WEEK 1: Clinical aspects and treatment of tuberculosis Flashcards
Tuberculosis and other mycobacterial diseases are difficult to treat for several reasons.
Discuss why.
Mycobacteria replicate more slowly than “typical” bacteria.
This may seem to make the disease easier to control, but it makes pharmacotherapy more difficult because rapidly dividing cells are most metabolically active and therefore susceptible to antibiotic chemotherapy.
Exist in a dormant state, making them resistant to nearly all antibiotics.
In the host, they live inside human cells, and therefore antimicrobials that have poor intracellular penetration are ineffective.
Cell walls that are structurally different from typical gram-positive and gram-negative bacteria.
The outermost layer of mycobacteria consists of
phospholipids and mycolic acids that make a waxy layer that resists penetration from antibiotics.
Outline Active Pulmonary Tuberculosis signs and symptoms.
Cough > 2weeks
Fever
Night sweats
Weight loss
Lymphadenopathy
Chest pains
h/o exposure
Outline Active extrapulmonary tuberculosis symptoms.
Lymphadenopathy
Bone
Liver
CNS
Adrenal
TB meningitis
GI/ abdominal/peritonitis
Pleural
Outline characteristics of HIV-TB infection.
Influenced by degree of immunosuppression.
Manifestations as extra-pulmonary
IRIS vs Paradoxical reactions
Atypical presentations
Drug toxicities.
What is IRIS?
Discuss IRIS pathophysiology.
Definition: Immune Reconstitution Inflammatory Syndrome (IRIS) is a condition seen in some patients who begin antiretroviral therapy (ART) for HIV infection. It occurs when the immune system begins to recover and responds to a previously acquired opportunistic infection with an overwhelming inflammatory response, making the symptoms of the infection worse.
Key Features:
*Timing: IRIS typically occurs within the first few weeks to months after initiating ART.
*Triggers: It is triggered by the immune system’s recovery and subsequent response to infections that were already present in the body but were not causing significant symptoms due to the immune system’s prior weakened state.
*Common Infections: Opportunistic infections commonly associated with IRIS include tuberculosis (TB), cytomegalovirus (CMV), cryptococcal meningitis, and Mycobacterium avium complex (MAC).
Types of IRIS:
- Paradoxical IRIS:
Occurs when an existing infection being treated with antimicrobials worsens after starting ART. - Unmasking IRIS:
Occurs when a previously undiagnosed infection becomes clinically apparent after starting ART due to the recovering immune system mounting an inflammatory response against it.
Symptoms:
*Symptoms depend on the underlying infection but can include fever, lymphadenopathy, respiratory symptoms, and worsening of the infection site symptoms.
*In the case of TB-IRIS, symptoms may include high fever, lymph node enlargement, and worsening respiratory symptoms.
Management:
*Treatment of Underlying Infection: Continue treatment for the opportunistic infection.
*Anti-inflammatory Therapy: Corticosteroids may be used to manage severe inflammatory responses.
*Monitoring and Supportive Care: Regular monitoring and supportive care to manage symptoms and prevent complications.
Prevention:
*Gradual initiation of ART in patients with severe immune suppression and high-risk infections to minimize the risk of IRIS.
*Preemptive treatment of known opportunistic infections before starting ART when possible.
Define paradoxical reactions.
Paradoxical Reactions:
Definition:
Paradoxical reactions refer to a clinical worsening of a known infection after starting treatment, despite appropriate antimicrobial therapy.
Context:
Commonly observed in patients undergoing treatment for infections such as tuberculosis (TB) or other bacterial, fungal, or viral infections.
Mechanism:
The exact mechanism is unclear but may involve a temporary imbalance in immune regulation, leading to an exaggerated inflammatory response to the dying organisms or their antigens.
Presentation:
*Symptoms often worsen within days to weeks after starting treatment.
*Clinical manifestations are specific to the infection being treated and may include fever, enlarged lymph nodes, abscess formation, and worsening of local infection symptoms.
Common Infections Involved:
Tuberculosis (TB), bacterial infections, fungal infections.
Management:
*Continue the current antimicrobial therapy as the reaction is typically self-limiting.
*Anti-inflammatory medications like corticosteroids may be used to manage severe symptoms.
*Close monitoring and supportive care are essential.
Describe the MOA of Pyrazinamide.
State its adverse effects.
What spectrum of bacteria does it act on?
Duration of use?
As part of the initial four-drug regimen for active tuberculosis, it enables the overall duration of therapy to be shortened from 9 months to 6 months
Generally used only in the first 2 months of tuberculosis therapy.
MOA
Unclear
Bactericidal
CNS penetration: only when meninges are inflamed.
Spectrum
Active only against M. tuberculosis.
Adverse Effects
*Hyperuricemia: Can rarely precipitate gout, leading to withdrawal of pyrazinamide from the regimen and an extension of the duration of tuberculosis therapy.
*Arthralgias also occur and are separate from hyperuricemia; these can be managed with over-the-counter pain medications.
*Hepatotoxicity.
Dose-dependent Hyperuricemia is predictable and
Describe the MOA of Ethambutol.
State the spectrum of bacteria it covers.
Outline its adverse effects.
Used in the initial four-drug phase of active tuberculosis.
MOA
*Ethambutol inhibits the enzyme aribinosyl transferase III, which blocks production of arabinogalactan.
Because arabinogalactan is a component of the cell wall of mycobacteria but not “typical” bacteria, the microbial activity of ethambutol is limited to mycobacteria.
Bacteriostatic
CNS penetration: only when meninges are inflamed
Spectrum
Mycobacterium tuberculosis, Mycobacterium avium–intracellular complex, Mycobacterium kansasii
Adverse Effects
-Optic neuritis
*Often manifesting as decreased visual acuity or the inability to differentiate red from green.
*Dose dependent.
*Use of ethambutol in children younger than 5 years old is not recommended, because they are generally not able to reliably perform the vision tests needed for monitoring.
-Rash and drug fever(rare)
-Cause peripheral neuropathy
Describe the MOA of Rifampicin.
Spectrum of coverage?
Adverse effects?
Contraindications?
They are protein synthesis inhibitors that inhibit transcription of DNA to bacterial messenger RNA.
One of the two most important drugs in tuberculosis pharmacotherapy
Induces the cytochrome P450 system, and patients receiving them should always be screened for drug interactions.
Active against many “typical” bacteria as well and are sometimes added to other therapies, particularly to treat difficult MRSA infections.
MOA
Protein synthesis inhibitors that work by inhibiting RNA polymerase, preventing transcription by blocking the production of messenger RNA.
Bactericidal
CNS penetration: only when meninges are inflamed.
Spectrum
Good: most mycobacteria
Moderate: Staphylococcus, Acinetobacter, Enterobacteriaceae
Poor: “typical” bacteria as monotherapy, some very rare mycobacteria
Adverse Effects
*Their potent induction of metabolism can lead to sub-therapeutic concentrations of other drugs that can manifest with devastating clinical consequences, such as loss of seizure control (anticonvulsants) or organ rejection (antirejection agents).
*Colors secretions (urine, tears, etc.) orange-red and can actually stain contact lenses (nonpermanent and not harmful
*Hepatotoxicity.
*Rash, nausea, vomiting, and hypersensitivity (often fever)
Contraindications
Hepatic failure (relative contraindication)
Pregnancy (relative contraindication
Describe the MOA of Isoniazid.
Spectrum??
Adverse effects?
It is one of the two most important drugs in tuberculosis pharmacotherapy (the other being rifampin
Effective against both actively growing and dormant mycobacteria thus used in the treatment of both active and latent tuberculosis.
MOA
*Prevents the synthesis of mycolic acids in the cell wall by inhibiting enzymes that catalyze their production.
*Bactericidal
*CNS penetration: variable (20–100% of serum concentration
Spectrum
Active only against M. tuberculosis and M. kansasii.
Adverse Effects
*Hepatotoxicity
Many patients will experience asymptomatic elevations in liver transaminases early in therapy.
In most cases, these will resolve on their own and the patient can complete treatment.
However, if the enzyme levels are many times the upper limit of normal and/or the patient experience symptoms of hepatitis (nausea, abdominal pain, jaundice), the drug needs to be stopped to prevent severe liver damage.
*Peripheral neuropathy.
Prevented by administering Pyridoxine (vitamin B6), which is recommended for patients at risk for developing neuropathy (e.g., diabetics, pregnant women, alcohol abusers) however there is no downside in recommending it to all your patients receiving isoniazid.
*Optic neuritis
*Seizures
*Drug-induced lupus
*Hypersensitivity (rash/drug fever.)
Standard susceptibility testing takes weeks instead of days to perform, so empiric regimens are often given for extended durations.
For tuberculosis, the standard of care for patients with active infections is to start with a four-drug regimen, so compliance and careful watching for drug interactions are important.
Outline the four drugs used as first-line treatment.
PERI: Pyrazinamide, Ethambutol, Rifampin and Isoniazid.
What Tb drug can be used as both prophylaxis and treatment?
Isoniazid
Describe the MOA of Streptomycin and its side effects.
Bactericidal
*Ototoxicity
*Cochleotoxicity
*Nephrotoxicity.
Describe the Intensive phase (initial phase) of TB treatment.
Intensive phase (initial phase)
*4 drugs for 2 months
*The aim of the intensive phase is to decrease the symptoms of TB, reduce the infectiousness of the patient and minimize the development of drug-resistance.
Describe the Continuation phase of TB treatment.
*2/3 drugs for four months
*The continuation phase is necessary to cure the patient and prevent relapse.
*Requires frequent sputum testing to guide treatment outcome.
