Vancomycin – Fools Gold or the Holy Grail?

I’ve meant to write a post about the antibiotic vancomycin for many years. It is an antibiotic that has become a work-horse in so many hospitals. Many patients refer to it as “the powerful stuff”.  Included in the WHO Model List of Essential Medicines, the most important medicines needed in a basic health system, it is in fact “powerful stuff” by virtue of being an antibiotic. Yet its use is wrought with problems. In fact, many physicians and nurses hate to deal with it. I’m sure before there were pharmacy driven vancomycin dosing protocols, infectious disease specialists were consulted just to dose vancomycin properly. Despite these difficulties vancomycin is yet to be kicked off its pedestal. Unbelievable!

The Discovery of Antibiotics

One will need to be familiar with the discovery of antibiotics to understand the impact of vancomycin on our lives. We are yet to celebrate the centennial of the discovery of antibiotics even though antibiotics are used willy-nilly these days on ourselves, our pets, and our food, and even though we now talk about being on the brink of the post-antibiotic era where we may no longer have effective antibiotics because of drug resistance and lack of new antibiotic development. Amazing!

Penicillin arrived just in time for World War II

Penicillin, the very first antibiotic, wasn’t discovered until 1928. We have come a long way since then, true, but it seems we are just as rapidly on the decline now. Awful!

Before the fortuitous discovery of penicillin from the Penicillium mould in 1928, moulds and fermented materials had been noticed to have healing properties but no-one really knew why and how. Penicillin, after it was finally refined and used for the first time in the early 1940s, just in time for World War II, saved many lives. It is probably in part to blame for the subsequent population boom!

Creation of Antibiotic Discovery Teams

In either case, the few decades following were rich in antibiotic discovery because although penicillin was a perfect drug for a myriad of infections, there were several other major infections that it was ineffective for. Tuberculosis was one.  Several pharmaceutical companies created antibiotic discovery teams to investigate soil samples from around the world, looking for moulds and other microbes from which they could extract chemicals with antimicrobial activity. Thus came in rapid succession streptomycin from Streptomyces griseus which did wonders in treating tuberculosis, chloramphenicol from Streptomyces venezuelae, and erythromycin from yet another streptomyces (actinomyces) to name a few.

Penicillin Resistant Staphylococcus

By the 1950s though, penicillin no longer worked against Staphylococcus, a genus of bacteria that causes a great number of human infections. Eli Lilly, an American pharmaceutical company, opened a discovery team to look for a replacement antibiotic.

In 1952, a missionary in Borneo (Indonesia) sent a sample of dirt to a friend, Dr. Kornfield, who happened to be an organic chemist at Eli Lilly. Streptomyces orientalis was isolated from the soil. From this compound 05865 was isolated. Compound 05865 was found to have activity against penicillin resistant Staphylococcus aureus (PRSA), most other gram positive organisms, clostridium species, and Neisseria gonorrhea, which is a gram negative organism. Most other gram negative organisms were intrinsically resistant. A few gram positive organisms including leuconostoc, pedicococcus, Erysipelothrix rhusiopathiae, and most lactobacillus, were also intrinsically resistant.

Mississippi Mud (Compound 05865) Becomes Vancomycin

Known as Mississippi mud because of its brown colour, compound 05865 had to be purified over and over before it could be used. The resulting drug, vancomycin, from the word vanquished, was successful in treating patients with staphylococcal infections who had experienced treatment failure with other antibiotics. This gave rise to its status as a wonder-drug.

Based on anecdotal data, FDA approval for the clinical use of vancomycin came quick because of its urgent need. As an aside, it was also used successfully to treat a patient with post-operative micrococcal colitis (acute staphylococcal iliocolitis) earning it an FDA indication for use in that setting. Robust clinical studies of vancomycin to confirm efficacy and best dosage had not yet been completed. It remained on the back burner though as a last resort medication for several reasons.

First, two other beta-lactam antibiotics related to penicillin, methicillin and cephalothin, had been created that were effective against penicillin resistant staph aureus (PRSA). Second, vancomycin had an undesirable toxicity profile. Tinnitus in people with renal failure or on other ototoxic drugs; infusion related chills, rash or vein irritation, a syndrome later known as red man syndrome; nephrotoxicity; hypotension; and reversible neutropenia and or thrombocytopenia were some noted toxicities that were felt to be related to impurities in the compound.

Researchers began to believe that problems could be avoided by careful monitoring of serum concentration of the drug. The search was on to decide how to ensure adequate therapeutic concentrations while avoiding toxicity. Nomograms were constructed for use. Some scientists and physicians individualized vancomycin dosing by always measuring serum concentrations. No randomized control studies were ever performed to show what may be the best therapeutic level for various infections.

By the 1980s, there had been a dramatic increase in the use of vancomycin. Studies in the 1990s showed that the nephrotoxicity and ototoxicity potential of vancomycin was not any worse than drugs considered non-nephrotoxic, however the historical stigma lingers on.

Vancomycin for C.difficile infection

Pseudomembranous enterocolitis, later to be known as Clostridium difficile infection with or without colitis, had come on the scene by the late 1970s, and vancomycin in oral form, known to be poorly absorbed from the intestine, was the drug of choice. What happened next was a dramatic emergence of vancomycin resistant enterococci (VRE) identified first in Europe in 1986. Vancomycin use, especially as oral formulation, was once again curtailed, out of concern that enterococcus, a naturally occurring organism in our bowel flora could share its van resistance gene with other organisms. This concern and restriction, incidentally, led to the widespread off-label use of metronidazole as first-line therapy for Clostridium difficile infections.

Vancomycin for MRSA

By then, the 1980s, staphylococcus had become resistant to methicillin (MRSA) as well. In addition, Streptococcus pneumoniae was developing resistance to penicillin. Vancomycin became increasingly used for MRSA infections often in combination with other drugs such as trimethropim-sulfamethoxazole, gentamicin, and rifampin because of treatment failure with standard beta-lactam therapy. In this manner it was found to be quite efficacious. It was soon suspected though that vancomycin as monotherapy against MRSA was not as equivalent to the efficacy of a beta-lactam antibiotic against MSSA. In vitro when compared to nafcillin it demonstrated delay in MSSA bacteria eradication.

Generic Vancomycin

Eli Lilly’s patent on vancomycin expired in the 1980s opening up the market for many vancomycin generics. Nowadays, it is not uncommon to see true drug exanthems (allergic rashes) in reaction to vancomycin. We’ve also returned to measuring serum levels to determine efficacy. Troughs only though. No more peaks.

Searching for Vancomycin Replacement

After sixty years of existence there is still loads to learn about vancomycin. With all its dosing difficulties and adverse side effect profile, a headache for patient, nurse, and physician alike, there is a perpetual search to look for a replacement. But as difficult a drug as it is, it is yet to be toppled. All the newer competitors, quinipristin/dalfopristin (1999), linezolid (2000) daptomycin (2003), televancin (2009), ceftaroline (2010) and oritavancin (2014) have managed only to be non-inferior, that is “not worse than”, in clinical trials. None is clearly superior except perhaps linezolid for MRSA pneumonia and fidaxomicin for C.difficile infection.

Being non-inferior to vancomycin though doesn’t mean a lot, sadly. We need an antibiotic that is superior or “better than” vancomycin. It would be ground-breaking if an antibiotic was found that was superior to beta-lactam antibiotics even. Beta-lactam antibiotics remain superior to vancomycin for susceptible organisms which is why patients are doing themselves no favours by claiming penicillin allergies they do not truly have.

Vancomycin Still King

 As troublesome as vancomycin is it does not seem as if it is going anywhere anytime soon. It took about 50 years for the first VRSA (vancomycin resistant Staphylococus aureus) to be identified. It was identified in Michigan in 2002 in a patient that had carried both VRE and MRSA. MRSA had acquired the vanA resistance gene from the VRE a risk theorized a couple of decades earlier. Luckily, VRSA infections are still quite rare to come across.

Vancomycin, a steadfast drug, did not and does not need to be marketed. It speaks for itself and continues to lead the pack unfazed by all the attempted coup d’etats by the fancy and extraordinarily expensive newcomers.