Vancomycin Pharmacology Quiz
JOHN C. ROTSCHAFER, PHARM. D.
MARNIE PETERSON, PHARM.D.
and JEFF JOHNSON
Vancomycin is primarily effective against gram-positive cocci.
Staphylococcus aureus and Staphylococcus epidermidis, including both methicillin-susceptible (MSSA & MSSE) or resistant-species (MRSA & MRSE), are usually sensitive to vancomycin with minimum inhibiting concentrations (MIC) less than 1.5 mg/L. Higher MICs reported for S. aureus date from the late 1950s or early 1960s. Most strains of streptococcus are sensitive to vancomycin.
Vancomycin is considered bactericidal (MBC/MIC < 4) except with enterococci and some tolerant (MBC/MIC > 32) staphylococci. When staphylococcal tolerance has been demonstrated, most physicians add a second antibiotic such as an aminoglycoside or rifampin to the regimen. Enterococcal infections should be treated with vancomycin combined with either streptomycin or gentamicin. Vancomycin is also effective against the anaerobes, diphtheroids and clostridium species, including C. difficile.
Vancomycin lacks antimicrobial activity against gram negatives: Enterobactericeae, Pseudomonas, Legionella pneumoniae and Mycobacteria; Fungi, Viruses and Chlamydia.
Significant controversy has occurred in recent years regarding the efficiency by which vancomycin kills gram positive bacteria and the potential misuse of the drug by a multitude of prescribers. Several studies have shown that with both staphylococci and enterococci vancomycin does not kill the bacteria as quickly or sterile the blood as rapidly as nafcillin or ampicillin, respectively. For this reason many authors suggest that unless the patient has an allergy to beta-lactams or has a methicillin resistant staphylococcal infection, the patient might be better served using a beta-lactam agent over vancomycin.
Concern over the ever increasing problems with vancomycin resistant enterococci (VRE) prompted the Center for Disease Control to issue a statement suggesting appropriate prescribing criteria vancomycin (MMWR 44:No RR-12, September 22, 1994). Vancomycin is not recommended for:
Routine surgical prophylaxis
Treatment of a single positive blood culture for coagulase negative staphylococci
Empiric therapy of a febrile neutropenic patient where no evidence of gram positive infection exists
Continued empiric therapy
Selective gut decontamination
Primary therapy for pseudomembraneous colitis
Topical application or irrigation
Treatment of MSSA or other susceptible gram positive infections in dialysis patients
Prophylaxis in CAPD patients
Prophylaxis in low birth weight infants
Systemic or local prophylaxis for indwelling central or local catheters
Concentration Independent Killing
Vancomycin is considered to be a concentration independent or time dependent killer of bacteria. Therefore, increasing antibiotic concentrations beyond the therapeutic threshold will not result in faster killing or eliminate a larger portion of the bacterial population.
Vancomycin also seems to kill bacteria better under aerobic rather than anaerobic conditions. As both staphylococci and streptococci can grow under either aerobic or anaerobic conditions, this factor could be of concern in special situations.
With agar dilution and broad dilution techniques a minimum inhibiting concentrations of < 5 mg/l indicates susceptibility. A susceptible organism will have an MIC of < 3 mg/L and a minimum bactericidal concentrations of < 6 mg/L.
Vancomycin and Rifampin
The combination of vancomycin and rifampin has been used when tolerant staphylococcus sp. are isolated. Presently, some in vitro reports suggest that rifampin adds little antimicrobial activity and may cause antagonism. In one report, rifampin was synergistic in only 1 of 43 strains of S. aureus. Before adding Rifampin to the vancomycin regimen, the clinician might consider obtaining serum inhibitory titers (SIT's) and serum bactericidal titers (SBT's) which can be repeated after the rifampin has been started and reached steady state. A change of more than one tube dilution in the titers (going from a 1:8 dilution to a 1:32 dilution) could be considered evidence that the addition of rifampin is actually benefiting the patient.
In clinical situations such as endocarditis or osteomyelitis, where treatment may continue for six weeks, the addition of rifampin may increase the risk of an adverse drug reaction. Rifampin is also a potent liver enzyme inducer increasing the risk of several drug-drug interactions. The drug is also expensive and stains clothing, contacts, and various body fluids such as urine a reddish orange color.
Mechanism of Action
Vancomycin has been proposed to interact with bacteria in three fashions: A direct effect on the cytoplasmic membrane, inhibition of RNA synthesis, and inhibition of cell wall mucopeptide synthesis. The action of drug on the cell wall appears to be predominant and occurs at a site distinct from that of penicillins and cephalosporins. The multiple modes of antibacterial action of vancomycin may explain why clinically no L phase variant micro-organisms have appeared.
Presently, increasing levels of vancomycin resistance have been seen with Staphylococcus hemolyticus and enterococci. There is also significant concern that the plasmid (VanA) conveying vancomycin resistance in enterococci could be transferred to Staphylococcus aureus. This development would be a catastrophic effect in attempting to manage staphylococcal infections as no therapy is identified to treat such infections.
Vancomycin is derived from Streptomyces orientalis. Parenterally, it is available in vials as lyophilized powder providing 500 mg of vancomycin.
For infections confined to the bowel, a 10 gm oral suspension, and 125 mg and 250 mg capsules are available. If needed, the parenteral product can be mixed in cherry syrup and administered orally. Both products are marketed under the trade name Vancocin.
Although vancomycin is a relatively old antibiotic, its structure and molecular weight were not identified until 1978. To date, vancomycin is the only commercially available glycopeptide antibiotic in the United States.
Adverse Drug Reactions (ADR)
A variety of adverse reactions have been associated with vancomycin: fever, rash, phlebitis, neutropenia, nephrotoxicity, auditory toxicity, interstitial nephritis and several infusion-related reactions. Many of these reactions may have been due to impurities of the earlier preparations. The incidence of infusion reactions associated with vancomycin: (chills and fever, and nephrotoxicity) is greatly reduced with the newer formulations.
Reports of vancomycin toxicity in the 1950s and 1960s referred to the older preparations. Many of the reports of ototoxicity and nephrotoxicity were in situations where concomitant aminoglycoside therapy was used. Many patients may have had unrecognized renal or eighth cranial nerve dysfunction prior to the start of vancomycin therapy. Also, in many of these reports, the vancomycin dose was excessive for the patients stated renal function. Definitions also cause interpretation problems and prospective criteria for renal and/or auditory toxicity were not stated. Caution should be exercised when interpreting vancomycin levels reported to be associated with the onset of toxicity. Most investigators did not specify when levels were obtained in relation to the time that the dose was administered.
The Red Man Syndrome
A curious effect of vancomycin is an anaphylactoid or pseudo-anaphylactoid reaction. This infusion related effect known as the red neck or red man syndrome, appears related to the rapid infusion of larger doses of vancomycin. It begins 10 minutes after infusion and generally resolves within 15 to 20 minutes after stopping the infusion. Additionally, patients may experience a hypotensive episode with a 25 to 50% reduction in systolic blood pressure. Tachycardia, chest pain, dyspnea, urticaria, and welling of the face, lips and eye lids.
It has been suggested that symptoms of Red Man Syndrome were histamine mediated however, other investigators have been unable to confirm the findings of Polk et. al.. Odio has reported a 35% incidence of this reaction in children receiving vancomycin prophylactically for CSF shunt placements. Another infusion related reaction described by patients is a throbbing pain in the back and neck. Extending the administration of vancomycin to 1 hour or limiting the rate of infusion to <12 mg/kg/hour should prevent most infusion-related reactions.
Vancomycin toxicity was retrospectively studied by Farber in 98 patients. He noted a 13% incidence of phlebitis, a 1 to 3% incidence of fever and rash, and a 2% incidence of neutropenia. However, this report of adverse drug reactions may be overstated because of the inclusion of many potentially high risk patients. Of interest in this study was the observations that patients on vancomycin and an aminoglycoside experienced a 35% incidence of reversible nephrotoxicity (more than expected with either antibiotic alone). Those receiving vancomycin alone had an incidence of 5%. Farber also observed that patients with nephrotoxicity had trough concentrations of 20 to 30 mg/L. Vancomycin ototoxicity has been reported with peak serum concentration of 80 to 100 mg/L. Geraci (1958) identified 2 patients with vancomycin induced ototoxicity. One of whom had a history of renal disease, an elevated BUN on admission and a recorded diastolic blood pressure of zero. Serum concentrations determined 3 to 6 hours after the dose was administered, ranged from 80 to 95 mg/L. The biexponential nature of the vancomycin serum concentration time curve renders it impossible to know the true peak concentrations in this case. Certainly, it was substantially higher than the reported 80 to 95 mg/L. Traber reported the occurrence of ototoxicity in a patient who, at one hour post infusion, had serum concentrations (referred to as peak concentrations) of < 50 mg/L. Again, the true peak in this patient would be higher and likely in the toxic range as defined by Geraci.
In summary, the adverse reactions associated with vancomycin are widely known but their incidences are relatively infrequent. In the medical literature from 1956 to 1984, there are approximately 20 cases each of ototoxicity and nephrotoxicity. Many of these cases are complicated by concomitant aminoglycoside therapy and pre-existing renal problems.
True hypersensitivity reactions to vancomycin are rare, less than 1%. Patients experiencing a reaction to vancomycin should be carefully evaluated to determine if this is an infusion related reaction or hypersensitivity reaction.
Clearly, a reaction that resembles a true hypersensitivity can result from rapidly infused, large doses of vancomycin. Immediately stopping the antibiotic infusion and lengthening subsequent infusion periods usually eliminates these reactions