Download Bacteria and mycobacteria

Infectious Diseases
BACTERIA
AND
MYCOBACTERIA
Classification by Susceptible Organism
• A microbe is a unicellular or small multicellular
organism.
• Microbes that are capable of producing disease are
called pathogens.
• Types of microbes include:
– Bacteria
– Viruses
– Protozoa
– some Algae and Fungi
– some Worms (Helminths)
Drugs to treat Infection
• Drugs used to treat infection can be classified
according to the type of microbe they affect.
• The major classifications include:
Antibacterial drugs
Antiretroviral drugs
Antiparasitic drugs
Anti-helminthic drugs
Antiviral drugs
Antifungal drugs
Antiprotozoal drugs
Classification by Mechanism of Action
Antimicrobial drugs work in a variety of ways:
– Inhibit organism’s cell wall synthesis
– Disrupt organism’s cell wall permeability
– Inhibit of protein synthesis of organism
– Inhibit of nucleic acid synthesis of organism
– Inhibit of metabolic pathways of organism
(antimetabolites)
– Inhibition of enzyme activity
Selective Toxicity
• Selective toxicity is the ability to suppress or kill an
infecting microbe without injury to the host.
• Selective toxicity is achievable because the drug
accumulates in a microbe at a higher level than in
human cells.
• The drug has a specific action on cell structures or
biochemical processes that are unique to the
microbe.
• Understanding selective toxicity has made
antimicrobial drugs safe and effective for managing
infection in humans.
Challenge Question
The most common location of drug resistant
bacteria is
A. Inner city apartments
B. Homeless shelters
C. Jails
D. Hospitals
Challenge Question
The most common location of drug resistant
bacteria is
A. Inner city apartments
B. Homeless shelters
C. Jails
D. Hospitals
D. Hospitals - Hospitals are more likely than any
other location to harbor resistant bacteria!
Antibiotics
• Antibiotics generally refer to the classification of
drugs used to combat bacteria
• In addition to being classified by their mechanisms of
action, antibiotic drugs are further classified as:
Bacteriostatic (slow growth of bacteria)
Bacteriocidal (kill the bacteria)
Antimicrobial Resistance
• Antimicrobial resistance is a microbe’s
resistance to a drug.
• Antimicrobial resistance is a major problem,
especially in highly developed countries where
antimicrobial agents are used daily.
Factors that Facilitate the Development
of Drug Resistance
• Too low of an antibiotic dosage
• Too long of a time between doses
• Inadequate duration (days) of medication
therapy
• Patients frequently stop taking antibiotics when
they feel better.
• Preventative use of antibiotics or use for viruses.
• Presence of antibiotics in commercially prepared
meats?
Pathophysiology: Methicillin-Resistant
Staphylococcus Aureus (MRSA)
• The Staph pathogen is widely resistant to all of the
penicillins, not just methicillin.
• Many strains of MRSA are also resistant to other
antibiotics.
• Closely related to MRSA is methicillin-resistant
Staphylococcus epidermidis (MRSE).
• MRSE frequently colonizes the nasal passages of health
care workers, resulting in the spread of nosocomial
infections.
• Vancomycin is the drug of choice to manage infections
caused by MRSA and MRSE.
Pathophysiology: Penicillin-Resistant
Streptococcus Pneumoniae
• In the past, penicillins have successfully treated
pneumococcal infections.
• Because they are used so frequently, particularly
in children and the elderly, strains of penicillinresistant streptococci are emerging.
• To decrease penicillin resistance among
Streptococcus pneumoniae, the CDC suggested
that
– Clinicians stop using drugs as prophylaxis for otitis media.
– Patients at increased risk of infections should be immunized.
Pathophysiology: VancomycinResistant Enterococcus (VRE)
• Enterococcus – a gastric infection - is generally
treated with a combination of antibiotics: an
aminoglycoside with a penicillin or an
aminoglycoside with a cephalosporin.
• The penicillin or cephalosporin damages the
bacterial cell wall and allows the aminoglycoside to
penetrate the cell.
• Strains of Enterococcus have developed resistance to
penicillin, gentamicin, and vancomycin.
Pathophysiology: Multiple Drug–
Resistant Mycobacterium Tuberculosis
(MDR-TB)
• Multiple drug–resistant TB is increasingly common.
• Although some of the bacilli are inherently resistant,
others develop resistance over the long course of TB
treatment, which can last as long as 2 years.
• The cause of MDR-TB is inadequate drug therapy.
• To decrease the incidence of MDR-TB, multiple drug
therapy is implemented at the onset of treatment,
followed by a decrease in the number of drugs.
Pathophysiology: Nosocomial
Infections
• A nosocomial infection is an infection that occurs in
a hospital or hospital-like setting.
• According to the WHO, an estimated 2 million
patients annually in the US acquire a nosocomial
infection.
• They occur because hospitals have:
– A high prevalence of pathogens
– A high prevalence of compromised hosts
– An efficient mechanism of transmission from patient to
patient.
Pathophysiology: Extended Spectrum
Beta-lactamase Colonization
• Beta-lactamases are enzymes that provide
resistance to β-lactam antibiotics such as penicillins
and cephalexin by breaking the antibiotics'
structure.
• Some people carry beta-lactamases in their bodies
and are called “colonized”.
• There is evidence that the prevalence of Extended
Spectrum Beta-lactamase (ESBL)producing bacteria
have been gradually increasing in acute care
hospitals leading to the spread of drug resistance.
General Considerations for Selecting
Antimicrobial Therapy
• The most important factor in managing
infections is to “match the drug with the bug.”
• Several factors must be considered when
choosing the drug of choice or an alternative:
-Identification of the pathogen
-Drug spectrum
-Time to affect the pathogen
-Patient assessment
-Drug susceptibility
-Drug dose
-Site of infection
Drug Susceptibility
• To choose the right drug for the infection, a drug
susceptibility test is optimal.
• The site of infection is frequently a clue to the
causative agent.
• Prescribing antibiotic treatment before the
pathogen has been definitively identified is
called empiric therapy.
• The most common test to identify drug
susceptibility is called a culture and sensitivity.
Drug Susceptibility (cont.)
Disk diffusion
test:
This is the most
commonly
performed test
to determine
drug
susceptibility.
Drug Spectrum
• Choosing a drug with the narrowest possible
spectrum is important.
• The range of microbes against which a drug is active
is its spectrum.
• Narrow-spectrum drugs affect only a few
microorganisms, whereas broad-spectrum drugs
affect many microorganisms.
• Broad-spectrum antibiotics encourage drug
resistance
• An alternative to the use of broad-spectrum
antimicrobials is combination therapy.
Drug Spectrum (cont.)
• Combination therapy is used frequently for an initial
severe infection in which the pathogen is unknown.
• Once the pathogen is known, the appropriate drug
can be administered.
• Although combination therapy has many benefits, it
also has many disadvantages compared with
monotherapy.
Drug Dose:
• Choosing the antimicrobial agent with the lowest
effective dose is important.
• Pediatric doses are often calculated as mg/kg/day.
Duration
• Choosing the antimicrobial agent that takes the
shortest time to affect the pathogen is equally
important.
• The drug must remain at the site of infection at high
drug concentrations for a long enough time.
• The duration of treatment depends on:
– The type of pathogen
– The site of infection
– The presence or absence of host defenses.
• The duration of antimicrobial treatment is generally 7
to 10 days, but it may be extended to 30 days or more
for some infections.
Site of Infection
• To be effective, a drug must be able to reach the
site of infection at a high concentration.
• Poor vascularization = Poor drug concentrations
• Areas difficult to get antimicrobials into include:
– Brain and meninges
– Inner ear
– Within a closed abscess
– Around foreign objects, e.g. Pacemakers or
Prosthetic joints
Patient Assessment Factors
• Health status:
– Immune status and other diseases of the patient.
• Life span and gender:
– Infants and the elderly are most vulnerable to drug
toxicity.
• Culture and inherited traits:
– Some genetic factors may influence antimicrobial
therapy; e.g. CyP450 liver enzyme metabolism
– Global health factors
Challenge Question
___________ is prescribing antibiotics before
identification of the pathogen.
A. Empiric therapy
B. Standard of care
C. Prophylactic therapy
D. Inoculation therapy
Challenge Question
Empiric therapy is prescribing antibiotics
before identification of the pathogen.
Monitoring Antimicrobial Therapy
• Successful antimicrobial therapy eradicates the
infection.
• Some antimicrobial agents have the ability to induce
toxic adverse effects.
• Serum drug levels should be monitored for drugs
that have a high potential for severe adverse effects.
• Serum peak (high) and trough (low) levels may be
measured.
The goal is to keep the serum drug level within
the therapeutic margin.
Bacterial Cell Physiology
• Bacteria are surrounded by a rigid cell wall that is
responsible for maintaining the integrity of the
internal cellular environment.
• The interior of the cell has a high osmotic pressure.
• If the bacterial cell wall is not intact, the internal
osmotic pressure draws fluid into the cell until it
bursts.
• Even when the cell wall is breached by an antibiotic,
bacterial death may not occur because of bacterial
resistance.
Pathophysiology
• Bacteria may cause infections in any body
organ, structure, or fluid.
• In addition to the original bacterial infection,
the loss of certain “good” bacteria may result
in a superinfection.
• Drugs that affect the bacterial cell wall must
be able to penetrate the cell wall to bind to
molecular targets on the cell.
Beta-lactamase
• Beta-lactamase drugs are
enzymes that disrupt the
beta-lactam ring of the
cell wall.
Penicillins
• Penicillins were the first antibiotics.
• Identified in 1929 and developed by Alexander
Fleming from Penicillium molds.
• Subsequent versions of penicillin have been
developed to decrease the adverse effects of the
drug and to modify its ability to act on resistant
bacteria.
• Penicillins are also called beta-lactam antibiotics
• Penicillins are classified as narrow spectrum.
Prototype drug: Penicillin (Amoxicillin)
Penicillin: Core Drug Knowledge
• Pharmacotherapeutics
– Infections caused by susceptible gram-positive
bacteria
• Pharmacodynamics
– Inhibits the third and final stage of bacterial cell wall
synthesis
• Side effects
– GI upset
• Adverse effects
– Rash, fever, wheezing, possibly allergy (anaphylaxis
and death)
Cephalosporins
• The cephalosporins are similar to penicillins in
structure and in activity
• Also considered beta-lactam antibiotics.
• 4 generations of cephalosporins have been
introduced, each group with its own spectrum of
activity.
Prototype drug: cephalexin (Keflex)
Cefalexin: Core Drug Knowledge
• Pharmacotherapeutics
– Treats many kinds of infections
• Pharmacodynamics
– Disrupts bacterial cell wall synthesis
• Side effects
– GI symptoms, headache, dizziness, lethargy
• Adverse effects
– Rash, paresthesias (numbness & tingling), and
nephrotoxicity
Vancomycin
• Vancomycin (Vancocin) is a complex and unusual
antibiotic.
• It is the only drug in its class.
• The use of Vancomycin is limited by its toxicity.
• Vancomycin is usually used when other
antibiotics fail to resolve an infection.
• It is able to eradicate most gram-positive
pathogens.
Vancomycin: Core Drug Knowledge
• Pharmacotherapeutics
– Treating bacterial septicemia, endocarditis, bone and
joint infections
• Pharmacodynamics
– Inhibits cell wall synthesis by altering the cell’s
permeability
• Adverse effects
– Ototoxicity and nephrotoxicity
Challenge Question
The oral form of vancomycin is used to treat
A. Gastric ulcers
B. Prostatitis
C. Rupture of diverticulum
D. Clostridium difficile
Challenge Question
The oral form of vancomycin is used to treat
A. Gastric ulcers
B. Prostatitis
C. Rupture of diverticulum
D. Clostridium difficile
D. Clostridium difficile
Oral administration is used in treating some GI
infections, such as clostridium difficile (C. diff)
ANTIBIOTICS
AFFECTING
PROTEIN
SYNTHESIS
Inhibition of Protein Synthesis
• Ribosomes from human cells and those from
bacterial cells are structurally different.
• Some antibiotics bind with or interact with the
bacterial ribosomes thus inhibiting the bacterial
cell’s protein synthesis and causing cell death
• Examples:
– Tetracyclines
– Aminoglycoside antibiotics
– Erythromycin and clindamycin
– Chloramphenicol
Physiology
• The process of protein synthesis in cells is
divided into two sections: transcription and
translation.
– Transcription occurs within the nucleus, producing
messenger ribonucleic acid (mRNA).
• RNA combines with Amino Acids (taken in
through diet) in the cytoplasm to create
proteins.
Protein Synthesis
Antibiotics that Affect Protein Synthesis
• A protein synthesis inhibitor is a substance that stops or
slows the growth or proliferation of cells by disrupting
the processes that lead directly to the generation of new
proteins in the cell.
• It usually refers to antibiotics that act at the ribosome
level - either on the ribosome itself or on the translation
factor.
Trivia fact: Ricin, the chemical toxin derived from the
Castor Oil Plant (Castor Beans) works in this manner. Ricin
has been implicated in biological terrorism attacks.
Macrolide Antibiotics
• The macrolide antibiotics have been in use since
1952.
• They are characterized by molecules made up of
large-ring lactones.
• Macrolides are bacteriostatic or bactericidal in
susceptible bacteria.
Prototype drugs:
Erythromycin, Azithromycin (Zithromax)
Azithromycin: Core Drug Knowledge
• Pharmacotherapeutics
Treat Legionnaire disease, Mycoplasma pneumoniae
pneumonia, diphtheria, chlamydial infections, and
chancroids (boils on the genitals)
• Pharmacodynamics
Inhibiting RNA-dependent protein synthesis at the
chain elongation step
• Side effects
– GI symptoms
• Adverse effects
– Urticaria (hives), Rash, Interstitial nephritis
Aminoglycosides
• Aminoglycosides have been in use since 1944.
• They are extremely effective antibiotics for
treating severe infections.
• However, their use is limited because of the
potential for serious adverse effects.
Prototype drug: Gentamicin
Gentamicin: Core Drug Knowledge
• Pharmacotherapeutics
– Serious infections
• Pharmacodynamics
– Entering the bacterial cell and binding to the 30S
ribosomal subunit
• Adverse effects
– Neurotoxicity, nephrotoxicity, ototoxicity, and
neuromuscular blockade
Oxazolidinones
• Oxazolidinones are the first new class of
antibiotics developed specifically for treating
methicillin-resistant Staphylococcus aureus
(MRSA) infections.
Prototype drug: linezolid (Zyvox)*
MRSE Abscess
*not on
list
Inhibition of Nucleic Acid Synthesis
• Many bacteria use enzymes for replication that
do not exist in human cells.
• Nucleic acid synthesis in cells is dependent on
folic acid (folate):
– Fluoroquinolones inhibit DNA-gyrase, an
enzyme needed for bacterial DNA replication.
• Ciprofloxacin (Cipro), Levofloxacin
(Levaquin)
– Sulfonamides inhibit bacterial folate synthesis
• Sulfamethoxazole (Bactrim)
Quinolones/Fluoroquinolones
• Quinolones/Fluoroquinolones are effective for
aerobic gram-negative and gram-positive
infections.
• Like cephalosporins, quinolones are subdivided
into 4 generations.
Prototype drug: ciprofloxacin (Cipro)
Ciprofloxacin: Core Drug Knowledge
• Pharmacotherapeutics
– Active against aerobic gram-negative organisms
• Pharmacokinetics
– Administered: oral, parenteral, and topical.
Metabolism: liver. Excreted: urine and feces.
• Pharmacodynamics
– Inhibits deoxyribonucleic acid (DNA) gyrase, an
enzyme needed for bacterial DNA replication
Ciprofloxacin: Core Drug Knowledge
(cont.)
• Contraindications and precautions
– Allergy, pregnancy, and lactation
• Side effects
– GI upset, headache, and restlessness
• Adverse effects
– Arthropathy: Inflammation of one or more joints
Challenge Question
The most clinically important adverse reaction
of ciprofloxacin (Cipro) is:
– A. Photosensitivity
– B. Arthropathy
– C. Hepatotoxicity
– D. Neurotoxicity
Challenge Question
The most clinically important adverse reaction
of ciprofloxacin (Cipro) is:
B. Arthropathy
The most clinically important adverse reaction is
arthropathy (joint disease).
This often irreversible adverse reaction can
occur in children under 18 years of age.
Medications to Treat Urinary Tract Infections
Physiology
• Normally, several host defenses protect a person
from UTI.
– The urinary bladder is lined with a mucin layer that acts
as a barrier against bacterial invasion.
• Elderly and postmenopausal women produce less
mucin and therefore are at a higher risk for UTI.
• Another host defense is the washout phenomenon.
– When you urinate, you “wash out” organisms
• Immune mechanisms provide another host defense.
Pathophysiology
• Urinary tract infections can be:
– Complicated or uncomplicated,
– Acute, recurrent, or chronic.
Types
• Asymptomatic bacteriuria: no symptoms of UTI
• Cystitis: infection of the lower urinary tract
• Prostatitis: associated with urethritis or cystitis
• Acute pyelonephritis: infection of the kidneys
and renal pelvis
Diagnosis of UTI
• Diagnosis of UTI is based on the patient’s symptoms
and a positive urine dipstick test.
• A urinalysis (UA) is required for women who are
pregnant or over the age of 55, men with urinary
symptoms, and patients with recurrent symptoms.
– A successful UA requires a midstream or cleancatch urine specimen.
• When obtaining urine for a UA from a catheterized
patient, the urine should be withdrawn from the
proximal port on the catheter tubing and not from
the urine collection bag.
Sulfonamides
• Sulfonamides have been the mainstay of
treatment for UTIs for many years.
• Unfortunately, the incidence of sulfonamideresistant bacteria has steadily increased.
Prototype drug:
sulfamethoxazole/trimethoprim (SMZ-TMP)
(Bactrim DS, Septra DS)
Sulfamethoxazole-Trimethoprim: Core
Drug Knowledge
• Pharmacotherapeutics
– Uncomplicated UTIs and systemic infections
• Pharmacokinetics
– Administered: oral. Metabolism: liver. Peak: 4 hours.
• Pharmacodynamics
– Interferes with the synthesis of folic acid (folate) in
the offending organism.
Sulfamethoxazole-Trimethoprim: Core
Drug Knowledge (cont.)
• Side effects
– Nausea, vomiting, diarrhea
• Adverse effects
– Hematologic effects (e.g., anemia)
• Maximizing therapeutic effects
– Administer SMZ-TMP 1 hour before or 2 hours after a
meal with a full glass of water to enhance the absorption
of the drug.
• Minimizing adverse effects
– Administer SMZ-TMP with a full glass of water.
– Fluid intake should increase by 1.5 L/day.
Urinary Tract Antiseptics
• Urinary tract antiseptics are drugs that work by
local action because high serum levels are not
achievable.
Prototype: Nitrofurantoin (Macrodantin,
Macrobid)
– Presumed to interfere with several bacterial
enzyme systems
– Although nitrofurantoin has a broad spectrum of
activity, it is not an effective systemic drug because
it is rapidly excreted by the kidneys.
– Contraindicated in patients with renal impairment
Urinary Tract Analgesic
• Phenazopyridine (Pyridium) is used frequently
for UTIs but does not have any antibacterial
activity.
• The precise mechanism of action is not known.
• It is excreted in the urine, where it exerts a
topical analgesic effect.
– It is indicated for the symptomatic relief of pain,
burning, frequency, and urgency.
– It is important to teach the patient that his or her
urine will appear orange or dark red.
• Side effects
– Headache, rash, pruritus (itching), and GI
disturbances.
Drugs Treating Mycobacterial
Infections
Disruption of Cell Wall Permeability
Drugs that disrupt the integrity of the bacterial cell
wall cause the cell to leak components that are
vital to its survival.
Challenge Question
Mycobacteria are slow-growing microbes that
require short treatment.
A. True
B. False
B. False! Mycobacteria are slow-growing
microbes that require prolonged treatment,
generally with multiple medications. Many of
the antimycobacterial drugs may be used for
more than one type of infection.
Pathophysiology (Examples)
• Tuberculosis (TB) is a mycobacterial infection that is
found most frequently in the lungs.
– TB is an airborne disease spread by droplet nuclei.
Symptoms of active TB include night sweats, cough,
low-grade fever, fatigue, weight loss, and anorexia.
• Leprosy
– Is a chronic infectious disease caused by M. leprae.
The disease mainly affects the skin, the peripheral
nerves, the mucosa of the upper respiratory tract,
and the eyes.
Drugs for Treating Mycobacterium
Tuberculosis Infection
• Anti-TB drugs are divided into first- and secondline drugs.
• First-line drugs are those that are effective for
treatment and have manageable toxicities.
• Because TB can easily become drug resistant,
combination therapy with three to four drugs is
common.
Prototype drug: isoniazid (INH)
Isoniazid: Core Drug Knowledge
• Pharmacotherapeutics
– Used to treat or prevent TB
• Pharmacokinetics
– Administered: oral or IM. Metabolism: liver.
Excreted: urine and feces. Peak: 12 hours.
• Pharmacodynamics
– Disrupts the synthesis of the bacterial cell wall of the
tuberculosis bacterium.
Isoniazid: Core Drug Knowledge (cont.)
• Contraindications and precautions
– Acute hepatic disease
• Adverse effects
– Hepatotoxicity, peripheral neuropathy, and
encephalopathy
• Drug interactions (lots!)
– Antiseizure drugs, alcohol, aluminum-based antacids,
benzodiazepines, disulfiram, enflurane,
ketoconazole, meperidine, warfarin
Isoniazid: Planning and Interventions
• Maximizing therapeutic effects
– Administer INH to the patient with an empty
stomach 1 hour before or 2 hours after meals to
increase absorption.
• Minimizing adverse effects
– Advise patients to report any symptoms of
hepatitis, including anorexia, malaise, fatigue,
jaundice, or nausea.
Drugs for Treating Mycobacterium
Leprae (Leprosy) Infection
• Multidrug therapy, the standard approach for
other mycobacterial infections, is also
recommended for treating leprosy.
• Rifampin is the drug of choice for both types of
leprosy.
• Rifampin is also used in Tuberculosis treatment
Prototype: Rifampin
Rifampin: Core Drug Knowledge
• Pharmacotherapeutics
– Treating leprosy.
– Used in TB Treatment as second line drug.
• Pharmacokinetics
– Administered: parenterally or orally. Metabolism:
liver. Excreted: feces.
• Pharmacodynamics
– Blocks initiation of RNA transcription
Rifampin: Core Drug Knowledge (cont.)
• Contraindications and precautions
– Hypersensitivity
• Side/Adverse effects
– Discolor bodily fluids, GI disturbances, fever, chills,
headache, and fatigue
– Liver toxicity, renal toxicity
Rifampin: Teaching, Assessment, and
Evaluations
• Patient and family education
– Explain the potential effect of rifampin on the liver.
– Advise patients with soft contact lenses to consult
their ophthalmologist for an alternate form of
contacts or glasses as it may discolor tears and stain
the soft lenses.
• Ongoing assessment and evaluation
– Periodic testing of hematopoietic, renal, and hepatic
function should be arranged.
Homework: Case Study Assignment
• Review the Case Study: Strep Throat and answer the
associated questions.
• Post in the ‘Assignments’ tab.