joined to a second ring. The beta-lactam ring is essential for antibacterial actions

Penicillin G (benzylpenicillin)

bactericidal to a number of gram-positive bacteria and to some gram-negative bacteria

• active against most gram-positive bacteria (except penicillinase-producing staphylococci), gram-negative cocci (Neisseria meningitidis and non–penicillinase-producing strains of N. gonorrhoeae), anaerobic bacteria, and spiro- chetes (including Treponema pallidum)

• four salts: (1) potassium penicil- lin G, (2) procaine penicillin G, (3) benzathine penicillin G, and (4) sodium penicillin G

• IM = All forms

• Intravenous = potassium or sodium salts

• Renal excre- tion is accomplished mainly (90%) by active tubular secre- tion; the remaining 10% results from glomerular filtration

Adverse effects

• Allergic reactions (hapten) = immediate, accelerated, and delayed → Anaphylaxis (laryngeal edema, bronchoconstriction, severe hypotension) is an immediate hypersensitivity reaction mediated by IgE

- For patients who answer “yes,” the general rule is to avoid penicillins. If the allergy is mild, a cephalosporin is often an appropriate alternative.

-For many infections, vancomycin, erythromycin, and clindamycin are effective and safe alternatives for patients with penicillin allergy

• Other reactions include pain at sites of IM injec- tion, prolonged (but reversible) sensory and motor dysfunc- tion after accidental injection into a peripheral nerve, and neurotoxicity (seizures, confusion, hallucinations) if blood levels are too high.

• Inadvertent intraarterial injection can pro- duce severe reactions such as gangrene, necrosis, and slough- ing of tissue and must be avoided.

• Sodium penicillin G should be used with caution in patients on sodium-restricted diets.

Interactions

• when penicillins are present in high concentrations, they interact chemically with aminoglycosides and thereby inactivate the aminoglycoside → penicillins and aminoglycosides should never be mixed in the same IV solution

• - Toxic to ears and kidneys

Penicillin Allergy (GG)

•Development of penicillin allergy

•Skin tests for penicillin allergy

•Management of patients with a history of penicillin allergy

•Assess for penicillin allergy in each patient who will be receiving penicillin

• If history of mild reaction, consider cephalosporin

• If history of anaphylaxis, avoid administration of penicillin or cephalosporins

Types

•Immediate (reaction in 2 to 30 minutes)

•Accelerated (reaction in 1 to 72 hours)

•Delayed (reaction takes days or weeks to develop)

Anaphylaxis

•Laryngeal edema

• Would need intubation

•Bronchoconstriction due to release of histamines 

•Severe hypotension due to massive dilation 

Treatment

• Bring crash cart

•Epinephrine

•Respiratory support

•Prevention: Skin testing

PROPERTIES OF INDIVIDUAL PENICILLINS OTHER THAN PENICILLIN G

• Penicillin V = stable in stomach acid, good orally intake with meals

• Penicillinase-Resistant Penicillins (Antistaphylococcal Penicillins) = nafcillin, oxacillin, and dicloxacillin → used only against penicillinase-producing strains of staph- ylococci (S. aureus and S. epidermidis)

• Broad-Spectrum Penicillins (Aminopenicillins) = ampicillin and amoxicillin → large part to an increased ability to pen- etrate the gram-negative cell envelope

• Ampicillin = common side effects are rash and diarrhea

• Amoxicillin = more acid stable, produces less diarrhea

• Extended-Spectrum Penicillin (Antipseudomonal Penicillin) = Broad spectrum, piperacillin → susceptible to beta-lactamases and hence is ineffective against most strains of S. aureus → used primarily for infections with P. aeruginosa

• Penicillins Combined With a Beta-Lactamase Inhibitor = extend the antimicrobial spectrum of the penicillin

• Ampicillin/sulbactam (Unasyn)

• Amoxicillin/clavulanate (Augmentin, Clavulin )

• Piperacillin/tazobactam (Zosyn, Tazocin )

Ampicillin and Amoxicillin are penicillin-type antibiotics used to treat bacterial infections. They work by stopping bacteria from forming their cell walls, which causes the bacteria to die.

Common Uses

1. Respiratory infections

• Ear infections (otitis media)

• Sinus infections

• Strep throat

• Bronchitis

• Pneumonia

2. Urinary tract infections (UTIs)

3. Gastrointestinal infections

4. Skin and soft tissue infections

Differences Between the Two

Medication	Common Use	Special Notes
Ampicillin	Often used in hospitals for infections such as meningitis, respiratory infections, and GI infections	Frequently given IV or IM in hospital settings
Amoxicillin	Very commonly prescribed for ear infections, strep throat, and sinus infections, especially in children	Usually taken orally (capsule, tablet, or liquid)

Cephalosporins

beta-lactam antibiotics similar in structure and actions to the penicillins, low toxicity

• bactericidal, often resistant to beta-lactamases, and active against a broad spectrum of pathogens

• contains a beta-lactam ring fused to a second ring. The beta-lactam ring is required for antibacterial activity

• bind to penicillin- binding proteins (PBPs) and thereby (1) disrupt cell wall syn- thesis and (2) activate autolysins (enzymes that cleave bonds in the cell wall)

• Resistance = production of beta-lactamases, enzymes that cleave the beta-lactam ring and thereby render these drugs inactive

• Of the cephalosporins used in the United States, only nine can be administered by mouth (Table 90.2). Of these, only one, cefuroxime, can be administered orally and by injection

• eliminated by the kidneys

Cephalosporins generation uses

First generation = highly active against gram-positive bacteria

-Second generation = enhanced activity against gram-negative bacteria

-Third generation = broad spectrum of antimicrobial activity

-Fourth generation = highly resistant to beta-lactamases and has a very broad anti- bacterial spectrum

-Fifth generation = spectrum like that of the third- generation agents but with one important exception: cef- taroline is the only cephalosporin with activity against MRSA

•First generation: Widely used for prophylaxis against infection in surgical patients; rarely used for active infections

•Second generation: Rarely used for active infection due to narrow coverage, better for prevention 

•Third generation

• Preferred therapy for several infections

• Highly active against gram-negative organisms

• Able to penetrate the cerebrospinal fluid (CSF)

  • Good to treat meningitis

• Meningitis caused by enteric, gram-negative bacilli. Ceftazidime is of special utility for treating meningitis caused by P. aeruginosa.

• Nosocomial infections caused by gram-negative bacilli,

• Ceftriaxone and cefotaxime for infections caused by Neisseria gonorrhoeae (gonorrhea), H. influenzae, Proteus, Salmonella, Klebsiella, and Serratia; meningitis caused by Streptococcus pneumoniae.

•Fourth generation

• Commonly used to treat healthcare- and hospital-associated pneumonias, including those caused by the resistant organism Pseudomonas 

• For patients with burns

• Fifth generation

• Infections associated with methicillin-resistant Staphylococcus aureus (MRSA)

Cephalosporins adverse effects

• Allergic Reactions

• Bleeding

• •Thrombophlebitis

  •GI effects/Renal (seziures)

Interactions

• Two cephalosporins, cefazolin and cefotetan, can induce a state of alcohol intolerance

• As noted, cefotetan, cefazolin, and ceftriaxone can promote bleeding

• •Probenecid- another type of antibiotic 

  •Alcohol

  •Drugs that promote bleeding- ex: warfarin/ heparin 

  •Calcium and ceftriaxone

Carbapenems

beta-lactam antibiotics that have very broad antimicrobial spectra, although none is active against MRSA

• Ex = imipenem, meropenem, and ertapenem

Imipenem [Primaxin]

beta-lactam antibiotic, has an extremely broad antimicrobial spectrum—broader, in fact, than nearly all other antimicrobial drugs

• binds to two PBPs (PBP1 and PBP2)

• active against most bacterial pathogens, including organisms resistant to other antibiotics

• not absorbed from the GI tract and hence must be given IV

• Elimination is primarily renal

• *effective for serious infections caused by gram-positive cocci, gram-negative cocci, gram- negative bacilli, and anaerobic bacteria

Adverse effects

• GI effects (nausea, vom- iting, diarrhea) are most common

• Hypersensitivity reactions (rashes, pruritus, drug fever)

• Imipenem can reduce blood levels of valproate, a drug used to control seizures

Vancomycin (Vancocin)

Principal indications are Clostridioides difficile infection, MRSA infection, and the treatment of serious infections with susceptible organisms in patients allergic to penicillins

• major toxicity is renal failure

• does not interact with PBPs. Instead, it disrupts the cell wall (kill) by binding to molecules that serve as precursors for cell wall biosynthesis

• *active only against gram-positive bacteria

given parenterally (by slow IV infusion)

• drug of choice for severe CDI but not for mild CDI

• Adverse effects

  • Ototoxicity (reversible or permanent) 

  • “Red man” syndrome (histamine release)- massive flushing, and associated with fast infusions. 

  • Thrombophlebitis (common) - related to site of infection so that's why patients have central lines 

  • Thrombocytopenia (rare)

  • Allergy

Telavancin (Vibativ) - not on notes

active only against gram-positive bacteria

• inhibits bacterial cell wall synthesis + binds to the bacterial cell membrane and thereby disrupts membrane function

• pproved for IV therapy of complicated skin and skin structure infections and hospital- or ventilator-acquired pneumonia caused by sus- ceptible strains of the following gram-positive organisms

• Elimination is primarily renal

• The most common are taste disturbance, nausea, vomiting, and foamy urine.

• As with vancomycin, rapid infusion can cause red man syndrome, characterized by flushing, rash, pruritus, urticaria, tachycardia, and hypotension

• can prolong the QT interval

Aztreonam (Azactam, Cayston)

contain a beta-lactam ring, but the ring is not fused with a second ring.

• binds to PBP3

• inhibits bacterial cell wall synthesis and thereby promotes cell lysis and death

• narrow antimicrobial spectrum, being active only against gram-negative aerobic bacteria

• *highly resistant to beta-lactamases and therefore is active against many gram-negative aerobes that produce them

• must be administered parenterally (IM or IV) for systemic therapy

• eliminated by the kidneys primarily unchanged

• Most common effects are pain and thrombophlebitis at the site of injection

Fosfomycin [Monurol]

•Approved for single-dose therapy of uncomplicated urinary tract infection (UTI) caused by Escherichia coli or Enterococcus faecalis

•Disrupts the synthesis of peptidoglycan polymer strands that compose the cell wall

•Side effects

• Most common: Diarrhea, headache, vaginitis, nausea

TETRACYCLINES

broad-spectrum antibiotics, suppress bacterial growth by inhibiting protein synthesis

• bind to the 30 S ribosomal sub- unit and thereby inhibit the binding of transfer RNA to the messenger RNA–ribosome complex

• drugs enter bacteria by way of an energy-dependent transport system

• has resulted in increas- ing bacterial resistance → uses declined

• may be administered orally or IV

Uses

• Treatment of Acne, Peptic Ulcer Disease, Periodontal Disease, Oral/Topical Therapy

• •Rheumatoid arthritis

  •Mycoplasma pneumoniae

  •Lyme disease

  •Anthrax

  •Helicobacter pylori

• divided into three groups: short act- ing, intermediate acting, and long acting

• form insoluble chelates with calcium, iron, magnesium, aluminum, and zinc. The result is decreased absorption

• eliminated by the kidneys and liver

Adverse effects

•Absorption (in the GI tract): Chelation

• Not to take with Calcium supplements, milk products, iron supplements, magnesium-containing laxatives, and most antacids since it inhibits the action 

•Adverse effects

• Gastrointestinal irritation

• Effects on bone and teeth -> discoloration so rinse the mouth after you take it 

• Superinfection

• Hepatotoxicity (liver injury)

• Renal toxicity  

• Photosensitivity and other effects - avoid prolonged exposure to sunlight

*can also increase digoxin levels through increasing absorption in the GI tract and increase international normalized ratio levels by altering the vitamin K–producing flora in the gut. Patients taking digoxin or warfarin should undergo careful drug level monitoring

MACROLIDES: ERYTHROMYCIN

broad-spectrum antibiotics that inhibit bacterial protein synthesis

• relatively broad antimicrobial spectrum and is a preferred or alternative treatment for a number of infections

• inhibition of protein synthesis → binds to the 50 S ribosomal subunit and thereby blocks the addition of new amino acids to the growing peptide chain

• Bacteria can become resistant by two mechanisms: (1) pro- duction of a pump that exports the drug and (2) modification (by methylation) of target ribosomes so that binding of erythromycin is impaired

ERYTHROMYCIN

• active against most gram-positive bacteria, as well as some gram-negative bacteria (bacterastatic/protein synthesis)

• *first choice for several infections and may be used as an alternative to penicillin G in patients with penicil- lin allergy

• eliminated primarily by hepatic mechanisms, including metabolism by CYP3A4 (the 3A4 isoenzyme of cytochrome P450). Erythromycin is concentrated in the liver and then excreted in the bile. A small amount (10%–15%) is excreted unchanged in the urine

Therapeutic uses

•Whooping cough, acute diphtheria, Corynebacterium diphtheriae, chlamydial infections, M. pneumoniae, group A Streptococcus pyogenes

• Gonorrhea with chlamydia (normally together and treated together) 

•May be used as an alternative to penicillin G in patients with penicillin allergy

Adverse effects

• epigastric pain, nausea, vomit- ing, diarrhea

• QT Prolongation and Sudden Cardiac Death

• •Superinfections, thrombophlebitis, transient hearing loss

Interactions

• can increase the plasma levels and half-lives of several drugs, thereby posing a risk of toxicity

• Elevated levels are a concern with theophylline (used for asthma), carbamazepine (used for seizures and bipolar disorder), tacrolimus (used to prevent rejection of transplanted organs), digoxin (used in heart fail- ure and prevention of cardiac dysrhythmias), and warfarin (an anticoagulant)

Clindamycin (Cleocin, Dalacin C )

binds to the 50 S subunit of bacterial ribosomes and thereby inhibits protein synthesis → binds overlaps the binding sites for erythromycin and chloramphenicol

• active against most anaerobic bacteria (gram positive and gram negative) and most gram-positive aerobes

• used primarily for anaerobic infections outside the CNS (it does not cross the blood-brain barrier)

• may be administered orally, intramuscularly, or IV. Absorption from the GI tract is nearly complete and not affected by food

• undergoes hepatic metabolism to active and inac- tive products, which are later excreted in the urine and bile

• •Used as an alternative to penicillin

Adverse effects

• C. difficile–associated diarrhea

• •CDAD

  •Hepatic toxicity

  •Blood dyscrasias

  •Diarrhea

  •Hypersensitivity reactions

Linezolid (Zyvox)

first-in-class oxazolidinone antibiotic → activity against multi- drug-resistant gram-positive pathogens, including vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA)

• bacteriostatic inhibitor of protein synthesis → binds to the 23 S portion of the 50 S ribosomal subunit and thereby blocks formation of the initiation complex

• active primarily against aerobic and faculta- tive gram-positive bacteria

Five approved indications

• Infections caused by VRE
• Healthcare-associated pneumonia caused by S. aureus (methicillin-susceptible and methicillin-resistant strains) or S. pneumoniae (penicillin-susceptible strains only)

• Community-associated pneumonia caused by S. pneu- moniae (penicillin-susceptible strains only)

• Complicated skin and skin structure infections caused by S. aureus (methicillin-susceptible and methicillin-resistant strains), Streptococcus pyogenes, or Streptococcus agalac- tiae

• Uncomplicated skin and skin structure infections caused by S. aureus (methicillin-susceptible strains only) or S. pyogenes

Linezolid (Zyvox) adverse effects

• diarrhea, nausea, and headache

• cause reversible myelosuppression, manifesting as anemia, leukopenia, thrombocytopenia, or even pancytopenia → Complete blood counts should be done weekly

Interactions

• weak inhibitor of monoamine oxidase (MAO) and hence poses a risk of hypertensive crisis

• selective serotonin reuptake inhibitor (SSRI) can increase the risk of serotonin syndrome (because inhibition of MAO increases the serotonin con- tent of CNS neurons) → risk of hypertensive crisis

Retapamulin (Altabax) - not on notes

first-in-class pleuromutilin anti- biotic. The drug binds to the 50 S bacterial ribosomal sub- unit and thereby inhibits protein synthesis

• bacteriostatic at therapeutic concentrations.

• At this time, the drug is approved only for topical therapy of impetigo caused by S. pyogenes or methicillin-susceptible S. aureus

• Principal adverse effect is local irritation, which only 2% of users experience

Mupirocin - not on notes

topical antibiotic with two indications: (1) impetigo caused by S. aureus, S. pyogenes, or beta-hemo- lytic streptococci; and (2) elimination of nasal colonization by MRSA

• binds with bacterial isoleucyl transfer-RNA synthetase and thereby blocks protein synthesis

• bactericidal at therapeutic concentrations

• With appli- cation to the skin, local irritation can occur, but systemic effects occur rarely, if at all

• With intranasal application, the most common side effects are headache, rhinitis, upper respiratory congestion, and pharyngitis

Aminoglycosides

antibiotics used primarily against aerobic gram-negative bacilli → bactericidal (concentration dependent)

• disrupt protein synthesis, resulting in rapid bacterial death

• can cause serious injury to the inner ears and kidneys

• The agents used most commonly are gentamicin, tobramycin, and amikacin

• bind to the 30 S ribosomal subunit, causing (1) inhibition of protein synthesis, (2) premature termination of protein synthesis, and (3) pro- duction of abnormal proteins (secondary to misreading of the genetic code)

• *Of all the aminoglycosides, amikacin is least susceptible to inactivation by bacterial enzymes

• *To produce antibacterial effects, aminoglycosides must be transported across the bacterial cell membrane, a process that is oxygen dependent

• eliminated primarily by the kidneys

Uses

• IV/IM mostly

• Parental therapy = serious infections caused by aerobic gram-negative bacilli

• One aminoglycoside, gentamicin, is now commonly used in combination with either vancomycin or a beta-lactam anti- biotic to treat serious infections with certain gram-positive cocci, specifically Enterococcus species, some streptococci, and Staphylococcus aureus

• Oral therapy = used only for local effects within the intestine

• Topical therapy = application to the eyes, ears, and skin → used to treat conjunctivitis caused by susceptible gram-negative bacilli

Aminoglycosides adverse effects

can produce serious toxicity, especially to the inner ears and kidneys

• Ototoxicity

• Nephrotoxicity = (1) the total cumulative dose of aminoglycosides and (2) high trough levels → Serum creatinine and BUN should be monitored

•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 (eg, calcium gluconate)

•Blood dyscrasias

•Others

Interactions

• Penicillins and aminoglycosides are frequently used in com- bination to enhance bacterial kill → penicillins disrupt the cell wall and thereby facilitate access of aminoglycosides to their site of actio

• Cephalosporins and Vancomycin = weaken the bacterial cell wal

Adverse Drug Interactions

• Ototoxic Drugs = risk of injury to the inner ears is significantly increased by concurrent use of ethacrynic acid

• Nephrotoxic Drugs = increased by concurrent therapy with other nephrotoxic agents

• Skeletal Muscle Relaxants = can intensify neuromuscular blockade induced by pancuronium and other skeletal muscle relaxants

Aminoglycosides serum levels

*may be administered as a single large dose each day or as two or three smaller doses

*When once-daily dosing is used, we need to measure only trough levels. As a rule, there is no need to measure peak levels because when the entire daily dose is given at once, high peak levels are guaranteed.

• When drawing blood samples for aminoglycoside levels, timing is important. Samples for peak levels should be taken 30 minutes after giving an IM injection or after completing a 30-minute IV infusion.

•Dosing

•Single large dose each 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

•Samples for peak levels should be taken 30 minutes after giving an IM injection or after completing a 30-minute IV infusion

•Sampling for trough levels depends on the dosing schedule

•Divided doses: Take sample just before the next dose

•Once-daily doses: Draw a single sample 1 hour before the next dose; value should be very low—preferably close to zero

Gentamicin [Garamycin]

used primarily to treat patients with serious infections caused by aerobic gram-negative bacilli

• Primary targets are P. aeruginosa and the Enterobacteriaceae

• resistance to gen- tamicin is increasing, and cross-resistance to tobramycin is common. For infections that are resistant to gentamicin and tobramycin, amikacin is usually effective

• toxic to the kidneys and inner ears

• inactivated by direct chemical interaction with penicillins, and hence these drugs should not be mixed in the same IV solution

Adverse effects

•Nephrotoxicity

•Ototoxicity

Tobramycin - not on notes

more active than gentamicin against P. aeruginosa but less active against enterococci and Serratia

• Inhaled tobramycin is used for patients with cystic fibrosis

• can injure the inner ears and kidneys

• may also cause Clostridioides difficile–associated diarrhea

Amikacin - not on notes

(1) of all the amino- glycosides, amikacin is active against the broadest spectrum of gram-negative bacilli; and (2) of all the aminoglycosides, amikacin is the least vulnerable to inactivation by bacterial enzymes

• incidence of bacterial resistance to this agent is lower than with other major amino- glycosides (gentamicin and tobramycin)

• preferred agent for the initial treatment of infections caused by aerobic gram-negative bacilli in hospitals

Sulfonamides

first drugs available for the systemic treatment of bacterial infections (declines now)

• structural analogs of para-ami- nobenzoic acid (PABA)

• suppress bacterial growth by inhibiting synthesis of tetrahydrofolate, a derivative of folate

• block the step in which PABA is combined with pteridine to form dihydrop- teroic acid

• active against a broad spectrum of microbes + bacteriostatic

• UTI is the principal indication due to Escherichia coli + useful drugs for nocardiosis (infection with Nocardia asteroides) and infection with Listeria species or P. jiroveci

• *One sulfonamide—sulfasalazine—is used to treat patients with ulcerative colitis

• well absorbed after oral administration. When applied topically to the skin or mucous membranes, these drugs may be absorbed in amounts sufficient to cause systemic effects

Sulfonamides adverse effects

• most common of these are nausea and diarrhea

• hypersensitivity reactions = photosensitivity reactions, Stevens-Johnson syndrome

• blood dyscrasias = hemolytic anemia → periodic blood tests should be obtained

• Kernicterus can occur in newborns. → deposition of bilirubin in the brain (neurotoxic)

• Renal damage from crystalluria may occur → forming crystalline aggregates in the kidneys, ureters, and bladder → To minimize the risk for renal damage, adults should maintain a daily urine output of at least 1200 mL

Drug interactions

• can intensify the effects of warfarin, phenytoin, and sulfonylurea-type oral hypoglycemics (e.g., glipizide, glyburide)

*Cross-Hypersensitivity = only a shared sensitivity among sul- fonamide antibiotics but not a cross-sensitivity to nonantibio- tic sulfonamides

*sulfasalazine (Azulfidine, Salazopyrin), an antiinflammatory drug that breaks down into sulfapyridine, an antibiotic no longer available for pre- scription

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)

Systemic Sulfonamides

short-acting and intermediate-acting

• Sulfamethoxazole is the only intermediate-acting sulfon- amide available

• Sulfisoxazole is a short-acting sulfonamide → an oral suspension that contains sulfisoxazole combined with erythromycin (Pediazole). This combination product is approved for the treatment of otitis media in children

• Sulfadiazine is a short-acting sulfonamide

Topical Sulfonamides

associated with a high incidence of hypersensitivity and are not used routinely

• Sulfacetamide (Bleph-10) = used for superficial infec- tions of the eyes (e.g., conjunctivitis, corneal ulcer) → may cause blurred vision, sensitivity to bright light, headache, brow ache, and local irritation

• Silver sulfadiazine (Silvadene, Flamazine ) and Mafenide (Sulfamylon) = used to suppress bacterial colonization in patients with second- and third-degree burns → cause a blue-green or gray skin discoloration, so facial application should be avoided

Silver sulfadiazine and mafenide (tropical cream)

• Used to suppress bacterial colonization in patients with second- and third-degree burns

• Local application of mafenide frequently is painful due to metabolic acidosis 

• Application of silver sulfadiazine usually is pain free

• Systemic absorption

• Mafenide: Can suppress renal excretion of acid → Acidosis 

Trimethoprim

active against a broad spectrum of microbes + against some gram-positive bacilli

• inhibits dihydrofolate reductase, the enzyme that converts dihydrofolate to its active form: tetrahydrofolate

• suppresses bacterial synthesis of DNA, RNA, and proteins

• inhibits the bacterial enzyme at concentrations about 40,000 times lower than those required to inhibit the mamma- lian enzyme. This allows suppression of bacterial growth with doses that have essentially no effect on the host

• approved only for initial therapy of acute, uncomplicated UTIs caused by susceptible organisms + When combined with sulfa- methoxazole, trimethoprim has considerably more applications

Trimethoprim adverse effects

• itching and rash

• Gastrointestinal reactions (e.g., epigastric distress, nausea, vomiting, glossitis, stomati- tis) occur occasionally

• mega-loblastic anemia (a type of anemia with large erythrocytes), thrombocytopenia, and neutropenia—occur only in individu- als with preexisting folate deficiency → complete blood counts should be performed

• suppresses renal excretion of potassium and can thereby promote hyperkalemia → Patients at greatest risk are those taking high doses; those with renal impairment; and those taking other drugs that can elevate potassium, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), potassium-sparing diuretics, aldo- sterone antagonists, and potassium supplements

Trimethoprim (abbreviated TMP) and sulfamethoxazole (abbreviated SMZ or SMX)

result from inhibiting consecutive steps in the synthesis of tetrahydrofolate

• SMZ acts first to inhibit incorporation of PABA into folate; TMP then inhibits dihydrofolate reductase, the enzyme that converts dihydrofolate into tetrahydrofolate

• selectively toxic to microbes because (1) mammalian cells use preformed folate and therefore are not affected by SMZ, and (2) dihydrofolate reductases of mam- malian cells are relatively insensitive to inhibition by TMP

• active against a wide range of gram-positive and gram-negative bacteria

• preferred or alternative medication for a variety of infectious diseases. The combination is especially valuable for UTIs, otitis media, bronchitis, shigellosis, and pneumonia caused by P. jiroveci

-Pneumocystis Pneumonia = an infection caused by P. jiroveci

-Gastrointestinal Infections = drug of choice for infections caused by several gram-negative bacilli, including Yersinia enterocolitica and Aeromonas species

-can be used for otitis media and acute exacerbations of chronic bronchitis when these infections are caused by susceptible strains of H. influenzae or Streptococcus pneumoniae

-whooping cough, nocardiosis, brucellosis, melioidosis, listeriosis, and chan- croid

*may be administered orally or by IV infusion

Trimethoprim/sulfamethoxazole adverse effects

• nausea, vomiting, and rash

• Hypersensitivity reactions (including Stevens-Johnson syndrome)

• Blood dyscrasias (hemolytic anemia, agranulocytosis, leu- kopenia, thrombocytopenia, aplastic anemia)

• Kernicterus in neonates

• Renal damage

• CNS effects (headache, depression, hallucinations)

And like trimethoprim, the combination can cause the fol- lowing:

• Megaloblastic anemia (but only in patients who are folate deficient)

• Hyperkalemia (especially in patients on high doses, in those with renal impairment, and in those taking other drugs that can raise potassium levels)

• Birth defects (especially during the first trimester)

*Patients with AIDS are unusually susceptible to TMP/SMZ toxicity. In this group, the incidence of adverse effects (rash, recurrent fever, leukopenia) is about 55%

*Crystalluria can be avoided by maintaining adequate hydration

Interactions

• Consequently, like sulfonamides used alone, SMZ in the combination can intensify the effects of warfarin, phenytoin, and sulfonylurea-type oral hypoglycemics (e.g., glipizide)

• TMP/SMZ may also intensify bone marrow suppression in patients receiving methotrexate. As noted, drugs that raise potassium levels can increase the risk for hyperkalemia from TMP

Antifungal Agents

Systemic Mycoses

• Treatment can be difficult 

• Infections often resist treatment so used strongest medications 

• Treatment may require prolonged therapy with drugs that frequently prove toxic

-Due to chronic illnesses like diabetes and cancer

-Age like infants or old people 

Major Groups of Antifungal Agents

• Drugs for systemic mycoses/infections 

• Drugs for superficial mycoses/infections

• Systemic infections occur much less frequently than superficial infections but are more SERIOUS

•Note: A few drugs are used for both.

Drugs for Systemic Mycoses

•Opportunistic

•Immunocompromised host

• Candidiasis, aspergillosis, cryptococcosis, mucormycosis

• Primarily in debilitated or immunocompromised hosts (only happens on someone with poor immune system)

• If we healthy, these types of fungus WON’T get us

  • If we ain't as healthy, these fungus WILL get us 

•Nonopportunistic

•Can occur in any host/ anybody 

• Sporotrichosis (skin, upper extremities), blastomycosis (attack lungs), histoplasmosis (main organs of the body), coccidioidomycosis

• People are in their susceptible area. 

  • Animals/ pets 

Four Classes of Antifungal Drugs

1.Polyene antibiotics = binds to ergosterol and disrupt fungal cell membrane 

2.Azoles = inhibit synthesis of ergosterol and disrupt cell membrane 

3.Echinocandins = breaking DNA, fungistatic

4.Pyrimidine analogs = disrupt synthesis of RNA/DNA

Amphotericin B (Abelcet, AmBisome, Fungizone ) 

• Broad-spectrum antifungal agent (also used against some protozoa) 

• Belong to polyene antibiotics class due to conjugated double bonds 

• Highly toxic

  • Infusion reaction and renal damage occur in many patients

  • Must be given IV ; no oral administration

• Therapeutic Use

  • Drug of choice for most systemic mycoses for 6-8 weeks, but may last for 3-4 months 

  • Before amphotericin B, systemic fungal infections were usually fatal

• Mechanism of action

  • Binds to ergosterol (much more than cholesterol) in fungal cell membrane

    • Bacterial cell membranes lack sterols

    • Fungi damaged more than human cells

  • Increases permeability

  • Cell leaks intracellular cations (especially potassium)

  • Fungistatic or fungicidal

Amphotericin B (Abelcet, AmBisome, Fungizone )  adverse effects

• Infusion reactions (Phlebitis, hypersensitivity)

• Nephrotoxicity  ( monitor creatinine and renal function)

• Hypokalemia (at risk to develop arrhythmias) 

• Bone marrow suppression (lower white blood cells= risk for infections)

Drug interactions 

• Nephrotoxic drugs 

• Flucytosine = potentiates antifungal actions 

• Infusion reaction

  • Fever, chills, rigors, nausea, and headache

  • Has to be given slow

  • Caused by release of proinflammatory cytokines

  • Symptoms begin 1 to 3 hours after start of infusion and last for about 1 hour

  • Less intense with lipid-based amphotericin B formulations

  • Mild reactions: Pretreatment options

    • Diphenhydramine + acetaminophen + IV fluids (hydrate) 

    • Aspirin can help but may increase renal damage

  • meperidine or dantrolene can be given if rigors occur

  • Hydrocortisone can be given with caution

*Amphotericin infusion produces a high incidence of phlebitis; this can be minimized by changing peripheral venous sites often (or using central line), administering amphotericin through a large central vein, and pretreatment with heparin

Detailed Amphotericin adverse effects

• Nephrotoxicity

  • Extent of kidney damage related to total dose administered over the full course of treatment

  • total dose exceeds 4 g, residual impairment is likely

  • Damage can be minimized by infusing 1 L of saline on treatment days

  • Avoid concurrent use of other nephrotoxic drugs

    • Aminoglycosides, cyclosporines

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided

  • Monitor serum creatinine/BUN every 3 or 4 days

    • Reduce dosage if greater than 3.5 mg/dL

• Hypokalemia

  • Results from damage to kidneys

  • Potassium supplements may be needed

  • Monitor serum levels

• Hematologic effects

  • Can cause bone marrow suppression, resulting in normocytic, normochromic anemia

    • Anemia: Monitor hematocrit

    • Check for CBC (WBC, RBC, and platelets) 

IV Amphotericin B

• Test dose

• Check for precipitate, so only single line (no piggyback) 

• Assess for phlebitis

• Individualized dosing

Azoles

• Broad-spectrum antifungal drugs

• Alternative to amphotericin B for most systemic mycoses

• Lower toxicity for kidneys/other organs but liver toxicity can arise with long-term use (monitor liver functions)(ketoconazole more so) 

• Can be given orally

• Disadvantage

  • Inhibit P450 drug-metabolizing enzymes and can increase levels of many other drugs

    • Other drugs that metabolize C4(something) won’t metabolize as fast and can increase risk for toxicity. 

• Only 6 (itraconazole, ketoconazole (one of the worst on liver toxicity), fluconazole, voriconazole, isavuconazole, and posaconazole) are indicated for systemic mycoses 

Itraconazole [Sporanox]

• Azole group of antifungal agents

• Lower toxicity level

• Administered orally in capsules or suspension 

• Use

  • Systemic mycoses (alternative to amphotericin B)

• Mechanisms of action

  • Inhibits the synthesis of ergosterol

  • Inhibits fungal cytochrome P450–dependent enzymes

  • 40% of each dose is excreted in the urine as inactive metabolites

Itraconazole [Sporanox] adverse effects

• Cardiosuppression

  • Transient decrease in ventricular ejection fraction

    • Left ventricle 

  • Liver damage 

Watch for signs of liver dysfunction dysfunction

• Can inhibit drug metabolizing enzymes

• GI effects

  • Nausea, vomiting, diarrhea

• Other effects 

• Rash, headache, abdominal pain, and edema 

Drug interactions 

• Inhibition of Hepatic Drug metabolizing enzymes 

• Inhibits CYP3A4 -> cisapride, pimozide, dofetilide, and quinidine -> When present at high levels, these drugs can cause potentially fatal ventricular dysrhythmias 

• Drugs that raise gastric pH 

• Reduce absorption of drug, so administered at least 1 hour before drug 

Fluconazole [Diflucan]

• Azole group of antifungal agents

• Fungistatic

• Same mechanism of action as itraconazole

• Good PO absorption

  • IV and PO dosage the same

• Adverse effects

  • Nausea

  • Headache

  • Vomiting

  • Abdominal pain

  • Diarrhea

  • Main issue is liver function (toxicity)

Voriconazole [Vfend]

• Azole group of antifungal agents

• Broad spectrum of fungal pathogens

• Therapeutic Use Systemic mycoses of;

  • Candidemia (oral thrush) 

  • Invasive aspergillosis

  • Esophageal candidiasis

  • Scedosporium apiospermum–resistant infections

• Mechanism of action

  • Suppresses synthesis of ergosterol

• Adverse effects

  • Hepatotoxicity

  • Visual disturbances, hallucinations

  • Teratogenicity (pregnant woman CAN NOT have)

  • Hypersensitivity reactions

  • Nausea, vomiting, and abdominal pain

  • Headache

  • Drug interactions

Ketoconazole

• Azole group of antifungal agents

• Mechanism of action

  • Inhibits ergosterol

• Use: Alternative to amphotericin B for systemic mycoses

  • Less toxic and only somewhat less effective

  • Slower effects

  • More useful in suppressing chronic infections than in treating severe, acute infections

• Adverse effects (generally well tolerated)

  • (can be reduced if given with food)

  • Hepatotoxicity

    • Rare but potentially fatal hepatic necrosis

  • Effect on sex hormones

    • Can inhibit steroid synthesis in humans

    • Any ergosterol impacts hormones and adrenal glands 

  • Other adverse effects

    • Rash, itching, dizziness, fever, chills, constipation, diarrhea, photophobia (eyes), and headache -> adrenal insufficiency 

Posaconazole

• Newest member of azole family

• Binds with ergosterol in the fungal cell membrane, thereby compromising membrane integrity

• Adverse effects: Nausea, vomiting, headache, QT prolongation (arrhythmias)

• Drug Interactions: same with overall azole group

Echinocandins

• Newest class of antifungal drugs

• Disrupt the fungal cell wall

• Intravenous only

• Use: Aspergillus and Candida infections

-Caspofungin

-Micafungin

- Anidulafungin

Caspofungin

• First echinocandin available 

• Inhibit the biosynthesis of beta-1, 3-d-glucan, component of some fungi cell wall

• Approved IV therapy in patients unresponsive or intolerant of traditional agents 

• Excretion in urine and feces 

Adverse effects and use in pregnancy 

• Fever and phlebitis at injection site

• Headache, rash, nausea, and vomiting 

• Rash, facial flushing, pruritus, and sense of warmth -> release of histamine  

Drug interactions

• Drugs that induce cytochrome P450 may decrease levels of caspofungin. Powerful inducers include efavirenz, nelfinavir, rifampin, carbamazepine, dexamethasone, and phenytoin. Patients taking these drugs may need to increase their caspo- fungin dosage.

• Caspofungin can decrease levels of tacrolimus (Prograf), an immunosuppressant. If these drugs are taken concurrently, levels of tacrolimus should be monitored and the dosage increased as needed.

• Combining caspofungin with cyclosporine (Sandimmune, others) increases the risk of liver injury, as evidenced by a tran- sient elevation in plasma levels of liver enzyme. Accordingly, the combination should generally be avoided

Flucytosine [Ancobon]

Pyrimidine Analog

• Action 

• Taken by fungal cells to convert it by 5-fluorouracil (5-FU) that disrupts DNA/RNA synthesis  

• Therapeutic Use

  • Systemic- Serious infection with susceptible strains of Candida and Cryptococcus neoformans

• Resistance common

  • Often used with amphotericin B

• Readily absorbed from GI tract and eliminated by kidneys 

• Extreme caution required in patients with renal impairment or hematologic disorders

• Adverse effects

  • Hematologic

    • Bone marrow suppression (pancytopenia) -> placed on isolation due to immunocomprise status 

    • Adverse is when plasma levels of flucytosine exceed 100 mcg/mL 

  • Hepatotoxic (Liver) = perform liver function test

    • Inhibits hepatic drug-metabolizing enzymes

    • Can raise other drugs like cisapride, pimozide, dofetilide, and quinidine 

Superficial Mycoses

• Mycoses caused by two groups of organisms

  • Candida species

    • Usually in mucous membranes and moist skin (any place holds moisture, like folds) 

    • Chronic infections may involve scalp, skin, and nails

    • More prone to pt with diabetes 

  • Dermatophytic infections (e.g., ringworm)

    • Usually confined to skin, hair, and nails

    • Tinea pedis (ringworm of the foot, or “athlete’s foot”), tinea corporis (ringworm of the body), tinea cruris (ringworm of the groin, or “jock itch”), and tinea capitis (ringworm of the scalp)

Oral candidiasis (thrush)

• Vulvovaginal candidiasis

  • 75% of women experience at least once

  • Treatment = Swish and swallow 

  • Risk factors

    • Pregnancy, diabetes, debilitation, HIV, oral contraceptives, systemic glucocorticoids, anticancer agents, and systemic antibiotics

• Onychomycosis = fungal infection of nails 

• Difficult to treat and requires long- term therapy 

Candidiasis treatment

• Drugs

• Vulvovaginal candidiasis

  • 1-3 days topical therapy, suppository /vaginal 

  • Single dose of fluconazole

  • Adverse effects = Itching and discharge 

• Oral candidiasis

  • Topical: Nystatin, clotrimazole, miconazole, and amphotericin B

  • Immunocompromised patients may need oral therapy with fluconazole or ketoconazole

Onychomycosis (Fungal Infection of the Nails) treatment

• Thick green causing deformity of toe nails 

Difficult to eradicate and requires prolonged treatment

• Oral therapy

  • Lamisil and itraconazole (Sporanox)

• Topical therapy

  • Ciclopirox (Penlac Nail Lacquer)

  • Tavaborole (Kerydin) 

  • Efinaconazole (Jubila) 

Azoles uses

• Clotrimazole: Topical is drug of choice for dermatophytic infections and candidiasis of skin, mouth, and vagina

• Ketoconazole: Oral and topical therapy of superficial mycoses

• Miconazole: Topical drug of choice for dermatophytic infections and for cutaneous and vulvovaginal candidiasis

  • New buccal tablet is used for oropharyngeal candidiasis

• Itraconazole: Used for oral therapy of onychomycosis of the toenails or fingernails

• Fluconazole: used for oral therapy of vulvovaginal candidiasis, oropharyngeal candidiasis, and onychomycosis

• Econazole: Indicated for ringworm infections and superficial candidiasis

• Oxiconazole and sulconazole: Topical treatment of tinea infections

Griseofulvin [Grifulvin]

• Administered orally and absorption enhanced by dosing with fatty meal 

• Uses

  • Superficial mycoses

  • Ineffective systemic mycoses

• Inhibits fungal mitosis by binding to components of microtubules

Griseofulvin [Grifulvin] adverse effects

• Transient headache (will go away) 

• Rash

• Gastrointestinal effects (nausea, vomit, diarrhea) 

• Insomnia

• Tiredness

Nystatin [Mycostatin]

• Polyene antibiotic

• Used only for candidiasis

• Drug of choice for intestinal candidiasis

• Also used for candidal infections in skin, mouth, esophagus, and vagina

• Can be administered orally (swish and swallow) or topically (local irritation)

Allylamines

Naftifine

• Terbinafine (lamisil) 

• Action = Inhibits squalene epoxidase with resultant inhibition of ergosterol synthesis → cell death

• Available in topical (ringworm) and oral (ringworm and onychomycosis) formulations 

• Adverse effects = Headache, diarrhea, dyspepsia, and abdominal pain

• Other effects = Skin reaction, disturbance of taste, and risk of liver failure 

• Tests of serum alanine and aspartate aminotransferases recommended 

• Look for signs of liver dysfunction -> persistent nausea, anorexia, fatigue, vomiting, jaundice, right upper abdominal pain, dark urine, pale stools 

• Butenafine

Other Drugs for Superficial Mycoses

• Tolnaftate

• Undecylenic acid

• Ciclopirox

Helminths

•  Parasitic worms (round/flat)

  •  Helminthiasis: Worm infestation

  •  Frequently asymptomatic; treatment not always indicated (not always worth it to treat it)

  •  More than 2 billion people affected worldwide (most prevalent in areas with poor sanitation)

  •  Most frequent site of infection: Intestine (others include liver, lymphatic system, and blood vessels)

Anthelmintics

•  Agents used against parasitic worms

•  Classes and common names of parasitic worms

  •  Nematodes (roundworms)

    • These could migrate : D to the brain. 

    • Intestines, tissue

    • giant roundworm, pinworm, hook

    • worm, whipworm, and threadworm.

    • pork roundworms (responsible for trichinosis)

    • Filariae

    • Drug of choice = Albendazole 

  •  Cestodes (tapeworms)

    • Beef, pork, fish

    • Drug of choice = Praziquantel 

  •  Trematodes (flukes)

    •  Blood, liver, intestines, lung

    • Drug of choice = Praziquantel or Triclabendazole 

Nematode Infestation (Intestinal)

• Ascariasis (giant roundworm)

  •  Most prevalent infestation: 1 in 3 people affected worldwide

  •  Results in serious complications if worms migrate to pancreatic duct, bile duct, gallbladder, or liver

  •  Uncommon in North America

  • Drugs of choice are albendazole, mebendazole, and ivermectin.

•  Ancylostomiasis and necatoriasis (hookworm)

  • common in warm humid regions.

  • Adult hookworms attach to the wall of the small intestine and suck blood.

  • infestation is associated with chronic blood loss and progressive anemia

  • Nausea, vomiting, and abdominal pain may accompany the infestation.

  • Albendazole, mebendazole, and pyrantel pamoate are the treatments of choice.

•  Trichuriasis (whipworm)

  • thrives in warm humid environments.

  • Larvae and adult worms inhabit the large intestine.

  • may live for 10 years or more.

  • Albendazole is the treatment of choice.

•  Strongyloidiasis (threadworm)

  • common in warm, humid environments.

  • Larval and adult threadworms inhabit the small intestine

  • Deadly but symptoms are usually absent

  • Mild infestation may cause abdominal pain and occasional diarrhea.

  • Severe infestation can cause vomiting, massive diarrhea, dehydration, electrolyte imbalance, and secondary bacteremia.

  • Ivermectin is the treatment of choice

• Enterobiasis (Pinworm Infestation)

  • transmission occurs most often among people who live in closed, crowded conditions.

  • commonly occurs in children aged 5 to 10 years.

  • Adult pinworms inhabit the ileum and large intestine.

  • Life span is approximately 2 months.

  • Drugs of choice are albendazole, mebendazole, and pyrantel pamoate.

Nematode Infestation (Extraintestinal)

• Trichinosis (pork roundworm)

  • acquired by eating undercooked pork that contains encysted larvae of Trichinella spiralis.

  • Adult worms reside in the intestine, whereas larvae migrate to skeletal muscle and become encysted.

  • Symptoms of trichinosis include gastrointestinal (GI) upset, fever, muscle pain, and sore throat.

  • Potentially lethal complications (heart failure, meningitis, neuritis) arise in some patients.

  • Albendazole is the drug of choice for killing adult worms and migrating larvae.

  • Prednisone (a glucocorticoid) is given to reduce inflammation during larval migration.

•  Wuchereriasis and brugiasis (Lymphatic Filarial Infestation)

  • They invade the lymphatic system and, when infestation is heavy, lymphatic obstruction occurs, resulting in elephantiasis (usually of the scrotum or legs).

  • “filarial fever” may develop.

  • Symptoms include chills, fever, headache, nausea, vomiting, constipation, and lymphadenitis.

  • The drug of choice for killing both filarial species is diethylcarbamazine. 

•  Onchocerciasis (river blindness)

  • found in streams and rivers of Mexico, Guatemala, northern South America, and equatorial Africa.

  • transmitted to humans by the bite of certain flies.

  • causes dermatologic and ophthalmic symptoms.

  • Ocular lesions caused by the infiltration and death of microfilariae within the eye result in optic neuritis, optic atrophy, and then blindness.

  • The drug of choice for treating onchocerciasis is ivermectin.

Cestode Infestation

•  Taeniasis (beef and pork tapeworm)

  • eating contaminated undercooked beef or pork that contains tapeworm larvae.

  • Adult tapeworms live attached to the wall of the small intestine.

  • treated with praziquantel

•  Diphyllobothriasis (fish tapeworm)

  • acquired by ingestion of undercooked fish that is infested with tapeworm larvae.

  • Adult worms inhabit the ileum.

  • Treated with praziquantel

Trematode Infestations

•  Schistosomiasis (blood fluke)

  • infestation with blood flukes of any species

  • The acute phase subsides in 3 to 4 months.

    • Symptoms during this phase include lymphadenopathy, fever, anorexia, malaise, muscle pain, and rash.

  • In the chronic phase, schistosomes take up residence in the vascular system, primarily in veins of the intestines and liver.

    • produce intestinal polyposis, hepatosplenomegaly, and portal hypertension.

  • praziquantel is the treatment of choice.

•  Fascioliasis (liver fluke)

  • Fasciola hepatica (sheep liver fluke) and Clonorchis sinensis (Chinese liver fluke).

  • inhabit the biliary tract.

  • Symptoms are anorexia, mild fever, fatigue, aching in the region of the liver

  • The preferred drug for use against F. hepatica is triclabendazole

  • The preferred drugs for use against C. sinensis are praziquantel and albendazole.

•  Fasciolopsiasis (intestinal fluke)

  • most common in Southeast Asia.

  • Adult worms inhabit the small intestine.

  • usually asymptomatic, but people experience ulcerlike pain, constipation or diarrhea, and bowel obstruction may occur.

  • Praziquantel is the treatment of choice.

 Mebendazole [Vermox]

• broad spectrum, usefully got mixed infestation

• drug of choice for most intestinal roundworms, pinworms, hookworms, and giant roundworms.

• Mechanism of Action

  • prevents uptake of glucose by susceptible intestinal worms.

    • Glucose deprivation causes slow death of worm

• Adverse Affect 

  • Systemic effects are rare BUT

• most concerning are bone marrow suppression and liver impairment (ONLY PROBLEM WITH HIGH DOSES OR PROLONGED TREATMENT)

Albendazole [Albenza]

• drug of choice for infestation with hookworms, pinworms, whipworms, Chinese liver flukes giant roundworms, and pork roundworms

• active against many cestode and nematode parasites, including larval forms of Taenia solium and Echinococcus granulosus.

• Since the US is picky 

  • drug is approved only for parenchymal neurocysticercosis (caused by larval forms of the pork tapeworm, T. solium) and cystic hydatid disease of the liver, lung, and peritoneum (caused by larval forms of the dog tapeworm, E. granulosus.)

• Mechanism of Action

  • inhibits polymerization of tubulin → prevents formation of cytoplasmic microtubules

Albendazole [Albenza] adverse effects

• Generally well tolerated 

  • liver impairment could occur

    • Liver function should be assessed before each cycle of treatment and 14 days later.

  • Could cause granulocytopenia, agranulocytosis, and even pancytopenia

    • Due to suppression of bone marrow function from the drug

      • Observe for signs and symptoms of anemia (pallor, weakness), leukopenia (evidence of infection), and thrombocytopenia (increased bruising and bleeding).

      • Blood cell counts should be obtained before each cycle of treatment and 14 days later.

Pyrantel pamoate [Pin-X]

• active against intestinal nematodes

• alternative to mebendazole or albendazole

• Mechanism of Action

  • depolarizing neuromuscular blocking agent that causes spastic paralysis of intestinal parasites.

• Adverse Effects

  • “gasping syndrome”

    • respiratory distress, cardiovascular collapse, seizures, and metabolic acidosis.

  • common effects are GI reactions (nausea, vomiting, diarrhea, stomach pain, cramps). Possible central nervous system effects include dizziness, drowsiness, headache, and insomnia.

Praziquantel [Biltricide]

• active against flukes and cestodes (tapeworms) and is the drug of choice for tapeworms, schistosomiasis, and other fluke infestations.

• Mechanism of action

  • produces spastic paralysis, causing detachment of worms from body tissues.

  • disrupts the integument of the worms, making them vulnerable to host defenses

• Adverse effects

  • Transient headache

  • Abdominal discomfort

  • Drowsiness

  • Uncommon 

    • bradycardia, atrioventricular heart block, dysrhythmias, and elevated liver enzymes.

Diethylcarbamazine [Hetrazan]

• not marketed in the United States.

• drug of choice for filarial infestations, kills microfilariae of W. bancrofti, B. malayi, and Loa loa.

• Mechanism of action

  • reduces muscular activity

    • Causes parasite to dislodge

  • Alter surface of property of parasite

    • Makes them vulnerable to host defense

• Adverse Effects

  • Direct

    • Headache, weakness, dizziness, N/V

  • Indirect

    • rashes, intense itching, encephalitis, fever, tachycardia, lymphadenitis, leukocytosis, and proteinuria.

 Ivermectin [Stromectol]

• active against many nematodes. 

• Has two indications: onchocerciasis (a major cause of blindness worldwide) and intestinal strongyloidiasis

• Mechanism of Action

  • disrupts nerve traffic and muscle function in target parasites.

    • opening chloride channels on the cell surface, which allows chloride ions to rush into nerve and muscle cells.

• Adverse Effects 

  • Pruritus

  • Rash

  • fever 

  • lymph node tenderness

  • bone and joint pain.

  • Mazotti reaction- allergic and inflammatory response to the death of microfilariae rather than to the drug.

    • do not occur in patients treated for strongyloidiasis.

 Moxidectin [Moxidectin]

• treatment of onchocerciasis (river blindness)

• Mechanism of action

  • Unknown….

    • increased cellular permeability followed by influx of calcium →paralysis

• Adverse Affects

  • Flulike symptoms 

  • Mazotti response

Malaria

life-threatening disease caused by protozoa of genus Plasmodium transmitted via mosquito (transfusion and replication)

• Is preventable and curable 

• Two subtypes of malaria: 

  • vivax malaria from Plasmodium vivax 

  • falciparum malaria from Plasmodium falciparum (less common but more severe) 

• primaquine, atovaquone/proguanil, and tafenoquine are used for the prevention of relapse

• Treatment objects: treatment of acute tracks, prevention of relapse, prophylaxis

P. VIVAX MALARIA

• Most common form of malaria

• Relatively mild and self-limiting

• Drug resistance is relatively uncommon

• Symptoms can be treated with medication

• After 26 days, merozoites emerge from hepatocytes and begin their attack on erythrocytes (not enough oxygen).

• Symptoms peak (extreme fatigue) and decline every 48 hours

• Cyclic reinfection and cell lysis

P. FALCIPARUM MALARIA

• Less common than P. vivax malaria

• Much more severe than P. vivax malaria

• Without treatment, 10% of victims die

• Many strains are drug resistant

• Symptoms appear at irregular intervals

• Can destroy up to 60% of circulating red blood cells (RBCs) resulting in profound anemia and weakness.

ANTIMALARIAL THERAPY

•Erythrocytic forms are killed relatively easily

•Exoerythrocytic forms are much harder to kill

•Sporozoites do not respond to drugs at all

•Three objectives of treatment

• Treatment of acute attack

• For patients with vivax malaria, clinical cure will not prevent relapse because hypnozoites remain in the liver

• Prevention of relapse

• Prophylaxis

Selection 

• Based on two factors 

- Goal of treatment 

- Drug resistance of causative strain 

- Will use antimalarial drug and antibiotics at the same time 

Major Antimalarial Drugs

• Not for people with sickle cell disease as they are immune to malaria themselves 

Chloroquine (Aralen) 

• Drug of choice for many forms of malaria

• High activity against erythrocytic forms

• Not active against exoerythrocytic forms

• Doses required for prophylaxis are low

• High doses for treatment are taken only briefly

• Mild to moderate attacks + prophylaxis, works against some strains

• AE: GI effects (abdomenal discomfort, nausea, diarrhea), visual disturbance, pruritus headache, drug accumulates in the liver

Primaquine

Used for hepatic forms of malaria 

• prevents relapse of P. vivax

• AE: most serious and frequent effect is hemolysis (RBC destroyed)  in pt with G6PD (glucose-6-phosphate dehydrogenase deficiency an X-linked inherited trait) 

• Populations affected: Iranians, Sephardic Jews, Greeks Sardinians

Quinine

• Replaced by more effective and less toxic agents (chloroquine) 

• Used for chloroquine-resistant Plasmodium, mostly P. falciparum (severe malaria) 

• Active against erythrocytic forms of malaria 

• recommend to use with doxycycline, tetracycline, or clindamycin with IV quinine 

• AE: Frequently causes mild cinchonism (characterized by tinnitus, headache, visual disturbance, nausea, diarrhea), contraindicated for pt with optic neuritis or tinnitus

  • hemolysis in pt with G6PD deficiency 

  • increase in ventricular rate, contraindicated for pt with afib

  • severe hypoglycemia via hyperinsulinemia 

  • infant hearing loss at high doses during pregnancy (pregnancy risk category x) 

QUINIDINE GLUCONATE

•Only parenteral drug approved

•More cardiotoxic than quinine, may also cause hypotension and acute circulatory failure.

•Requires continuous electrocardiographic (ECG) monitoring and frequent blood pressure monitoring

•Both IV quinidine and PO quinine should be accompanied by doxycycline, tetracycline, or clindamycin

Mefloquine

• Used for chloroquine resistant P. falciparum and P. vivax

• Unknown mechanism of resistance 

• AE: low dose used for prophylaxis- n/d, syncope

  • Higher dose for acute attack- GI disturbances, nightmares, altered vision, headache

  • risk of severe cardiac dysrhythmias 

  • CNS toxicity: vertigo, confusion, psychosis, convulsions, psychiatric symptoms

• Drug Interaction: 

  • Strong inhibitors of CYP3A4 such as ketoconazole = increase concentration

  • Strong inducers of CYP3A4 = decrease concentration

Tafenoquine  [Arakoda (prophylaxis), Krintafel (prevent relapse)] 

• Active against both P. vivax and P. Falciparum

• AE: most common is keratopathy (ocular dryness with tiny erosions of cornea)

  • Other common effects: headache, diarrhea, back pain, and methemoglobinemia (hemoglobin cannot carry O2)

  • hemolytic anemia in pt with G6PD deficiency

  • Less common: hypersensitivity reactions, psychiatric effects 

• Drug interaction: 

  • Dofetilide (an antidysrhythmic)

  • Warfarin 

Artemisinin Derivatives

• Most effective for multidrug resistant falciparum malaria, not for prophylaxis

  • Artemether and Lumefantrine combo [Coartem]

    • Oral treatment of uncomplicated falciparum malaria

    • Generally, well tolerated 

    • AE: adults- headache, anorexia, dizziness, weakness, joint and muscle pain

      • Children- fever, cough, vomiting, anorexia, and headache

      • Prolong QT interval

    • Drug interactions

      • Drugs that prolong QT interval (quinine, erythromycin, ketoconazole)

      • Strong inhibitors of CYP3A4 = increase levels

• Artesunate 

  • Only drug approved for severe malaria

  • Used with mefloquine, doxycycline, clindamycin

Atovaquone/Proguanil  [Malarone]

Prophylaxis and treatment of malaria caused by chloroquine- resistant Plasmodium

• Both drugs active against erythrocytic and exoerythrocytic plasmodial forms

• Atocaquone itself can be used for pneumocystis pneumonia  

• AE: well tolerated together

  • rash with atovaquone by itself

  • oral ulceration + GI effects with proguanil by itself

• Drug interactions: 

tetracycline and rifampin can reduce levels of atovaquone by as much as 50%

Antibacterial Drugs

• Tetracyclines such as doxycycline and tetracycline

  • Used for chloroquine resistant malaria

  • Combined with quinine

• Clindamycin with quinine

  • Used for chloroquine resistant P. falciparum or P. vivax

  • AE: colitis secondary to overgrowth of the bowel with C. Diff.

Protozoal Infections

• Increasing world travel by Americans

• Increased immigration from regions of high infection rates

• Increase in protozoal infections in the United States

• Major Protozoal infections

  •  Cryptosporidium parvum

  • Giardia lamblia

  • Toxoplama gondii

• Trichomoniasis vaginalis = vaginal discharge, itching, UTIs 

• Cryptosporidiosis - infection in the intestinal tracts of human

• Giardiasis - infection in the upper small intestine

• Pneumocystis jiroveci pneumonia

• Trichomoniasis

• American trypanosomiasis (Chagas’ disease)

• African trypanosomiasis (sleeping sickness) - at the beginning starts with mild symptoms, if left untreated leads to serious neurological issues and maybe death 

• ***GI issues, diarrhea (monitor electrolytes) ***

Principal Protozoal Infections in the United States

• Trichomoniasis

  • Metronidazole, tinidazole, secnidazole

• Giardiasis

  • Metronidazole, tinidazole, nitazoxanide

Drugs of Choice for Protozoal Infections

• Metronidazole [Flagyl, Protostat]

  • Active against several protozoal species and anaerobic bacteria

  • Drug of choice for symptomatic intestinal amebiasis and systemic amebiasis

  • Adverse effects

    •  Nausea, headache, dry mouth, unpleasant metallic taste, harmless darkening of urine

    • If combined with alcohol, may cause disulfiram-like reaction

• Tinidazole [Tindamax]

  • Antiprotozoal drug similar to metronidazole

  • Indicated for: Adults: Trichomoniasis

  • Adults, children over age 3: Giardiasis, intestinal amebiasis, amebic liver abscesses

  • Adverse effects: metallic taste, stomatitis, anorexia, dyspepsia, nausea, and vomiting

• Nitazoxanide

  • Adverse effects: abdominal pain, diarrhea, vomiting, and headache

• Paromomycin

  • Adverse effects: nausea, vomiting, abdominal pain, diarrhea, and gastroesophageal reflux

• Pyrimethamine

  • Adverse effects: anorexia, vomiting, and megaloblastic anemia due to folate deficiency

• Eflornithine