Vancomycin

Vancomycin

Vancomycin is an antibiotic produced by Streptococcus orientalis and Amycolatopsis orientalis. With the single exception of flavobacterium, it is active only against gram-positive bacteria, particularly staphylococci. Vancomycin is a glycopeptide of molecular weight 1500. It is water soluble and quite stable.

Mechanisms of Action & Basis of Resistance

Vancomycin inhibits cell wall synthesis by binding firmly to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide (Figure 43–5). This inhibits the transglycosylase, preventing further elongation of peptidoglycan and cross-linking. The peptidoglycan is thus weakened, and the cell becomes susceptible to lysis. The cell membrane is also damaged, which contributes to the antibacterial effect.

Resistance to vancomycin in enterococci is due to modification of the D -Ala-D -Ala binding site of the peptidoglycan building block in which the terminal D -Ala is replaced by D -lactate. This results in the loss of a critical hydrogen bond that facilitates high-affinity binding of vancomycin to its target and loss of activity. This mechanism is also present in vancomycin-resistant S aureus strains (MIC 16 mcg/mL), which have acquired the enterococcal resistance determinants. The underlying mechanism for reduced vancomycin susceptibility in vancomycin-intermediate strains (MICs 4–8 mcg/mL) of S aureus is not known. However these strains have altered cell wall metabolism that results in a thickened cell wall with increased numbers of D-Ala-D-Ala residues, which serve as dead-end binding sites for vancomycin. Vancomycin is sequestered within the cell wall by these false targets and is unable to reach its site of action.

Antibacterial Activity

Vancomycin is bactericidal for gram-positive bacteria in concentrations of 0.5–10 mcg/mL. Most pathogenic staphylococci, including those producing lactamase and those resistant to nafcillin and methicillin, are killed by 2 mcg/mL or less. Vancomycin kills staphylococci relatively slowly and only if cells are actively dividing; the rate is less than that of the penicillins both in vitro and in vivo. Vancomycin is synergistic in vitro with gentamicin and streptomycin against Enterococcus faecium and Enterococcus faecalis strains that do not exhibit high levels of aminoglycoside resistance.

Pharmacokinetics

Vancomycin is poorly absorbed from the intestinal tract and is administered orally only for the treatment of antibiotic-associated enterocolitis caused by C difficile. Parenteral doses must be administered intravenously. A 1-hour intravenous infusion of 1 g produces blood levels of 15–30 mcg/mL for 1–2 hours. The drug is widely distributed in the body. Cerebrospinal fluid levels 7–30% of simultaneous serum concentrations are achieved if there is meningeal inflammation. Ninety percent of the drug is excreted by glomerular filtration. In the presence of renal insufficiency, striking accumulation may occur (Table 43–2). In functionally anephric patients, the half-life of vancomycin is 6–10 days. A significant amount (roughly 50%) of vancomycin is removed during a standard hemodialysis run when a modern, high-flux membrane is used.

Clinical Uses

The main indication for parenteral vancomycin is sepsis or endocarditis caused by methicillin-resistant staphylococci. However, vancomycin is not as effective as an antistaphylococcal penicillin for treatment of serious infections such as endocarditis caused by methicillin-susceptible strains. Vancomycin in combination with gentamicin is an alternative regimen for treatment of enterococcal endocarditis in a patient with serious penicillin allergy. Vancomycin (in combination with cefotaxime, ceftriaxone, or rifampin) is also recommended for treatment of meningitis suspected or known to be caused by a highly penicillin-resistant strain of pneumococcus (ie, MIC > 1 mcg/mL). The recommended dosage is 30 mg/kg/d in two or three divided doses. A typical dosing regimen for most infections in adults with normal renal function is 1 g every 12 hours. The dosage in children is 40 mg/kg/d in three or four divided doses. Clearance of vancomycin is directly proportional to creatinine clearance, and the dosage is reduced accordingly in patients with renal insufficiency. For functionally anephric adult patients, a 1-g dose administered once a week is usually sufficient. Patients receiving a prolonged course of therapy should have serum concentrations checked. Recommended trough concentrations are 10–15 mcg/mL.

Oral vancomycin, 0.125–0.25 g every 6 hours, is used to treat antibiotic-associated enterocolitis caused by C difficile. Because of the emergence of vancomycin-resistant enterococci and the selective pressure of oral vancomycin for these resistant organisms, metronidazole had been preferred as initial therapy over the last two decades. However, recent clinical data suggest that vancomycin is associated with a better clinical response than metronidazole for more severe cases of C difficile enterocolitis. Therefore, oral vancomycin may be used as a first line treatment for severe cases or for cases that fail to respond to metronidazole.

Adverse Reactions

Adverse reactions are encountered in about 10% of cases. Most reactions are minor. Vancomycin is irritating to tissue, resulting in phlebitis at the site of injection. Chills and fever may occur. Ototoxicity is rare and nephrotoxicity uncommon with current preparations. However, administration with another ototoxic or nephrotoxic drug, such as an aminoglycoside, increases the risk of these toxicities. Ototoxicity can be minimized by maintaining peak serum concentrations below 60 mcg/mL. Among the more common reactions is the so-called "red man" or "red neck" syndrome. This infusion-related flushing is caused by release of histamine. It can be largely prevented by prolonging the infusion period to 1–2 hours.

HYDROXYUREA

Hydroxycarbamide (INN) or hydroxyurea (brand names include Hydrea and Droxia) is an antineoplastic drug, first synthesized in 1869, used in myeloproliferative disorders, specifically polycythemia vera and essential thrombocythemia. It is also used to reduce the rate of painful attacks in sickle-cell disease and has antiretroviral properties in diseases such as AIDS.

Mechanism of action

One mechanism of action is thought to be based on its reduction of production of deoxyribonucleotides[1] via inhibition of the enzyme ribonucleotide reductase by scavenging tyrosyl free radicals as they are involved in the reduction NDPs.[2]

In the treatment of sickle-cell disease, hydroxycarbamide increases the concentration of fetal hemoglobin. The precise mechanism of action is not yet clear, but it appears that hydroxycarbamide increases nitric oxide levels, causing soluble guanylyl cyclase activation with a resultant rise in cyclic GMP, and the activation of gammaglobulin synthesis necessary for fetal hemoglobin (by removing the rapidly dividing cells that preferentially produce sickle hemoglobin).[2][3]

[edit]Uses

Hydroxycarbamide is used for the following indications:

Myeloproliferative disease (primarily polycythemia vera and essential thrombocytosis[4])

Sickle-cell disease[5] (breaks down cells that are prone to sickle, as well as increasing fetal hemoglobin content)

AIDS as an adjunct to ddI in combination antiretroviral therapies[6]

Second line treatment for psoriasis[7] (slows down the rapid division of skin cells)

Biochemical research as a DNA replication inhibitor[8] that causes deoxyribonucleotide depletion and results in DNA double strand breaks near replication forks (see DNA repair)

Treatment for systemic mastocytosis[citation needed]

[edit]Dose

The dose depends on the indication, but tends to be 500 milligrams once a day when treatment is initiated. In myeloproliferative disease, further increases are determined by the response of the cell count and whether myelosuppression (decreased production of other blood cells) develops.[citation needed]

In sickle-cell disease, the initial daily dose is 15 mg per kilogram body weight (or less in reduced kidney function); after two weeks, a fall in the hemoglobin and platelet count and an increase in MCV (mean corpuscular volume) (size of the red blood cells) is to be expected. The dose is then increased every two weeks with monitoring of the full blood count until the dose is either 35 mg/kg or cytopenias develop.[2]

[edit]Side effects

Reported side-effects are: drowsiness, nausea, vomiting and diarrhea, constipation, mucositis, anorexia, stomatitis, bone marrow toxicity (which may take 7–21 days to recover after the drug has been discontinued), alopecia (hair loss), skin changes, abnormal liver enzymes, creatinine and blood urea nitrogen.[9]

Due to its effect on the bone marrow, regular monitoring of the full blood count is vital, as well as early response to possible infections. In addition, renal function, uric acid and electrolytes, as well as liver enzymes, are commonly checked.[citation needed]

Hydroxycarbamide has been used primarily for the treatment of myeloproliferative diseases, which has an inherent risk of transforming to acute myeloid leukemia. There has been a longstanding concern that hydroxycarbamide itself carries a leukemia risk, but large studies have shown that the risk is either absent or very small. Nevertheless, it has been a barrier for its wider use in patients with sickle-cell disease.[2]

[edit]Contraindications

Contraindications are: severe anemia, neutropenia.[citation needed]

[edit]Use in pregnancy

Category D - investigational or post-marketing data show risk to the fetus. However, potential benefits may outweigh the potential risk. Generally this rating is reserved for drugs with no safer alternatives.[9]

[edit]Synthesis

Hydroxyurea was first synthesized in 1869 by Dresler and Stein from hydroxylamine and hydrogen cyanide; the industrial process is analogous.[10] Hydroxyurea may also be synthesized by reaction of ethyl carbamate with hydroxylamine; hydroxylamine displaces the ester to give the amide.[11]

Labetalol

Labetalol is formulated as a racemic mixture of four isomers (it has two centers of asymmetry). Two of these isomers—the (S,S)- and (R,S)-isomers—are relatively inactive, a third (S,R)- is a potent blocker, and the last (R,R)- is a potent blocker. Labetalol has a 3:1 ratio of B:alpha antagonism after oral dosing. Blood pressure is lowered by reduction of systemic vascular resistance (via blockade) without significant alteration in heart rate or cardiac output. Because of its combined - and -blocking activity, labetalol is useful in treating the hypertension of pheochromocytoma and hypertensive emergencies. Oral daily doses of labetalol range from 200 to 2400 mg/d. Labetalol is given as repeated intravenous bolus injections of 20–80 mg to treat hypertensive emergencies

Emergency hypertension: 40-80mg every 10 minutes

Labetalol

Labetalol is formulated as a racemic mixture of four isomers (it has two centers of asymmetry). Two of these isomers—the (S,S)- and (R,S)-isomers—are relatively inactive, a third (S,R)- is a potent blocker, and the last (R,R)- is a potent blocker. Labetalol has a 3:1 ratio of B:alpha antagonism after oral dosing. Blood pressure is lowered by reduction of systemic vascular resistance (via blockade) without significant alteration in heart rate or cardiac output. Because of its combined - and -blocking activity, labetalol is useful in treating the hypertension of pheochromocytoma and hypertensive emergencies. Oral daily doses of labetalol range from 200 to 2400 mg/d. Labetalol is given as repeated intravenous bolus injections of 20–80 mg to treat hypertensive emergencies

Protamine

Excessive anticoagulant action of heparin is treated by discontinuance of the drug. If bleeding occurs, administration of a specific antagonist such as protamine sulfate is indicated. Protamine is a highly basic peptide that combines with heparin as an ion pair to form a stable complex devoid of anticoagulant activity. For every 100 units of heparin remaining in the patient, 1 mg of protamine sulfate is given intravenously; the rate of infusion should not exceed 50 mg in any 10-minute period. Excess protamine must be avoided; it also has an anticoagulant effect. Neutralization of LMW heparin by protamine is incomplete. Limited experience suggests that 1 mg of protamine sulfate may be used to partially neutralize 1 mg of enoxaparin. Protamine will not reverse the activity of fondaparinux. Excess danaparoid can be removed by plasmapheresis

Piperacillin/Tazobactam

Piperacillin/tazobactam

Antibiotic Class:

Beta-lactam/beta-lactamase inhibitor

Antimicrobial Spectrum:

Staphylococcus aureus (methicillin susceptible), Coagulase negative Staphylococci, Streptococcus pneumoniae (penicillin susceptible), Streptococcus spp., Haemophilus influenzae, Moraxella catarrhalis, Neisseria meningitides, Neisseria gonorrhoeae, Enterobacteriaceae, E. coli, Pseudomonas aeruginosa

Mechanism of Action:

The beta-lactamase inhibitors are recognized as substrates for the beta-lactamases produced by bacteria. This allows the actual beta-lactams to attack the bacterial cell wall by binding to penicillin binding proteins

Pharmacodynamics:

Time dependent killer (Time > MIC)

Pharmacokinetics:

(of the tazobactam)

Dose 200mg: Cmax: 29 mcg/L; Protein binding: 20-23%; Volume of distribution: 0.18-0.33L/kg; Table 5

Adverse Effects:

No new adverse effects are seen as a result of adding beta-lactamase inhibitors to beta-lactam antibiotics. The adverse reactions would remain the same for the parent compound

Dosage:

IV: Complete listing on Table 6

Dosing in adults:

Mild/Moderate: 2.25-3.375g q6h

Severe: 3.375-4.5g q6h

Dosing in pediatrics:

Not indicated in children < 12 years of age

Table 8

Disease state based dosing:

Renal failure: CrCl > 40mL/min: 3.375g q4-6h

CrCl 20-40mL/min: 2.25g q6h

CrCl < 20mL/min: 2.25g q8h

Hepatic failure: Dosage adjustment not necessary

Table 9

Dosing during Continuous Renal Replacement Therapy

CVVH (Continuous venovenous hemofiltration): 2.25g IV q6h

CVVHD (Continuous venovenous hemodialysis): 2.25-3.375g IV q6h

CVVHDF (Continuous venovenous hemodiafiltration) 2.25g-3.375g IV q6h

Note: CVVH is mainly for fluid removal alone. Many institutions will employ more CVVHD or CVVHDF which combine dialysis with fluid removal.

Contraindications/Warnings/Precautions:

Precautions: hypersensitivity to penicillins, history of gastrointestinal disease, particularly colitis, renal impairment

Drug Interactions:

Live Typhoid Vaccine - decreased immunological response to the typhoid vaccine

Methotrexate – increased methotrexate toxicity

Probenecid - increased piperacillin levels

Vecuronium - enhanced and/or prolonged neuromuscular blockade which may lead to respiratory depression and paralysis

Pregnancy:

Category B: No evidence of risk in humans but studies inadequate.

Monitoring Requirements:

Therapeutic: Culture and sensitivities, serum levels, signs and symptoms of infection, white blood cell count

Toxic: Urinalysis, BUN, SCr, AST and ALT, skin rash, Neutropenia and leukopenia,

Brand names/Manufacturer: Zosyn/Wyeth pharmaceuticals

Cisplatin

Cisplatin has major antitumor activity in a broad range of solid tumors, including non-small cell and small cell lung cancer, esophageal and gastric cancer, head and neck cancer, and genitourinary cancers, particularly testicular, ovarian, and bladder cancer. When used in combination regimens, cisplatin-based therapy has led to the cure of nonseminomatous testicular cancer. In terms of clinical pharmacology, cisplatin and the other platinum analogs are extensively cleared by the kidneys and excreted in the urine. As a result, dose modification is required in the setting of renal dysfunction

Cisplatin has a number of side-effects that can limit its use:

Nephrotoxicity (kidney damage) is a major concern. The dose is reduced when the patient's creatinine clearance (a measure of renal function) is reduced. Adequate hydration and diuresis is used to prevent renal damage. The nephrotoxicity of platinum-class drugs seems to be related to reactive oxygen species and in animal models can be ameliorated by free radical scavenging agents (e.g., amifostine). Nephrotoxicity is a dose-limiting.

Neurotoxicity (nerve damage) can be anticipated by performing nerve conduction studies before and after treatment.

Nausea and vomiting: cisplatin is one of the most emetogenic chemotherapy agents, but this symptom is managed with prophylactic antiemetics (ondansetron, granisetron, etc.) in combination with corticosteroids. Aprepitant combined with ondansetron and dexamethasone has been shown to be better for highly emetogenic chemotherapy than just ondansetron and dexamethasone.

Ototoxicity (hearing loss): unfortunately there is at present no effective treatment to prevent this side effect, which may be severe. Audiometric analysis may be necessary to assess the severity of ototoxicity. Other drugs (such as the aminoglycoside antibiotic class) may also cause ototoxicity, and the administration of this class of antibiotics in patients receiving cisplatin is generally avoided. The ototoxicity of both the aminoglycosides and cisplatin may be related to their ability to bind to melanin in the stria vascularis of the inner ear or the generation of reactive oxygen species.

Electrolyte disturbance: Cisplatin can cause hypomagnesaemia, hypokalaemia and hypocalcaemia. The hypocalcaemia seems to occur in those with low serum magnesium secondary to cisplatin, so it is not primarily due to the Cisplatin