Inj amphoterium
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amphotericin B injection pharmacology mechanism dosage indications
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Here is a detailed overview of Injection Amphotericin B:
Injection Amphotericin B (Inj. AmB)
Class & Source
- Class: Polyene macrolide antifungal antibiotic
- Source: Produced by Streptomyces nodosus
- Chemistry: Heptaene macrolide - contains 7 conjugated trans-double bonds and an aminosugar (mycosamine) connected via a glycosidic bond. Amphoteric properties (hence the name) from a carboxyl + primary amino group.
Mechanism of Action
Amphotericin B exerts its antifungal effect by binding ergosterol in the fungal cell membrane (ergosterol is the fungal equivalent of cholesterol). Two proposed mechanisms:
- Pore formation - inserts into the membrane and forms channels, increasing permeability and causing leakage of intracellular ions and molecules
- Ergosterol sequestration (sponge model) - recent evidence suggests AmB aggregates sequester ergosterol from the lipid bilayer, leading to fungal cell death
Because mammalian cells use cholesterol instead of ergosterol, AmB has selective toxicity for fungi - though it does bind cholesterol to a lesser degree, which accounts for its toxicity.
The drug is fungicidal (kills fungi) rather than merely fungistatic.
Formulations
Since amphotericin B is nearly insoluble in water, it requires special formulations:
| Formulation | Description | Dose (mg/kg/day) |
|---|---|---|
| C-AMB (Fungizone) | Conventional - complexed with sodium deoxycholate; micelles | 0.5-1 |
| ABCD | Amphotericin B colloidal dispersion | 3-4 |
| ABLC | Amphotericin B lipid complex | 5 |
| L-AMB (AmBisome) | Liposomal amphotericin B | 3-5 |
Lipid formulations were developed to reduce toxicity - the lipid vehicle acts as a reservoir, reducing non-specific binding to human cell membranes. Liposomal AmB (L-AMB) has the least toxicity of all formulations.
Key rule: All formulations must be infused in 5% dextrose - no electrolytes added, as electrolytes cause the colloid to aggregate.
Spectrum of Activity
Amphotericin B has the broadest antifungal spectrum of any agent. Active against:
- Candida spp. (all, except C. lusitaniae and sometimes C. auris)
- Aspergillus spp. (except A. terreus and A. nidulans - primary resistance)
- Cryptococcus neoformans
- Histoplasma capsulatum
- Blastomyces dermatitidis
- Coccidioides immitis
- Mucor/Rhizopus (Mucormycosis) - one of few agents active here
- Paracoccidioides brasiliensis
- Talaromyces marneffei
Resistant organisms: Aspergillus terreus, A. nidulans, Scedosporium, Lomentospora, Trichosporon spp.
Also active against the protozoan Leishmania (visceral leishmaniasis).
Indications (First-Line Uses)
| Indication | Preferred Formulation | Dose |
|---|---|---|
| Cryptococcal meningitis (HIV) | L-AMB | 3-5 mg/kg/day x 2 weeks induction |
| Disseminated histoplasmosis | L-AMB | 3 mg/kg/day |
| Mucormycosis | L-AMB | 5 mg/kg/day |
| Talaromycosis | L-AMB | 3 mg/kg/day |
| Visceral leishmaniasis | L-AMB | Single dose 40 mg/kg OR 30 mg/kg + miltefosine |
| Invasive aspergillosis (azole-resistant) | L-AMB | 3 mg/kg/day |
| Empirical therapy in febrile neutropenia | L-AMB | 3 mg/kg/day |
Dosing & Administration
- Route: IV infusion only
- Infusion time: Over 2-6 hours (never rapid - can cause acute hyperkalemia and ventricular fibrillation in renal failure)
- Test dose: 1 mg IV over 15 minutes before the first dose (10 mg for L-AMB) - to gauge infusion reactions
- Conventional dose: 0.5-1 mg/kg/day IV
- Liposomal dose: 3 mg/kg/day (up to 5 mg/kg for mucormycosis)
- Intravenous fluid: 5% dextrose only - no saline/electrolytes
- Use in-line filters >1 micron (filters <0.22 micron remove drug)
Adverse Effects
Infusion-Related Reactions (Acute - nearly universal with C-AMB)
- Fever, chills/rigors, headache, nausea, vomiting, hypotension, muscle spasms
- Much less common with L-AMB
- Management: slow infusion rate; premedicate with paracetamol (acetaminophen), antihistamines, meperidine (for rigors), or corticosteroids
Cumulative/Chronic Toxicity
- Nephrotoxicity - most significant; occurs in nearly all patients on C-AMB:
- Reversible component: decreased renal perfusion (prerenal) - attenuated with sodium loading (normal saline infusion)
- Irreversible component: renal tubular injury, usually with cumulative dose >4 g
- Renal tubular acidosis, potassium wasting, magnesium wasting
- Anemia - reduced erythropoietin from renal tubular damage
- Hepatotoxicity - occasional raised LFTs
- After intrathecal use: chemical arachnoiditis, seizures, serious neurologic complications
Lipid formulations significantly reduce nephrotoxicity - 3x higher doses achieve the same efficacy with less renal damage.
Drug Interactions
| Interaction | Effect |
|---|---|
| Other nephrotoxic drugs (aminoglycosides, cyclosporine) | Worsens azotemia |
| Flucytosine (5-FC) | AmB-induced renal dysfunction increases 5-FC levels → toxicity |
| Sodium stibogluconate (in leishmaniasis) | Combination should be avoided - increased toxicity |
| Corticosteroids | Reduce infusion reactions but can worsen hypokalemia |
Other Routes of Administration
- Intrathecal: Rarely used for coccidioidal or refractory fungal meningitis; significant toxicity
- Intravitreal: Single dose of 5-10 mcg for fungal endophthalmitis
- Topical eye drops: Mycotic keratitis/corneal ulcers
- Bladder irrigation: Candidal cystitis (no significant systemic absorption)
- Intra-articular injection: Fungal arthritis
Resistance Mechanism
When resistance develops:
- Reduced ergosterol biosynthesis
- Synthesis of alternative sterols that bind AmB less avidly
- Production of oxidant scavengers
Development of resistance in normally susceptible species during therapy is rare - a major advantage of AmB.
Key Memory Points
- "Gold standard" broad-spectrum antifungal - widest spectrum available
- Acts on ergosterol (like other antifungals, but fungicidal vs. fungistatic azoles)
- Nephrotoxicity is the dose-limiting toxicity with conventional formulation
- Lipid formulations = less nephrotoxicity, same spectrum
- Infuse in D5W only - no electrolytes
- Pre-hydrate with normal saline to reduce nephrotoxicity
- Drug of choice for mucormycosis and cryptococcal meningitis
Sources: Katzung's Basic and Clinical Pharmacology, 16th Ed.; Goldman-Cecil Medicine; Goodman & Gilman's Pharmacological Basis of Therapeutics
What is pelvic filariasis
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pelvic filariasis Wuchereria bancrofti clinical features pathology
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Now I have comprehensive information. Here is the full answer:
Pelvic Filariasis
What Is It?
"Pelvic filariasis" is not a separate disease but rather a specific anatomical distribution of lymphatic filariasis (LF) - a parasitic infection caused by filarial nematodes (thread-like worms) that settle in and obstruct the pelvic and genital lymphatics. It is part of the spectrum of bancroftian filariasis (caused by Wuchereria bancrofti), which is the only filarial species that specifically targets genital and pelvic lymphatics.
Causative Organisms
| Species | Pelvic/Genital Involvement |
|---|---|
| Wuchereria bancrofti | Yes - exclusively causes genital and pelvic lymphatic disease |
| Brugia malayi | Rarely (genitalia not typically involved) |
| Brugia timori | Rarely |
W. bancrofti causes >90% of all lymphatic filariasis cases worldwide.
Life Cycle & Transmission
- Vector: Female mosquitoes (Culex, Anopheles, Aedes) - bite an infected person, ingest microfilariae, which mature into infective larvae (L3) in 10-14 days
- Entry: Infective L3 larvae are deposited on skin during a subsequent mosquito bite and penetrate the wound
- Migration: Larvae travel to central lymphatic vessels, particularly the inguinal, iliac, and periaortic lymphatics and male genitalia (epididymis, spermatic cord, testes)
- Maturation: Adult worms develop over 6-9 months; adults live 5-7 years
- Microfilaremia: Mated females release microfilariae into blood, showing nocturnal periodicity (peak at night, coinciding with peak mosquito activity)
Pelvic/Genital Lymphatics Specifically Involved
Adult W. bancrofti worms preferentially reside in:
- Inguinal lymph nodes and lymphatics
- Iliac lymphatics (pelvic)
- Spermatic cord lymphatics
- Epididymis
- Testicular lymphatics
- Retroperitoneal lymphatics (leading to rupture and chyluria)
Stages of Disease
Stage 1: Asymptomatic Microfilaremia
- Blood positive for microfilariae but no clinical symptoms
- Subclinical lymphatic dilation may already be present on ultrasound (scrotal lymphangiectasia, microscopic hematuria/proteinuria)
- Patient acts as a reservoir in the community
Stage 2: Acute Manifestations (Recurrent episodes over months-years)
Acute Adenolymphangitis (ADL) / Filarial Fever
- Retrograde lymphangitis (extends peripherally, unlike bacterial lymphangitis which extends centrally - an important distinguishing feature)
- Painful inguinal lymphadenopathy + fever + chills
- Erythema overlying affected skin
- Episodes last ~1 week and recur repeatedly
Pelvic/Genital Acute Manifestations (exclusive to W. bancrofti)
- Funiculitis - inflammation of the spermatic cord
- Epididymo-orchitis - painful swelling of epididymis and testes
- Scrotal lymphangitis - ruptured lymphatic vesicles on scrotal skin ("lymph scrotum") that produce a whitish discharge
- Pelvic pain from iliac lymphadenitis
Dermatolymphangioadenitis (DLA)
- Fever, chills, myalgias, headache
- Edematous inflammatory plaques, hyperpigmentation, vesicles, and ulcers (often at a prior skin injury site)
- Thought to be driven by secondary bacterial superinfection
Stage 3: Chronic Obstructive Lesions (develops 10-15 years after first attack)
Progressive fibrosis and obstruction of lymphatics leads to permanent structural changes:
Hydrocele - most common chronic manifestation of bancroftian filariasis in men
- Accumulation of fluid in the tunica vaginalis
- Can become massive and debilitating
- Fluid contains cholesterol crystals, RBCs, hemosiderin
- Eventually causes thickening and calcification of the tunica vaginalis
Lymphedema of Genitalia (Elephantiasis)
- Chronic pitting edema progresses to non-pitting "woody" edema
- Massive enlargement of scrotum, penis, vulva
- Elephantiasis affects (in decreasing frequency): legs, scrotum, arms, penis, vulva, breasts
- Subcutaneous fibrosis + epithelial hyperkeratosis
- Secondary bacterial/fungal infections common
Chyluria
- Rupture of retroperitoneal/perirenal lymphatics into the renal pelvis or bladder
- Milky white urine (lymph mixed with urine)
- May be intermittent
- More severe form is chylocele (chylous fluid in tunica vaginalis)
Lymph Scrotum
- Ruptured dermal lymphatic vesicles on scrotal skin
- Oozes milky lymphatic fluid
Pathology
Histological features:
- Adult worms (live, dead, or calcified) in dilated lymphatics or lymph nodes, surrounded by:
- Mild/no inflammation (live worms tolerating immune evasion)
- Intense eosinophilia with hemorrhage and fibrin (recurrent filarial funiculoepididymitis)
- Granulomas (immune reaction to dead/dying worms)
- Dilated lymphatics with polypoid infoldings
- Dilation of dermal lymphatics, widespread lymphocytic infiltrates, focal cholesterol deposits in elephantoid skin
- Epidermis thickening and hyperkeratosis
Immune evasion mechanisms of the worms:
- Elastases and trypsin-like proteases - facilitate tissue invasion
- Surface glycoproteins with antioxidant function - protect against reactive oxygen species
- Cystatins - impair MHC class II antigen presentation
- Serpins - inhibit neutrophil proteases
- TGF-β and macrophage migration inhibition factor homologues - dampen immune response
- Wolbachia (endosymbiont bacteria) - required for worm development; drives proinflammatory responses and contributes to lymphedema
Diagnosis
| Test | Details |
|---|---|
| Night blood smear | Thick/thin Giemsa-stained smear at midnight (nocturnal periodicity); direct microfilaria visualization; ~250-320 µm long |
| Concentration techniques | Knott's concentration, membrane filtration - increase sensitivity |
| Rapid immunochromatographic card test | Detects circulating W. bancrofti antigen (adult worm); can be done any time of day; no equivalent for Brugia |
| Scrotal/pelvic ultrasound | "Filarial dance sign" - pathognomonic; shows live adult worms moving in spermatic cord or scrotal lymphatics |
| PCR | Highly sensitive; currently research use only |
| Serology | Limited value due to cross-reactivity with other nematodes |
Individuals with elephantiasis may be amicrofilaremic - diagnosis then rests on clinical history + compatible epidemiology + antigen test/ultrasound.
Treatment
Antifilarial Drugs
| Drug | Mechanism | Use |
|---|---|---|
| Diethylcarbamazine (DEC) 6 mg/kg single dose | Microfilaricidal + partially macrofilaricidal | Drug of choice for active infection |
| Ivermectin 200 µg/kg | Microfilaricidal | Used in mass drug administration |
| Albendazole 400 mg | Macrofilaricidal | Combined with DEC or ivermectin |
| Doxycycline 200 mg/day x 6 weeks | Kills Wolbachia endosymbionts → impairs worm viability and microfilaria production | Adjunct; reduces VEGF-C and lymphatic dilation |
WHO Mass Drug Administration (MDA) combinations:
- Non-onchocerciasis/non-loiasis endemic areas: DEC + ivermectin + albendazole (all 3 drugs)
- Onchocerciasis co-endemic: Ivermectin + albendazole (DEC omitted - can cause encephalopathy in Loa loa)
- Loiasis co-endemic: Albendazole alone
Management of Chronic Complications
| Complication | Management |
|---|---|
| Lymphedema | Skin hygiene, limb elevation, exercise, elastic stockings; not reversible with DEC except in early stages |
| Hydrocele | Surgical excision and eversion of the tunica vaginalis (hydrocelectomy); redundant scrotal skin excision if needed |
| Chyluria | Bladder origin - fulguration; renal origin - renal pedicle lymphatic disconnection (retroperitoneoscopy); instillation of sclerosants |
| Elephantiasis | Surgical reduction procedures rarely done (largely unsuccessful); focus on hygiene and prevention of secondary infection |
| Lymphedema/ADLA | Paracetamol, amoxicillin/oral penicillin for bacterial superinfection |
Epidemiology
- ~68 million people infected globally (down from much higher figures in 2000s due to MDA programs)
- Endemic in: sub-Saharan Africa, South/Southeast Asia, western Pacific, Haiti, Dominican Republic, parts of South America
- 3rd highest cause of disability-adjusted life years (DALYs) among parasitic infections
- In endemic communities, prevalence rises through the 3rd-4th decade of life
- Genital disease and elephantiasis rare before age 10
Key Summary Points
- Pelvic filariasis = W. bancrofti infection of pelvic and genital lymphatics (exclusive to W. bancrofti)
- Classic triad of chronic bancroftian filariasis: hydrocele + elephantiasis + chyluria
- ADL lymphangitis is retrograde (peripherally extending) - distinguishes it from bacterial lymphangitis
- "Filarial dance sign" on ultrasound is pathognomonic
- Wolbachia endosymbionts are a key treatment target (doxycycline)
- Chronic lymphedema is usually irreversible - prevention is key
Sources: Goldman-Cecil Medicine; Campbell Walsh Wein Urology; Robbins Cotran Pathologic Basis of Disease; Park's Textbook of Preventive & Social Medicine
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