Treatment of Infection
PHTY 615
Introduction
• Microorganisms (bacteria, protozoa, viruses, parasites) can invade
human tissue and cause a host of complications
– Mild to life-threatening
• Bodies natural defenses may be incapable of dealing with invasion
– Need pharmacological intervention
– Drug class common goal is selective toxicity
• Target pathogenic organism
• All drugs exert some influence on bodies natural tissue
• Infection is a common form of illness and PTs will certainly encounter
patients using antibiotics
Antibacterial Drugs
Bacterial Structure and Function
• Unicellular microorganisms
– Rigid cell wall
– Lacks true nuclear membrane
• Genetic material not confined to distinct area
– Usually contain subcellular organelles needed to synthesize proteins and maintain
cellular metabolism
– Need nourishing medium to provide metabolic substrates and maintain function
• Human tissue provides this
Pathogenic Effects of Bacteria
• Can multiply and compete with host cells for essential nutrients
• May directly harm human cells by releasing toxic substances
– Example
• Certain bacteria in GI system inhibit growth of other microorganisms that assist
in digestion of food and synthesis of nutrients
• Many bacteria effectively dealt with by bodies natural defenses
– Pathogenic bacteria can lead to sever infection and death
• Some bacteria may establish colonies and remain innocuous for extended periods of
time
– Colonies may proliferate when patient succumbs to some other disorder or illness
Bacterial Nomenclature and Classification
• Usually named according to genus or species
– Escherichia coli
• Escherichia = genus
• Coli = species
• Genus refers to bacteria with common genetic, morphologic, and
biochemical characteristics
• Species refers to physical, pathogenic, or other characteristics
• Example
– Streptococcus pyogenes = bacteria from Streptococcus genus commonly
associated with pyogenic or pus-producing characteristics
Bacterial Nomenclature and Classification
• Bacteria often categorized according to common characteristics
– Shape, histological staining, etc.
• Example
– Gram positive cocci
• Spherical bacteria (cocci)
• Retain discoloration during particular staining technique
Treatment of Bacterial Infections: Basic
Principles
Spectrum of Antibacterial Activity
• Some drugs effective against variety of bacteria
– Broad-spectrum agents
– Tetracycline effective against many gram-negative, gram positive, and
other types of bacteria
• Other drugs specific (Narrow-spectrum)
– Isoniazid specific to bacillus that causes tuberculosis
Bactericidal versus Bacteriostatic Activity
• Bactericidal
– Drugs that typically kill or destroy bacteria
• Bacteriostatic
– Do not kill bacteria
– Limit growth and proliferation
• Dosage of drug may determine whether drug is bactericidal or
bacteriostatic
– Erythromycin exhibit bacteriostatic activity at lower doses and bactericidal activity
at higher doses
Basic Mechanism of Antibacterial Drugs
• Ideally selective to bacteria while sparing normal tissue
• Mechanisms include
– Inhibition of bacterial cell wall synthesis and function
– Inhibition of bacterial protein synthesis
– Inhibition of bacterial DNA/RNA function
Inhibition of Bacterial Cell Wall Synthesis and
Function
• Penicillin, cephalosporins, and others inhibit synthesis of bacterial cell walls
• Selective toxicity
– Bacterial cell wall considerably different from normal human cell wall
• Rigidity of bacterial cell wall caused by presence of protein-polysaccharide structures
– Peptidoglycans
– Some drugs cause inadequate production of peptidoglycans and compromise the
integrity of the bacterial cell wall
• Other drugs directly punch a hole in the bacterial cell membrane impacting integrity
– Polymyxin antibiotics (polymyxin B, colistin)
Inhibition of Bacterial Protein Synthesis
• Large group of antibacterial agents inhibit or impair synthesis of bacterial
proteins
– Aminoglycosides
• Gentamicin, streptomycin, erythromycin, tetracycline
• Drugs enter bacterial cell and bind to specific ribosomal subunits
– Much greater affinity for bacterial ribosomes compared to human
– Block protein synthesis or cause ribosome to misread mRNA resulting in useless
protein
Inhibition of Bacterial DNA/RNA Synthesis and
Function
• Drugs directly or indirectly interfere with the structure, synthesis, and
function of DNA and RNA in susceptible bacteria
– Fluoroquinolones, sulfonamides
• Several drugs inhibit bacterial nucleic acid synthesis by inhibiting
production of folic acid
– Folic acid involved in synthesis of bacterial nucleic acids and a number of
essential AA
– Trimethoprim, Sulfonamide drugs
Specific Antibacterial Agents
Drugs Inhibiting Cell Wall Synthesis and
Function
• Penicillins
– First antibiotic, developed in the early 1940s
– Currently several forms of natural and semisynthetic penicillins
– Collectively referred to as beta-lactam antibiotics
– Bind to specific enzymatic protein within bacterial cell wall responsible for normal
synthesis and organization of cell wall
– Cell wall becomes impaired and cell dies
Classification and Use of Penicillins
• Classified according to chemical background, spectrum of antibacterial activity, or
pharmacokinetic features
• Naturally occurring penicillins (G and V) can be administered orally
– Narrow antibacterial spectrum
• Some semisynthetic penicillins (amoxicillin, ampicillin) have broader spectrum and
may be administered orally or parenterally depending on the agent
Classification and Use of Penicillins
• Penicillinase-resistant forms of penicillin
– Developed to overcome strains of bacteria that contain enzyme called
penicillinase
– Enzyme destroys penicillin rendering it ineffective
• These agents are the mainstay in treatment of infection and remain drug
of choice for a number of disorders
Adverse Effects
• Allergic reactions
– Skin rashes, hives, itching, difficulty breathing
– Reactions may be fairly minor and ameliorated by changing type of penicillin or
method of administration
– In others
• Reaction may be severe and lead to anaphylactic reaction (severe bronchoconstriction and CV
collapse)
• Prolonged Administration
– May cause CNS problems (confusion, hallucinations)
– Certain blood disorders (hemolytic anemia and thrombocytopenia)
• Other side effects
– GI problems such as nausea, vomiting, diarrhea
Cephalosporins
• Exert effect similar to penicillins
• Serve as alternative to penicillin if not effective or poorly tolerated
• May be drug of choice for certain urinary tract infections
• Multiple generations of cephalosporins (1-4) according to spectrum of
antibacterial activity
– 1st generation most narrow spectrum
– 4th generation broadest spectrum
• Adverse effects
– Allergic reaction similar to penicillin
– GI problems
• Diarrhea, nausea, vomiting
Other Agents that Inhibit Bacterial Cell Wall Synthesis
• Aztreonam (Azactam)
– Limited spectrum
– Useful against serious infections caused by certain gram negative bacilli
– Side effects are skin rashes, redness, and itching
• Bacitracin
– Group of polypeptide antibiotics
– Inhibit incorporation of AA and nucleic acid precursors into bacterial cell wall
– Fairly broad spectrum
– Usually applied topically to treat infection in superficial skin wounds
– Commercial preparations may contain other antibiotics such as neomycin
– Primary adverse effect in local hypersensitivity
Other Agents that Inhibit Bacterial Cell Wall Synthesis
• Colistin
– Used in combination with other agents (neomycin and hydrocortisone) to treat
topical infections of external auditory canal
• Cycloserine
– Broad-spectrum antibiotic used primarily as an adjunct in the treatment of
tuberculosis
• Imipenem and Cilastatin
– Used in combination
• Cilastatin enhances the bacterial effect of imipenem by inhibiting metabolic
inactivation in the kidneys
– Imipenem one of broadest spectrum antibacterials
– May have CNS abnormalities (Confusion, tremors, seizures)
Other Agents that Inhibit Bacterial Cell Wall Synthesis
• Meropenem
– Similar spectrum to imipenem
– May have CNS complications
• Polymyxin B
– Effective against many gram-negative bacteria including E. coli and Salmonella
– Systemic administration causes nephrotoxicity
• Drug therefore used to treat local superficial infections of skin, eyes, and mucous membranes
• Vancomycin
– Alternative to penicillin in variety of infections
– Bacteria resistant to vancomycin have emerged generating concern about continued use
– Adverse effects include hypersensitivity (rashes), GI disturbances, and possibly nephrotoxicity or
ototoxicity
Beta-Lactamase Inhibitors
• Certain bacteria produce enzymes known as beta-lactamases
• Enzyme binds to beta-lactam drug and destroy it
• These bacteria are resistant to penicillin
• Several drugs available that inhibit enzyme
– Clavulanate, sulbactam, tazobactam
• Drugs used in combination with penicillin to treat bacteria
Drugs That Inhibit Bacterial Protein Synthesis
• Aminoglycosides
– Streptomycin, gentamicin, neomycin
– Bind to certain ribosomes and cause changes in protein synthesis
– Leads to death of bacterial cell
– Very broad spectrum
• E. coli, Pseudomonas, and Salmonella, certain species of Staphylococcus
– Used to treat a variety of tissue and wound infections
– Adverse effects can be toxic
• Nephrotoxicity, Ototoxicity, Hypersensitivity
• Need to monitor levels in the bloodstream
Erythromycin and Other Macrolides
• Azithromycin, clarithromycin, dirithromycin are macrolide antibiotics
• Ribosome binding impairs protein synthesis
• Very broad spectrum group
• Class may be used as an alternative in patients allergic to penicillin
• Adverse effects
– GI distress common with bactericidal doses of erythromycin
– Erythromycin therefore usually given in bacteriostatic doses
– Some newer macrolides may produce fewer side effects but may cause allergic
reactions in susceptible individuals
Tetracyclines
• Effective in preventing bacterial protein synthesis
• Used to treat a variety of bacteria (Rickettsia, Spirochetes)
• Use as broad-spectrum antibiotic diminished somewhat secondary to
resistant strains
– Newer derivatives may be used to overcome resistance
• Used to treat Chlamydia, Rickettsia, certain Spirochetes
• GI distress, hypersensitivity, impaired growth and development of bone
and teeth
Drugs That Inhibit Bacterial DNA/RNA Synthesis and
Function
• Aminosalicylic Acid
– Inhibits folic acid synthesis in tuberculosis bacteria
– Drug used as adjunct to primary antitubercular agents isoniazid and rifampin
– Adverse effects
• GI problems, hypersensitivity reactions, and blood dyscrasias
• Clofazimine
– Drug appears to bind directly to bacterial DNA and prevent replication
– Effective against Mycobacterium leprae
• Used as an adjunct to treat leprosy
– Adverse effects
• Skin discoloration, abdominal pain, nausea, vomiting
Drugs That Inhibit Bacterial DNA/RNA Synthesis and
Function
• Dapsone
– Primary drug in treating leprosy
– Impairs folic acid synthesis
– Adverse effects
• Peripheral motor weakness, hypersensitivity, fever, hemolytic anemia
• Ethambutol
– Suppresses RNA synthesis (exact mechanism unknown)
– Used as a secondary agent to treat tuberculosis
– Adverse effects
• Joint pain, nausea, skin rash, itching, CNS abnormalities
Drugs That Inhibit Bacterial DNA/RNA Synthesis and
Function
• Fluoroquinolones
– Ciproflaxin (Cipro), Enoxacin (Penetrex), Levoflaxacin (Levaquin)
– Inhibit twisting of DNA necessary for nucleic acid replication
– Especially useful in treatment of UTIs
– Also used for GI infections, respiratory infections, osteomylitis, and gonorrhea
– Adverse effects
• CNS toxicity, GI distress, Allergic skin reactions
• May also cause tendon pain and inflammation and possibly lead to rupture (Achilles most
common)
• Rifampin
– Rifadin, Rimactane
– Impairs DNA replication
– One of principle agents used to treat tuberculosis and leprosy
– Adverse effects
• GI distress, hypersensitivity, liver dysfunction in those individuals with liver disease
Drugs That Inhibit Bacterial DNA/RNA Synthesis and
Function
• Sulfonamides
– Sulfadiazone, sulfamethizole
– Disrupt folic acid synthesis
– Used to treat certain UTIs
• May be applied topically to treat vaginal infections, opthalmic conditions, or other local
infections
– Adverse effects
• GI distress, skin sensitivity, allergic reactions
• Blood dyscrasias such as hemolytic anemia may occur with systemic therapy
Drugs That Inhibit Bacterial DNA/RNA Synthesis and
Function
• Trimethoprim
– Proloprim, Trimpex
– Inhibits folic acid production
– Used primarily to treat certain UTIs
– Adverse effects
• Headache, Skin rash, itching, decreased appetite
• Hyperkalemia (especially in older adults)
Resistance to Antibacterial Drugs
• Development of resistant strains is a serious problem
• Can be natural or acquired defense mechanism against certain drugs
• Bacteria can then be allowed to breed
• Bacteria resistance can result from several mechanisms
– Enzymatically destroy drug
– Bacterial cell modifies or masks itself
– Bacteria may mutate
– Drug penetration into bacteria altered
– Bacteria can develop efflux pump and expel drug
• Antibacterial resistance categorized according to the name of the drug and resistant
bacterial strain
– Vancomycin-resistant Staphylococcus aureus (VRSA)
• Antibacterial drugs should not be overused
Gram-Positive Resistance - United States, 1980-1999
Special Concerns In Rehabilitation Patients
• Many patients seen by PT will be taking antibacterial drugs
• Drugs may be administered to prevent or treat infection directly relating to rehab
program
– Topical agent for burns
• Drugs may also be administered to treat conditions not directly related to rehab
– Treat UTI or pneumonia
• Be aware of adverse effects
– Hypersensitivity, GI disturbances
• PT plays a role in preventing spread of bacteria
– Sterile technique
Antiviral Drugs
Introduction
• Virus is one of the smallest microorganisms
• Several types commonly infect human cells causing diverse range of
pathologies
– Common cold to AIDs
• Viruses must completely rely on metabolism of host cell to function
– Selective destruction of virus often difficult
Viral Structure and Function
• Classification
– According to physical, biogenic, and pathogenic characteristics
• Can be broken up broadly into DNA or RNA viruses and then subdivided according to other
characteristics
– DNA=Hepatitis B, RNA=AIDs
• Viral Characteristics
– Core of viral DNA or RNA surrounded by protein shell (capsid)
– Some surrounded by viral membrane or envelope
– Virus does not contain any of the components necessary to replicate itself or synthesize proteins
• Needs host cell machinery
• Viral Replication
– Absorption, penetration and uncoating, biosynthesis, maturation and release
Specific Antiviral Drugs
Sites of Drug Action
Acyclovir and Valacyclovir
• Acyclovir (Zovirax) effective against herpes virus infections
– Also effective against other members of the herpes family
• Varicella-zoster and Epstein-Barr
– Can be administered topically, orally, or intravenously
• Valacyclovir (Valtrex) is precursor of acyclovir
– Converted to acyclovir in GI tract when taken orally
– Allowing for higher acyclovir concentrations and efficacy once absorbed
Acyclovir and Valacyclovir
• Mechanism of Action
– Inhibits viral DNA replication by impacting DNA polymerase enzyme activity
– Drug also incorporated into DNA strand halting further production of DNA
• Adverse Effects
– Topical application may produce local irritation of cutaneous and mucosal tissue
– Prolonged systemic administration may cause headache, dizziness, skin rashes
and GI upset
Amantadine and Rimantadine
• Amantadine (Symmetrel) and Rimantadine (Flumadine) used to prevent and treat
influenza A
– Prophylactic administration 70-90% effective in preventing influenza A
– Also decrease severity and duration if infected
• Mechanism of Action
– Blocks uncoating of viral nucleic acid within host cell
– May also interfere in assembly of viral components later in replication process
– Dual effect makes drug more effective
• Adverse Effects
– CNS symptoms (confusion, loss of concentration, dizziness)
• Elderly individuals particularly susceptible
Cidofovir
• Cidofovir (Vistide)
– Used to treat CMV retinitis in people with AIDS
– Mechanism
• Inhibits viral DNA replication
– Side effects
• Nephrotoxicity, headache, GI disturbances
Famciclovir and Penciclovir
• Penciclovir administered topically to treat herpes simplex infections of lips and face
• Famciclovir is precursor to Penciclovir (prodrug)
– Converted following oral administration
– Used to treat genital herpes
• Mechanism of action
– Inhibits viral DNA synthesis and replication
• Adverse effects
– Topical application may cause skin irritation at application site
– Oral administration may cause headache, dizziness, GI disturbances
Foscarnet
• Foscavir
– Used to treat Cytomegalovirus (CMV) retinitis in patients with AIDS
– May also help control other infections in patients with compromised immune
system
– Mechanism of action
• Inhibits DNA polymerase enzyme necessary for viral DNA replication
– Adverse effects
• Impaired renal function, hematologic disorders (anemia), GI disturbances (cramps, nausea),
CNS toxicity
Ganciciclovir
• Cytovene
– Used to treat patients with AIDS who have problems related to CMV
infection
– Mechanism of action
• Inhibits DNA polymerase activity
– Adverse effects
• Anemia and other hematologic disorders, GI disturbances, CNS disturbances
Protease Inhibitors
• Inhibit HIV protease enzyme
– Needed to manufacture HIV proteins
– Prevent synthesis and maturation of HIV
• Prenavir (Agenerase), Indinavir (Crixivan), Nelfinavir (Viracept)
• Mechanism of Action
– Binds to HIV protease enzyme and prevents it from acting on substrates
– Virus cannot fully develop
• Adverse effects
– Alterations in fat deposits (increased in abdomen)
– Abnormal blood lipid levels
– Insulin resistance
Reverse Transcriptase Inhibitors
• RTIs used to inhibit replication and proliferation of type I human
immunodeficiency virus
– Act on specific HIV enzyme (HIV reverse transcritpase) needed to convert RNA to
DNA
– Effective in reducing HIV proliferation
• Zidovudine (Retrovir) also known as AZT
• Adverse effects
– Anemia, fever, chills, nausea, diarrhea, myopathy, peripheral neuropathies
Interferons
• Group of proteins producing a number of positive physiologic and pharmacologic
effects
• Enable healthy cells to resist infection from a variety of viruses
– Control cell differentiation, limit excessive cell proliferation, modify certain immune processes
• Produced naturally in certain human cells and tissues
• Pharmacologic applications
– Type I interferons used to treat hepatitis B and C infection
– Cancer treatment secondary to effect on controling abnormal cell proliferation
– May decrease multiple sclerosis exacerbations
• Adverse effects
– Flulike symptoms, loss of appetite, nausea, vomiting, diarrhea, unusual tiredness
Vaccines
• Prevent viral infection by stimulating the endogenous production of immune factors
that will selectively destroy invading virus
• Given to healthy individuals
• Vaccines usually contain the whole or a part of a virus that has been completely or
partially inactivated
• Several vaccines presently available for serious infections
– Polio, smallpox, rabies, measles, mumps, rubella, hepatitis A and B, and influenza
• Drawbacks
– Some vaccines only partially effective and infection still occurs in a % of individuals
– Several require readministration (boosters)
HIV and AIDS
• HIV selectively attacks certain cells in the immune system such as CD41 lymphocytes
– Leads to immunocompromised state known as AIDS
• Presently 2 forms of HIV (1 and 2) although 1 is more prevalent
• Fatal condition for which there is no cure
• Treatment continually changing
• Two main strategies
– Controlling the proliferation and effects of HIV in infected individual
– Treatment and prevention of opportunistic infections
HIV and AIDS
• Inhibition of HIV proliferation (Anti-retroviral therapy)
– Nucleoside reverse transcriptase inhibitors
• Zidovudine (Retrovir, AZT) first approved drug and others with similar mechanism now
available
• Inhibit reverse transcriptase enzyme
– Protease inhibitors
• Impair HIV protease enzyme
– Nonnucleoside reverse transcriptase inhibitors
• Inhibit function of reverse transcriptase enzyme
• Number of drugs developed continues to grow
HIV and AIDS
• Anti-HIV drug combinations
– Highly active antiretroviral therapy (HAART)
• Simultaneous use of at least three agents
• Example
– 2 RTIs and 1 protease inhibitor
– Good evidence that HAART is effective in delaying the progression of HIV
– Have been shown to reduce viral load to undetectable levels
• But does not completely eradicate virus
• Virus can remain sequestered in tissues and hidden from HAART
– Problems
• 20-50% of individuals do not respond adequately to HAART
• Side effects can negatively impact adherence
The Birth of HIV/AIDS Therapeutics
Short-term Clinical Effects of HAART
• Resolution of HIV-induced symptoms
• Marked reduction of HIV load in plasma
• Increase in CD-4 cell counts
• Control of active O.I.’s (e.g.: MAC, CMV)
• Reduction in the incidence of new O.I.’s
• Reduction of hospital days, and need for home IV therapies/ nutrition
• 50% reduction in mortality rate in NY
Management of Opportunistic Infections
• AIDS patients usually succumb to variety of opportunistic
infections
– Viral, bacterial, other microbial invaders
• Early detection very important
• Drug of choice dependent on the infection
Special Concerns In Rehabilitation Patients
• Patients seen by PT may be taking antiviral drugs to treat
conditions not directly related to treatment
• Be aware of adverse effects at these may have a large impact
on ability to carry out your treatment