Ciana Hughes

Sponsor: Janet Rinehart-Kim

Vancomycin: changing the face of medicine or slowly eliminating human life?

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Abstract

Vancomycin was a popular antibiotic when created in the early 1950s. It was

originally used to treat penicillin resistant staphylococci. Treatment with vancomycin was

halted due to the invention and use of other antibiotics that were less toxic and just as

effective. The use of this antibiotic resurfaced when MRSA appeared and this was the

cause of the rapid increase of Vancomycin usage across the globe. The benefit of using

this antibiotic was that it was a new way to treat infections that could not be cured by

other antibiotics, but the side effects and consequences seem to outweigh this advantage.

There are numerous side effects ranging from fever, abnormal change in urination, to

more detrimental effects such as nephrotoxicity that can lead to renal failure ad

convulsions. This paper will discuss the history of the antibiotic Vancomycin, its clinical

use and downfall due to an increase of antibiotic resistance and the side effects it causes

for the patients using it. Numerous case studies were observed to assess the efficacy of

Vancomycin and to see if there are other antibiotics out there that are much safer for

clinicians to use. Overall it was founded that although Vancomycin does have the ability

to treat patients, the side effects are still a major problem. Further research must be done

to determine the serum levels being the cause of toxicity. There are other antibiotics that

have similar treatment abilities and those must be further researched as well to see if

there can be an adjustment to the treatment of these gram-positive pathogens.

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Introduction

Vancomycin is a frequently used antibiotic when others fail to treat a bacterial

infection, but the toxicity and efficacy are still significant obstacles that raise the question

of whether the side effects of taking the antibiotic is worth using it to treat the infection.

Vancomycin served as an extremely effective method of treating enterococcal and

staphylococcal infections when it was first discovered. The rapid increase of routine use

of this antibiotic led to an increase of resistant bacterium. In the early 1980s, Vancomycin

use increased historically, with over a 100-fold increase over the next twenty years

(Levine, 2006). Two events were predominately responsible for the rebirth of

Vancomycin use. The first was the introduction of Pseudomembranous enterocolitis.

Vancomycin had a tremendous response to P. enterocolitis because it acts well against

both Staphylococcus aureus and Clostridium difficile, which are the pathogens that

causes this infection. The second event was the appearance of resistant pathogens

including MRSA and penicillin resistant Streptococcus pneuomoniae. The successful

treatment of infections caused by these pathogens led to the exponential usage of

Vancomycin and paved the way for this antibiotic to be the frontrunner of treating gram

positive bacteria.

History of Vancomycin

Vancomycin was engineered in 1952 as an antibiotic used to treat infections

caused by Staphylococcal bacterium. This antibiotic came about from a missionary

sending a dirt sample to Dr. Kornfield, who worked as a chemist at the Eli Lily Company.

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This company started a program in the 1950s that aimed for discovering antibiotics with

the ability to treat infections that could not be treated by penicillin. The organism

Streptomyces orientalis was isolated from this sample and it was discovered that it

produced a substance named compound 05865. Compound 05865 is active against

most gram-positive organisms including the penicillin resistant staphylococci, some

anaerobic organisms, and N. gonorrehae (Levine 2006). After numerous successful

laboratory studies scientists moved forward by initiating experimentation with animals

that suggested Compound 05865 may be safe and efficient enough for humans. Before

clinical trials could be conducted, the compound had to be purified. The compound

received the nickname Mississippi Mud because of its brown mud-like appearance, but

was renamed Vancomycin after an alteration from picric acid precipitation to the passage

over an ion-exchange resin. The name vancomycin was originated from the term

vanquish. From the time of creation until 1995 there was an exponential increase of use

of Vancomycin in the US, France, Italy, Germany, the United Kingdom, and The

Netherlands. Over 14,000 kg of Vancomycin were consumed over the course of twenty

years. (Levine 2006). The use of vancomycin was halted due to the question of efficacy

and the toxic effect it had on patients. Vancomycin began being used as a last resort

behind safer antibiotics that failed to treat the infections.

Benefits of Vancomycin

In a study conducted using patients that volunteered to participate, vancomycin reached

therapeutic concentrations in various tissue compartments and resulted in successful

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treatment of serious staphylococcal infection in 8 of 9 patients, including one patient with

endocarditis. Six patients with endocarditis who had experienced prior therapy failure

with other antibiotics were also treated with vancomycin, in which five of the patients

were cured. There was only one failure that occurred in a patient with empyema, because

an adequate concentration could not be reached in the empyema pocket. The therapy

failure occurred in a patient who was admitted to the hospital with multiple

complications, including shock and intractable heart failure, and who died after receiving

treatment for 5 days. As information about vancomycin spread, it was requested for cases

for which other drugs had failed. Emergency shipments were made around the clock.

Extra supplies at one hospital were shipped to another, if needed. Ultimately, reports of

successful treatment were organized and submitted to the US Food and Drug

Administration, and in 1958, in the absence of an effective alternative, vancomycin was

immediately approved. Later published studies confirmed the efficacy of the drug.

However, methicillin, the first semisynthetic penicillin, was also approved in 1958,

followed shortly thereafter by cephalothin. Because of perceived toxicity, vancomycin

became reserved for patients with serious b-lactam allergies or patients with infections

caused by organisms that were resistant to the newer agents.

Side effects/ downsides to Vancomycin

Two of the most prevalent side effects associated with Vancomycin have been

Ototoxicity and Nephrotoxicity. This assumption (as there is no consistent evidence

proving this is a fact) was originally based on the observations of scientists that indicated

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a correlation of vancomycin to elevated serum levels in patients with renal failure, but

due to the widespread increased use of this antibiotic to treat MRSA in the 1970s those

rates were disproved since the impurities had been removed from the drug. Ototoxicity

has been observed rarely, presenting as tinnitus, but remain unproven because there is no

concrete evidence supporting that Vancomycin was the trigger or cause. There has been a

more significant case of patients who have been treated with Vancomycin dealing with

nephrotoxicity. There has been research on the relationship between initial vancomycin

concentration time and nephrotoxicity among hospitalized patients revealing that a

vancomycin exposure-toxicity response may exist and can best be explained by the

pharmacodynamic index (Lodise et al. 2009). Scientists have claimed that excessive

serum drug concentrations may be the cause of nephrotoxicity, and that monitoring or

decrease of serum concentrations would allow interventions that decrease toxicity.

(Ryback et al. 2009). There is also another theory that while the serum concentrations of

Vancomycin do not play a direct role in nephrotoxicity, the antibiotic could possibly be

interacting with other nephrotoxins that cause the increase in toxicity within the kidneys.

Both theories have been proven in a small percentage of studies, but there is still not

enough evidence as to what the exact relationship between Vancomycin and toxicity.

Many enterococcal and staphylococcal bacteria are rapidly building a resistance to

Vancomycin. Vancomycin resistant enterococci (VREs) were first reported in Europe in

1986 and in the United states a year later. These VREs triggered a release of certain

guidelines that are for use of Vancomycin by the Centers for Disease Control Hospital

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Infection Control Practice Advisory Committee. These guidelines state that Vancomycin

is only to be used under certain conditions. The largest concern that scientists had

regarding VREs was the possibility of these pathogens having the ability to spread their

resistance to other bacteria. Enterococci have many components, like transposons and

plasmids that permit the transfer of genetic material form one pathogen to another. There

was a study in 1992 that proved enterococcis resistance could be transferred to S. aureus

in vitro, however, there is no known evidence of this occurring naturally. But this fear

became a reality in the 1990s when patients were found to have been infected with

Vancomycin Resistant Staphylococci. It was discovered that the staphylococcus

developed the VanA gene from the VRE and this aided in it resistance.

There are numerous other common side effects that follow taking vancomycin.

Some of these included bladder pain, change in urine (bloody, cloudy,

increased/decreased, painful), convulsions etc. Red mans syndrome is a histamine like

response that has been associated with vancomycin typically only when there has been a

rapid infusion. This symptom can be characterized by the combination of pruritus,

angioedema, erythema, and hypotension.

There were two interesting case studies that were discovered on patients who have

used this antibiotic. The first case study setting was in a large, academic, tertiary-care

hospital where one hundred and ninety-one adults were hospitalized. These patients had a

normal baseline renal function and were given a minimum of forty-eight hours of

Vancomycin. Ninety-two of these patients also received at least forty-eight hours of

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intravenous piperacillin-tazobactam in addition to the prescribed Vancomycin. The other

ninety- nine patients were given solely Vancomycin as the control group. The purpose of

this retrospective cohort study was to determine whether the addition of piperacillin-

tazobactam will lead to an increased nephrotoxicity in the patients receiving Vancomycin

and to explore the factors that may increase the risk of Vancomycin induced

nephrotoxicity. (Burgess 2014). The results indicated that nephrotoxicity developed in

eight of the ninety-nine patients from the control group that only received the

Vancomycin, and fifteen of the patients from the combination group. From these results,

scientists concluded that the presence of piperacillin-tazobactam in patients in addition to

the Vancomycin led to a significant increase in nephrotoxicity. The second case study I

acquired researches the incidence and risk factors of acute kidney injury (represented by

the acronym AKI) and its association with multi high-dose Vancomycin in critically ill

patients. The purpose of this retrospective study was to determine the frequency and

identify the different risk factors of AKI when associated with continued intravenous

vancomycin therapy targeting the high serum levels of twenty to thirty milligrams per

liter in patients that were admitted into the ICU (Guillaume et al. 2017). The results

revealed that AKI was observed in twenty nine percent of the high dose treatments in

patients with severe acute illnesses. Scientists concluded from this study that the peak

serum concentrations (40 mg /L and above) were independently associated with AKI.

Another case study also researching AKI during vancomycin therapy discovered that in

critically ill children, the development of reversible AKI is associated with the

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administration of nephrotoxic drugs and elevated blood urea nitrogen levels (Totapally et

al. 2013).

Discussion

There has been recent research involving possible solutions regarding serum levels

of Vancomycin and its relationship to toxicity. Studies suggest that the dosage given to

the patient is linked to the toxicity of the antibiotic, so the treatment itself may not be the

sole problem at hand. Changing the dosage of Vancomycin could show that this antibiotic

is still efficient in treating the patients without being toxic. The intention of using these

different dosing regimens is to reduce toxicity, to achieve target levels faster and to avoid

treatment failure. (S. Tafelski et al. 2015). The phase IV study was conducted to compare

the safety and efficacy of intermittent infusion and continuous administration dosing

regimens. One hundred and twenty-five patients received vancomycin therapy, 39% with

intermittent and 61% with continuous administration. Acute renal failure during the ICU

stay occurred in 35% of patients with intermittent infusion versus 26% of patients with

continuous application. From this study, it can be concluded that continuous

administration of vancomycin allowed more rapid achievement of targeted drug levels

with fewer sub-therapeutic vancomycin levels observed. This might indicate that patients

with more severe infections or higher variability in renal function could benefit from this

form of administration without the toxic side effects. It is possible that aggressive

vancomycin dosing and prolonged administration of this antibiotic may be associated

with greater risk for renal toxicity in patients with MRSA (Jeffries et al. 2007).

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 Given that there have been more observed side effects than benefits found from

the use of Vancomycin, it is essential to consider alternate options that are just as

efficient, if not more, with less side effects to worry about. There have been studies that

show there are other antibiotics out there that can compete with the efficacy of

Vancomycin. One is Oritavancin. This antibiotic is newly discovered and developed and

is a lipoglycopeptide antibiotic that was created to combat gram-positive bacteria

including MRSA and those resistant to high concentrations of vancomycin. (Allen 2010).

Its concentration-dependent activity and prolonged half-life allow for single-dose

treatment. A study was conducted to compare the treatment of acute bacterial skin and

skin structure infections with a single dose of oritavancin versus the normal multi dose of

Vancomycin. Results showed that the single dose of Oritavancin had an exceptionally

similar clinical efficacy to the multi dose treatment with Vancomycin (Corey et al. 2014).

The efficacy results were evaluated by the type of pathogen being treated (MRSA) and

the frequency of adverse events. One could conclude that since a single dose of

oritavancin was just as effective to twice-daily vancomycin administered for 7 to 10 days

for the treatment of acute bacterial skin and skin-structure infections caused by gram-

positive pathogens, that this may be an antibiotic worth more research as the new

frontline of treatment. The second antibiotic that was compared to Vancomycin was

Daptomycin. Daptomycin is a lipopeptide antibiotic used in the treatment of systemic and

life-threatening infections caused by Gram-positive organisms. It was introduced as an

alternative to vancomycin after the CDC released their guidelines on the use of

Vancomycin due to VREs. This particular study compares Vancomycin and Daptomycin

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in treating MRSA with isolates of high vancomycin minimum inhibitory concentrations

the process presented in Figure 2. The results from this study indicate that daptomycin

shows significant efficacy in the treatment of bloodstream infections due to methicillin-

resistant Staphylococcus aureus isolates with high vancomycin minimum inhibitory

concentrations. (Kalimuddin et al. 2014). Even though these studies do not give all of the

answers needed to completely convert from Vancomycin altogether, there is significant

evidence that there are other options that should be researched in depth. This would help

guide physicians on the optimal treatment for these infections without the side effects

being a major factor.

Is the possibility of Vancomycin treating an infection worth the side effects it

causes? Vancomycin is an antibiotic that is typically used only as a last resort now due to

VRE guidelines, so at this point one can imply that if this antibiotic is deemed the

necessary treatment, both the patient and physician are aware of the risk and believe that

the treatment of the infection with this antibiotic is worth it.

Conclusion

Based on the research above, Vancomycin has been a successful option in treating

gram positive bacteria when others have fallen short. Although this antibiotic has been

the go to treatment for over fifty years, the building resistance alone shows that

Vancomycins glory days are slowly coming to an end. There is still no concrete evidence

proving or disproving vancomycin having a direct effect on toxicity, but all of the other

side effects should still raise fear in anyone considering to use it. For the best possible

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outcome of use for this drug, or even having it completely removed from human use,

there still needs to be extensive research conducted to determine if the efficacy is still

worth risking patients health and lives.

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Tables and Figures

Figure 1. The use of Vancomycin from 1975- 2000 in the United States, France, Italy,
Germany, the United Kingdom, and The Netherlands (Levine 2006)

Figure 2. The process of the case study that compares the efficacy of Daptomycin vs
Vancomycin. (Kalimuddin et al. 2014)

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