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- Discussion: 
    - for penicillin resistant to staph - MSSA / MRSA - and w/ enterococci endocarditis (in combination with aminoglycosides);
    - it is ineffective against gm neg bacterial (its large molecular weight keeps it from penetrating the outer cell membrane of
           gram-negative bacilli);
    - basic science:
           - blocks glycopeptide polymerization in the bacterial cell wall;
           - time-dependent bacteria killer:
                   - increasing antibiotic concentrations beyond the therapeutic threshold will not result in faster or more killing;
                   - follows concentration-dependent killing up to 1.0 mcg/mL;
                   - above minimum kill level there is concentration-independent killing;
                   - therefore it is the time above the MIC is most important, not the peak concentration obtained (as is with aminoglycosides);
                   - clinically concentrations need to be 3-5 times the MIC (which for staph is usually 1-2 mcg/ml);
                   - trough steady-state concentrations of 5-10 mcg/mL are usually adequate to resolve infections with susceptible organisms;
           - glycocalyx:
                  - vancomycin is a glycopeptide and may have intrinsic ability to bind to glycocalyx;
                  - note that with a glycocalyx formation, the MIC value (and the trough levels) will have to be higher;
                  - ref: In situ measurement of linezolid and vancomycin concentrations in intravascular catheter-associated biofilm
           - staph resistance to Vancomycin:
 note the MIC levels for staph;
                  - 0-2 suseptible
                  - 4-8 is intermediate
                  - resistant is great than 16;

- Therapeutic Options:

     - local applications:
              - properties of vancomyin in calcium sulfate
properties of vancomycin to cement
              - local antibiotic infusion into joints
              - direct application of powdered vancomycin: (to postop wounds and surgical cavities)
                      - references:
                               - Prophylactic intraop vancomycin and postop spinal wound infection: 1,512 surgical cases over a 6-year period.
                               - Intrawound application of vancomycin in thoracolumbar fusions: efficacy, drug levels, and patient outcomes.
                               - Reduced surgical site infections in patients undergoing posterior spinal stabilization of traumatic injuries using vancomycin powder.  
                               - Reduction of sternal infection by application of topical vancomycin.
                               - The effect of topical vancomycin applied to sternotomy incisions on postoperative serum vancomycin levels  
                               - Intrawound Vancomycin Powder Eradicates Surgical Wound Contamination. An in Vivo Rabbit Study
- Time dependent effectiveness of Vancomycin Powder in a Contaminated Traumatic Orthopaedic Wound Model.
                               - Reduced surgical site infections in patients undergoing posterior spinal stabilization of traumatic injuries using vancomycin powder.
Comparative effectiveness and cost-benefit analysis of local application of vancomycin powder in posterior spinal fusion for spine trauma: clinical article.
Serum and Wound Vancomycin Levels Following Intrawound Administration in Primary Total Joint Arthroplasty

    - IV dosing:
           - adult: 1gm IV q12 hr is classic starting dose;
           - once daily vs twice daily dose:
                  - Failure of once-daily vancomycin for staphylococcal endocarditis.
                  - Once-daily versus twice-daily intravenous administration of vancomycin for infections in hospitalized patients.
           - therapeutic range: (see online calculator)
                  - serum levels: 30-40 mmg/ ml after 1.5 hr; trough: 5-10 mcg/ml (may need higher trough with MRSA - 15 mcg/ml); 
                  - greater risk of nephrotoxicity at trough levels greater than 10 mcg/mL when vancomycin was used w/ nephrotoxic agent;
                  - most calculations today are based on vancomycin trough levels;
           - references:
                   - Summary of ASHP/IDSA/SIDP Vancomycin Monitoring Recommendations: A Focus on Osteomyelitis
                   - Pharmacokinetics of vancomycin: observations in 28 patients and dosage recommendations
                   - Vancomycin Treatment Against MRSA May Fail When MICs Are Lower Than Current Breakpoints
                   - Vancomycin Dosing
                   - High-Dose Vancomycin Therapy for Methicillin-Resistant Staphylococcus aureus Infections: Efficacy and Toxicity. 

     - misc application:
              - oral treatment of C. difficile induced psuedomembranous colitis; 
              - for c diff colitis: 500mg PO q6hr or 1gm PO q12hr for 7 days;
              - peds: 40-50 mg/kg/day q6hr (Levels: trough < 15; peak: 25-40) less than 30 days: 10-15 mg/kg q12hr;
              - prophylaxis of bacterial endocarditis: 1gm IV infused slowly over 1hr before procedure (or try vanc + gentamicin 30min
                       before procedure);

- Cautions:
      - avoid other nephrotoxic and ototoxic agents / must monitor serum levels and auditory function with chronic use;
      - good diffusion from blood into CSF only with inflammation;
      - Red Man Syndrome: slow rate of IV dosing:
              - typically infused over 1 hour;
              - note Red Man/Neck syndrome with fever; this is secondary to histamine release, try slowing IV rate; 
              - consider benadryl, zantac, tylenol.
             - references:
                       - Antihistamine prophylaxis permits rapid vancomycin infusion.
                       - Vancomycin-Induced Red Man Syndrome
                       - Rare case of "red man" syndrome in a female patient treated with oral vancomycin for Clostridium difficile diarrhoea
    - ototoxicity:
            - occurs with serum concentrations ranging from 80-100 mcg/mL
            - less common when used as a monotherapy;
    - renal insufficiency: 
less common when used as a monotherapy;
            - greater risk of nephrotoxicity at trough levels greater than 10 mcg/mL when vancomycin was used with a nephrotoxic agent;
            - there may be little correlation between nephrotoxicity and peak vancomycin levels;
            - must reduce dosage and be used cautiously in patients with renal failure;
            - 80% of drug will be excreted in to urine (w/ nl RF(x));
            - plasma protein binding may decrease substantially in ESRD and that hemodialysis does not correct these changes;
            - standard high efficiency hemodialysis does not significantly remove vancomycin due to the large molecular wt;
            - 70kg adult {gm/dosingintervalinhours} CrCl:>80: 1/12; CrCl:50-79: 1/12-24; CrCl:30-49: 1/24-36; CrCl:10-29: 1/48-72;
            - w/ mild renal failure (GFR more than 50 mL/min) should receive vancomycin every 24 to 72 hours, patients with moderate
                     renal failure (GFR 10 to 50 mL/min) should receive vancomycin every 72 to 240 hours;
            - CrCl of < 25 ml/min, give an initial single dose of 15 mg/kg and adjust dosage and interval based on serum creatinine conc;
            - patients with severe renal failure (GFR less than 10 mL/min) should receive vancomycin every 240 hours; 
            - dosage adjustment during dialysis:
                   - a dose of 1.9 mg/kg/24 hr for functionally anephric patients on hemodialysis or peritoneal dialysis will result in mean
                             steady-state serum levels of 15 mcg/mL; 
                   - there is a small but measurable removal of vancomycin in dialysis;
                   - manufacturer recommends a loading dose of 15 mg/kg followed by maintenance doses of 1.9 mg/kg/24 hr in anephric
                             patients on dialysis;
                   - ref: Nephrotoxicity of vancomycin, alone and with an aminoglycoside
            - allergy:
                   - references:
                            - Vancomycin-associated spontaneous cutaneous adverse drug reactions.
                            - A sixty-five-year-old man with rash, fever, and generalized weakness.
                            - Vancomycin-Induced Immune Thrombocytopenia.

References for Vancomycin:
      Vancomycin prophylaxis and elective total joint arthroplasty.
      Use of vancomycin and tobramycin polymethylmethacrylate impregnated beads in the management of chronic osteomyelitis.
      Limitations of vancomycin in the management of resistant staphylococcal infections.
      Vancomycin versus cefazolin prophylaxis for cardiac surgery in the setting of a high prevalence of methicillin-resistant staphylococcal infections

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