Mepropnen
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Here is a comprehensive overview of Meropenem, sourced from Goodman & Gilman's The Pharmacological Basis of Therapeutics:
Meropenem
Meropenem is a carbapenem β-lactam antibiotic and a derivative of thienamycin. Unlike imipenem, it does not require co-administration with cilastatin because it is not degraded by renal dipeptidase. It may also be co-formulated with the β-lactamase inhibitor vaborbactam.
Mechanism of Action
Like all β-lactams, meropenem binds to penicillin-binding proteins (PBPs), disrupting bacterial cell wall synthesis and causing death of susceptible organisms. It is highly resistant to hydrolysis by most β-lactamases.
Antimicrobial Spectrum
Meropenem's activity is broadly similar to imipenem, with key differences:
- Less active against gram-positive organisms (particularly Enterococcus)
- More active against gram-negative organisms
Susceptible organisms include:
- Most Enterobacterales (except carbapenemase-producing strains)
- Pseudomonas aeruginosa and Acinetobacter (though resistance is increasing)
- Anaerobes including Bacteroides fragilis
Meropenem/vaborbactam extends coverage to most carbapenemase-producing Enterobacterales, but not metallo-β-lactamase producers.
Pharmacokinetics (ADME)
- Not absorbed orally — administered IV
- Half-life (t½): ~1 hour
- Renal excretion: ~70% of the active drug recovered in urine
- Dose adjustment required in renal insufficiency
Standard Dosing
- Meropenem: 0.5–1 g IV every 8 hours in normal renal function
- Meropenem/vaborbactam: 2 g meropenem + 2 g vaborbactam IV every 8 hours in normal renal function
Adverse Effects
- Seizures — less common than with imipenem (meropenem has a lower seizure threshold risk)
- Nausea, vomiting
- Cross-reactivity possible in patients with severe β-lactam allergy (rare)
Clinical Uses
Meropenem is used for serious infections caused by multidrug-resistant organisms, including:
- Hospital-acquired / ventilator-associated pneumonia
- Complicated urinary tract infections (cUTI) — particularly with vaborbactam formulation (FDA-approved)
- Intra-abdominal infections
- Meningitis (including nosocomial)
- Febrile neutropenia
- Infections due to carbapenem-resistant Enterobacterales (CRE) — meropenem/vaborbactam reserved for MDR gram-negative pathogens
— Goodman & Gilman's The Pharmacological Basis of Therapeutics
— The Washington Manual of Medical Therapeutics
Caushing syndrome
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Cushing Syndrome
Cushing syndrome is the clinical condition resulting from prolonged exposure to excess glucocorticoids (hypercortisolism), either from endogenous overproduction or exogenous administration.
Epidemiology
- Rare: occurs in 2–5 per million people per year
- Requires multidisciplinary care: endocrinologists, neurosurgeons, internists, and adrenal surgeons
Pathophysiology & the HPA Axis
The hypothalamic-pituitary-adrenal (HPA) axis normally regulates cortisol:
- Hypothalamus → releases CRH (corticotropin-releasing hormone)
- Anterior pituitary → releases ACTH (corticotropin) in response to CRH
- Adrenal cortex (zona fasciculata) → secretes up to 20 mg of cortisol/day
- Cortisol feeds back negatively to suppress both CRH and ACTH
Cortisol secretion follows a circadian rhythm — highest in the morning, nadir at ~11 PM. Disruption of this rhythm is considered pathologic.
Causes (Classification)
| Category | Cause |
|---|---|
| Exogenous | Iatrogenic glucocorticoid administration (most common overall) |
| ACTH-dependent | Cushing disease (pituitary adenoma secreting ACTH) — most common endogenous cause; Ectopic ACTH syndrome (e.g., small cell lung cancer) |
| ACTH-independent | Adrenal adenoma, adrenal carcinoma, bilateral adrenal hyperplasia |
Cushing disease specifically refers to a pituitary ACTH-secreting adenoma — it is the most common cause of endogenous Cushing syndrome (~70%).
Clinical Features
Classic signs and symptoms:
- Central obesity — truncal fat deposition, buffalo hump, moon facies
- Skin changes — purple/violaceous striae, skin thinning, easy bruising, poor wound healing
- Muscle weakness — proximal myopathy
- Hypertension
- Hyperglycemia / diabetes mellitus
- Osteoporosis — due to cortisol's anti-anabolic effects on bone
- Psychiatric disturbances — depression, cognitive dysfunction, psychosis
- Hypogonadism / menstrual irregularities — from excess adrenal androgens
- Immunosuppression — increased susceptibility to infections
- Hypokalemia — especially in ectopic ACTH syndrome
Diagnosis
Screening tests (confirm hypercortisolism):
- 24-hour urinary free cortisol (elevated)
- Late-night salivary cortisol (elevated — reflects loss of circadian rhythm)
- Overnight low-dose dexamethasone suppression test (1 mg DST) — failure to suppress cortisol to <1.8 µg/dL is abnormal
Localization (once hypercortisolism confirmed):
- Plasma ACTH level:
- Low/undetectable → ACTH-independent (adrenal source)
- Normal/elevated → ACTH-dependent (pituitary or ectopic)
- High-dose DST and CRH stimulation test to distinguish pituitary vs. ectopic ACTH
- Pituitary MRI — for Cushing disease
- Inferior petrosal sinus sampling (IPSS) — gold standard for localizing pituitary source
- CT chest/abdomen — for ectopic ACTH source
- Adrenal CT/MRI — for adrenal causes
Treatment
| Cause | Treatment |
|---|---|
| Cushing disease (pituitary adenoma) | Transsphenoidal surgery (first-line); radiotherapy if surgery fails |
| Ectopic ACTH | Resect tumor if possible; bilateral adrenalectomy if not |
| Adrenal adenoma | Laparoscopic adrenalectomy |
| Adrenocortical carcinoma | Surgical resection ± mitotane |
| Exogenous | Taper and discontinue glucocorticoids |
Medical therapy (for unresectable or recurrent disease):
- Steroidogenesis inhibitors: ketoconazole, metyrapone, mitotane, etomidate
- Glucocorticoid receptor antagonist: mifepristone
- Pituitary-directed: pasireotide (somatostatin analog), cabergoline
Complications
- Cardiovascular disease (major cause of mortality)
- Adrenal insufficiency after surgery (requires glucocorticoid replacement during recovery)
- Persistent osteoporosis and fractures
— Campbell-Walsh-Wein Urology, 3-Volume Set
— Adams and Victor's Principles of Neurology, 12th Edition
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