Antimicrobial Therapies 3 (Antimycobacterials / Antifungals ) Flashcards
ANTIMYCOBACTERIAL
DRUGS
A LITTLE BACKGROUND
• Mycobacteria are rod-shaped aerobic bacteria that grow slowly—their cell walls contain mycolic acids
• These pathogens produce lipophilic cell walls that stain poorly with a Gram stain—once stained, these bacilli do not lose color when made acidic—thus the name Acid Fast Bacilli
• These infections cause slow-growing granulomatous lesions—and can occur anywhere in the body
BEFORE WE BEGIN….
• Mycobacterium tuberculosis can cause latent TB infection and active TB
• M. tuberculosis is leading infectious cause of death worldwide— ¼ of the world’s
population is infected with TB
• There is increasing occurrence of
nontubercular Mycobacterium—M. avium-
intracellulare, M. chelonae, M. abscessus, M.
kansasii, M. fortuitum
• M. leprae causes leprosy
ANTIMYCOBACTERIAL
DRUGS
DRUGS IN THE FAMILY….
Ethambutol
Isoniazid [INH]—prototype drug
Pyrazinamide
Rifabutin
Rifampin
Rifapentine
SECOND LINE DRUGS FOR TB
Aminosalicylic acid
Bedaquiline
Capreomycin
Cycloserine
Ethionamide
Aminoglycosides/Fluroquinolones/Macrolides
CHEMOTHERAPY
FOR
TUBERCULOSIS
M. tuberculosis is slow growing and
requires treatment for months – years
LTBI can be treated for 9 months with
INH or 12 once a week higher doses of
INH + Rifapentine
Active TB has to be treated with several
drugs for several months
Multi-drug resistant TB is typically
treated for 2 years
EXTREMELY DRUG
RESISTANT [XDR]
TUBERCULOSIS
This is a bacilli that is resistant to INH and
Rifampin and is resistant to any
fluoroquinolone and at least 1 of 3 injectable
2nd line agents—Amikacin, Kanamycin or
Capreomycin
Resistance in M. tuberculosis, when it is treated with one drug—so multiple drug therapy is used to suppress resistant strains
1st line agents—INH, Rifampin, Ethambutol and Pyrazinamide are the DOC and highly efficacious with tolerable SE profiles
Rifabutin or Rifapentine can replace Rifampin in certain scenarios
Active disease ALWAYS requires multiple drugs—3 or more with proven in vitro activity against the isolate
Clinical improvement occurs quickly—
weeks, but therapy is continued much
longer to kill persistent organisms and
prevent relapse
Standard therapy is INH, Rifampin,
Ethambutol and Pyrazinamide for 8
weeks, then INH and Rifampin for 16
more weeks
HOW DO WE DEAL
WITH DRUG
RESISTANCE??
• After susceptibility info is available, the regimen can be tailored to the individual
• 2nd line therapy for MDR-TB—disease resistant to INH and Rifampin—is treated with an aminoglycoside [Streptomycin, Kanamycin or Amikacin] or Capreomycin [all of these are injectables], a quinolone [Levofloxacin or Moxifloxacin], Ethambutol and Pyrazinamide [if sensitive to these] and one or more of these—Cycloserine, Ethionamide or PAS
For XDR-TB—Clofazimine and Linezolid
may be used
Patient adherence can be low with drug-
resistant disease as the therapy lasts more
than 6 months—DOT therapy is one
successful strategy to ensure completion
ISONIAZID
MOA
• Prodrug—activated by mycobacterial catalase peroxidase [KatG]
• Target enzymes that are essential for the synthesis of mycolic acid
• Inhibiting this acid leads to destruction of the tubercular cell wall
Antibacterial Spectrum
• Specific to M. tuberculosis
• M. kansasii may be susceptible at higher drug dosages
• Most nontubercular Mycobacteria are resistant to INH
• Drug works well on rapidly growing bacilli and intracellular organisms
Resistance
• Resistance follows chromosomal mutations
incapable of prodrug activation
• Acyl carrier mutated proteins
• Over expression of the target enzyme InhA
• Cross resistance can occur between INH and Ethionamide
Pharmacokinetics
• Readily absorbed after oral dose
• Food impairs absorption—especially high fat foods
• Drug diffuses into all body fluids, cell and caseous materials [necrotic tissue that looks lie cheese produced in the tubercular lesions]
• Drug levels in CSF is the same as in the serum
• INH undergoes N-acetylation and hydrolysis
• INH acetylation is genetically regulated, with fast acetylators having a 90” serum ½ life, while slow acetylators have a 3-4° serum ½ life
• Excretion is from glomerular filtration and secretion as metabolites
• Slow acetylators excrete more of the parent compound
ADEs
• Hepatitis
• If hepatitis is not recognized and INH is continued, death can be the result
• Chance of hepatitis increases with age, in those who are also on Rifampin and in those who drink ETOH daily
• Peripheral neuropathy—paresthesias of hands and feet—due to a relative Pyridoxine deficiency—daily supplementation with B6 is mandatory
• Convulsions—in those prone to seizures
• Rash and fever signal hypersensitivity
• INH inhibits breakdown of Carbamazepine and Phenytoin—so SE of these drugs of these can be amplified
RIFAMYCINS—
RIFAMPIN,
RIFABUTIN,
RIFAPENTINE
Group of similar macrocyclic antibiotics that are considered 1st line for TB
Rifampin has broader coverage
than does INH and can be used
for several bacterial infections
Resistant strains can occur
rapidly—so it is never given as
monotherapy for TB
MOA
• Blocks RNA transcription by interfering with the ß subunit of mycobacterial DNA-
dependent RNA polymerase
Antimicrobial Spectrum
• Bactericidal for intracellular and
extracellular mycobacteria, including M. tuberculosis, M. kansasii and M. avium complex [MAC]
• Effective for many Gram + and Gram –
pathogens and is used to prevent meningitis in those exposed to Meningococci or H. influenzae
• Highly active against M. leprae
Resistance
• Caused by mutations in affinity for the bacterial DNA-dependent RNA polymerase gene for the drug
Pharmacokinetics
• Absorption is adequate after oral dose
• Distribution occurs in all body fluids and organs
• Concentrations attained in the CSF are variable—10 to 20 percent of blood
concentrations
• Taken up by the liver and undergoes enterohepatic recycling
• Can induce liver CYP 450 enzymes and transporters—causing many drug interactions
• Rifampin undergoes autoinduction—causing shortened elimination ½ life over the 1st 2 weeks of dosing
• Elimination of the drug and its metabolites is via the bile and feces—a small amount
is excreted in the urine
• Urine/feces/other secretions will become orange-red in color; contact lens will be
stained
ADEs
• Nausea
• Vomiting
• Rash
• Hepatitis and death from liver failure [rare]
• Use cautiously in alcoholics, older patients and in those with chronic liver disease
• Modest increase in chance of liver
dysfunction when given with INH and Pyrazinamide
• When dosed intermittently at high dose, flu-like syndrome can occur—fever, chills, muscle aches that can progress to ARF, hemolytic anemia and shock
Drug Interactions
• Induces phase I CYP 450 enzymes and phase II enzymes—it can decrease the ½ life of co-administered drugs that are
metabolized by these enzymes
• HIV PIs
• Methadone
• OCP
• Prednisone
• Propranolol
• Quinidine
• Sulfonylureas
• Voriconazole
• Warfarin
This decreased ½ life may mean increasing the dose of the other drug, switch to a drug not affected by Rifampin or change Rifampin to Rifabutin
RIFABUTIN
Derivative of Rifampin—preferred to
treat TB in those that are HIV + on PIs
or several NNRTIs
It is less potent inducer of CYP 450
enzymes, thus less drug interactions
ADEs similar to Rifampin, but can also
cause uveitis, hyperpigmentation and
neutropenia
RIFAPENTINE
Has a longer ½ life than Rifampin
With INH, can be used weekly in those with LTBI and in selected HIV negative patients
with minimal pulmonary TB
PYRAZINAMIDE
Synthetic, oral agent used short-term
with INH, Rifampin and Ethambutol
MOA is unknown
Must be hydrolyzed by pyrazinamidase to pyrazinoic acid
Active against TB in acidic lesions and in macrophages
Distributes throughout body, penetrates
CSF
Can contribute to liver dysfunction
Causes uric acid retention [but gout
uncommon]
Most benefit occurs early in treatment—
so agent is only used 8 weeks in a 24
week regimen
ETHAMBUTOL
• Bacteriostatic and first line for mycobacteria
• Inhibits arabinosyl transferase—an enzyme important for the synthesis of mycobacterial cell wall
• Used with INH, Pyrazinamide and Rifampin pending cultures and susceptibility
• Distributes well throughout body, but CSF penetration is variable—question if it is adequate for TB meningitis
• Parent drug and metabolites are excreted in the urine
• ADEs—optic neuritis—which affects vision and ability to see red and green
• Risk increases with higher doses and in those with CKD
• Visual acuity and color discrimination should be checked before prescribing and periodically during therapy
• Uric acid excretion is decreased—caution in those with a history of gout
ALTERNATIVE SECOND LINE DRUGS
Streptomycin
• Aminoglycoside
• One of 1st TB drugs
• Action greatest for extracellular organisms
• If isolate is resistant to Streptomycin—can
be treated with Kanamycin or Amikacin [bacilli remain sensitive to these agents]
Para-Aminosalicylic Acid
• Works by folic acid inhibition
• Largely replaced by Ethambutol, but remains important part of many MDR-TB
regimens
Capreomycin
• Parenterally administered polypeptide that
inhibits protein synthesis very much like aminoglycosides
• Reserved to treat MDR-TB
• Careful monitoring of renal function and
hearing is needed
Cycloserine
• Oral TB drug that disrupts D-alanine incorporation into bacterial cell wall
• Distributes well throughout body fluids and CSF
• Excreted unchanged in the urine
• Accumulation in those with CKD
• ADEs—CNS disturbances [lethargy, difficulty concentrating, anxiety, SI] and
seizures have been seen
Ethionamide
• Structural analog of INH—disrupts mycolic acid synthesis
• MOA is not identical to INH, but some overlap in resistance patterns
• Widely distributed throughout the body and CSF
• Metabolism is in the liver to active and inactive metabolites
• ADEs limit its use—nausea, vomiting, hepatoxicity, hypothyroidism, gynecomastia,
alopecia, impotence and CNS have been reported
Fluoroquinolones
• Moxifloxacin and levofloxacin have a role
in MDR-TB
• Some NTM are also susceptible
Macrolides
• Azithromycin and Clarithromycin are used in regimens for several NTM—including MAC
• Azithromycin may be preferred for those at risk for drug interactions as Clarithromycin is both a substrate and an inhibitor of CP 450 enzymes
Bedaquiline
• ATP synthase inhibitor
• Approved to treat MDR-TB
• Given orally
• Active against many types of mycobacteria
• BB warning for QTc prolongation, monitoring of EKG is necessary
• Elevated LFTs has been seen, so these
must be monitored
• Metabolized by CYP 450 3A4
• Administration with strong CYP 450
3A4 inducers [such as Rifampin] should
be avoided
DRUGS FOR LEPROSY
• Skin infection with M. leprae
• Uncommon in US—but still a major problem world wide
DAPSONE
• Structurally related to sulfonamides; inhibits dihydropteroate synthase in the folate synthesis pathway
• Bacteriostatic for M. leprae; some resistant strains can be seen
• Also used to treat pneumonia from Pneumocystis jirovecii in the
immunosuppressed
• Well absorbed from the GI tract
• Distributed throughout the body, with high concentrations in the skin
• Hepatic acetylation
• Parent drug and metabolites are eliminated in the urine
• ADEs—hemolysis, methemoglobulinemia [highest risk in those with G6PD deficiency] and peripheral neuropathy
CLOFAZIMINE
• Phenazine dye
• MOA involves binding to DNA; its redox
properties causes formation of cytotoxic O2
radicals that are toxic to the bacilli
• Bactericidal
• Potentially useful to treat M. tuberculosis and NTM
• Recommended by WHO as part of a shorter
regimen [9-12 months] for MDR-TB
• Given orally; accumulates in the tissues, allowing intermittent therapy—does not enter the CNS
• Pink to brownish-black discoloration of the skin occurs—tell patient in advance
• Eosinophilic enteritis [requiring surgery] has occurred
• Has anti-inflammatory and anti-immune properties
• Erythema nodosum may not develop in patients on this drug
ANTIFUNGAL
DRUGS
OVERVIEW
• Infections from fungus are called mycoses
• May involve the skin only—cutaneous mycoses extending into the epidermis or may be subcutaneous or systemic
• Fungi have rigid cell walls composed of chitin rather than peptidoglycan [what is seen in bacteria]
• Fungal cell membrane contains ergosterol rather than cholesterol
• Fungi are generally resistant to antibiotics, and bacteria are resistant to antifungal agents
• Incidence of candidemia has been on the rise in the last decade—this is thought to be related to the increased number of patients with chronic immunosuppression—organ transplant patients, chemotherapy, biologics to treat autoimmune and/or HIV infection
ORGANISMS IN THE KINGDOM OF FUNGI…
• Newest bad actor—Candida auris
• Candida has 20 different species—it is a yeast that is considered part of our normal flora—overgrowth occurs in diabetics, those on long-term antibiotics and in those that are immunosuppressed
• Candidiasis is treated with polyenes, azoles, nucleoside analogs, echinocandins and allylamines—depending on infection site and
severity
• Echinocandins are preferred for invasive Candidiasis, candidemia and esophageal candidiasis
First isolated in 2009, this yeast is hard to
identify and difficult to treat
It affects all ages—especially those who have had long hospitalizations, been in an ICU, been in a NH, received indwelling medical devices or surgery, been on long term antibiotic therapy or TPN
MDR-C. auris is related to preventative use of antifungal drugs
90% of C. auris is resistant to Fluconazole, 30% is resistant to Amphotericin B and 5% are resistant to echinocandins
In 2019, in neonates 2 months and younger, the DOC is Amphotericin B deoxycholate
2nd line is liposomal Amphotericin B
If treatment fails, and no CNS
involvement has been identified, the
echinocandins can be considered
For adults and children older than 2 months, echinocandins are the DOC
