Vancomycin vs. Penicillin: How do they Differ Clinically?
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Vancomycin and penicillin are critical antimicrobial agents in the treatment of community-acquired as well as health-care acquired infectious diseases.
These antimicrobial agents have notable differences in the mechanism of action, pharmacokinetics, spectrum of activity, clinical uses, and antibiotic resistance.
Is Vancomycin the same as Penicillin?
Penicillin Mechanism of Action
Penicillin, the first β-lactam antibiotic, was identified in 1928 however due to the inability to produce the drug in larger quantities, it was not until 13 years later that it was introduced into clinical use.
The first clinical uses were described in 1942 thus ending the pre-penicillin era (Gaynes 2017).
Early in clinical use penicillin remained difficult to manufacture in large quantities, was impure due to the fermentation process necessary to produce it, and contained a mixture of several penicillins (F, G, X, and K).
Penicillin G, having the best qualities, was taken forward in development and further refined to produce a pure, isolated product. Although there is a multitude of new antibiotics that have been developed since penicillin still has a critical role in the antibiotic armamentarium.
Penicillin exerts its antibacterial effect by binding to proteins, called penicillin binding proteins or PBP, in the plasma membrane of the bacterial cell wall making it unstable such that the bacteria is vulnerable to lysis.
For penicillin to be effective and bind to PBP the compound must traverse through the periplasmic space which, depending on the bacteria, may be filled with beta-lactamase enzymes that are capable of degrading the β-lactam.
Limitations in the spectrum of coverage due to these enzymes will be discussed later.
The efficacy of β-lactam antibiotics is maximized by maintaining drug concentrations above the minimum inhibitory concentration (MIC) of the infecting pathogen at the site of the desired action and are reflected in the frequent dosing intervals or prolonged dosing strategies.
Vancomycin Mechanism of Action
Vancomycin belongs to the glycopeptide class and was isolated from Amycolatopsis Orientalis in 1953, an organism found in the soils of Borneo.
Originally, nicknamed “Mississippi Mud” due to brown color resulting from impurities, Vancomycin (brand name: Vancocin®) is now greater than 90% pure and utilized to treat gram-positive bacteria.
Intravenous vancomycin can be utilized for aerobic and anaerobic gram-positive bacteria whereas oral administration exhibits low systemic drug levels and is effective for Clostridioides difficile (formerly known as Clostridium difficile) colitis.
Glycopeptides inhibit cell wall synthesis at a step earlier than beta lactams by binding to D-alanyl-D-alanine, the peptide precursor, thus inhibiting peptidoglycan polymerization and transpeptidation reactions.
Ultimately this prevents the cross-linking of the cell wall peptidoglycan resulting in permeability and cell death.
Vancomycin is concentration independent and has the best efficacy when total antibiotic exposure as measured by the area under the curve or AUC to MIC ratio is greater than 400.
Vancomycin was introduced into clinical use in 1954.
The agent was a welcome addition to the meager antibiotic armamentarium available to treat gram-positive bacteria at that time, however, its use was largely superseded two years later by the introduction of methicillin.
It wasn’t until methicillin resistant Staphylococcus aureus (MRSA) isolates were widely circulating in the 1970s that vancomycin again had a niche. Since that time use of vancomycin has steadily increased paralleling the increases in MRSA.
Resistance to penicillin has developed over the almost 100 years since its discovery, however, there are many pathogens that remain routinely susceptible such as the Streptococcus pyogenes (group A) as well as Groups C, D, G, F, and R streptococcus.
Isolates of group B streptococcus (S. agalactiae) with reduced susceptibility to penicillin have become more common although penicillin remains an effective option.
Similarly, the Viridans group streptococci demonstrate growing resistance to penicillin especially amongst S. mitis and S. salivarius within this group.
The resistance mechanism for streptococcus to penicillin is a result of alterations in PBP rather than the beta lactamase enzymes that are the main cause of staphylococcus resistance (Berghash 1985).
Vancomycin remains a treatment option for these resistant streptococcal strains. Enterococcus on the other hand is far less susceptible to penicillin than streptococci.
Enterococci, mostly E. faecalis, can possess beta lactamases, chromosomal or plasmid mediated, that allow for evasion of penicillin.
Additionally, of the two most common enterococcal strains, E. faecium is less susceptible than E. faecalis to penicillin (Moellering 1979).
Enterococcus exhibits tolerance to antibiotics that work on the cell, including penicillins and vancomycin (Moellering 1991).
The mechanism behind the higher MICs in enterococcus is reduced affinity for PBP5. There are many PBP that have specialized functions within each bacteria, however, PBP5 can take on the function of all the other PBPs thus reducing the inhibition caused by penicillin and ampicillin and causing full resistance to antistaphylococcal penicillins, such as nafcillin, and cephalosporins (Al-Obeid 1990).
Notably, some enterococci have a unique tolerance to penicillins in that the percent of isolates killed decreases as the concentration of drug increases (Shah 1982).
Staphylococcus aureus are rarely susceptible to penicillin due to naturally occurring penicillinases (a type of beta lactamase).
Additionally, resistance can be the result of alterations in PBP2 caused by the insertion of SCCmec genes resulting in methicillin resistant S. aureus.
Coagulase-negative staphylococci (CoNS) demonstrate a similar prevalence of resistant isolates and mechanisms of resistance to penicillin as S. aureus with a couple of notable exceptions:
- S. saprophyticus was originally identified as being routinely susceptible to penicillin, likely due to the reduced production of beta-lactamase than other CoNS (Tollen 1981).
- Additionally, some S. lugdunensis maintains higher susceptibility to penicillin (Shah 2010).
Penicillin does have activity against gram-negative pathogens however over since its development penicillin has lost some activity especially as multi-drug resistant organisms have become more common.
Due to the nature of this article an in-depth review of penicillin’s gram-negative coverage will not be included.
Gram-negative coverage does include Neisseria spp, Actinobacillus spp, Capnocytophaga canimorsus, Eikenella corrodens, and Pasturella multocida.
Penicillin also maintains activity against anaerobic Gram-positive and Gram-negative cocci although resistance is seen more commonly (Warnke 2008).
This resistance is thought to be driven by alterations in PBP as these organisms either do not produce beta-lactamases is the case of gram positive cocci or produce them in low levels.
Anaerobic gram negative rods, on the other hand, do produce beta lactamases thus resulting in variable penicillin resistance. Most spirochetes, including Treponema pallidum, leptospiras, and Borrelia hermsii, are sensitive to penicillin.
The activity of penicillin against Borrelia burgdorferi, the spirochete that causes Lyme disease, is unclear due to non-standardized methods for determining sensitivity (Benach 1983).
Vancomycin is bactericidal with active against Staphylococcus aureus, CoNS, Streptococcus spp., Enterococcus spp., and anaerobic gram positive bacteria. Vancomycins activity against S. aureus, includes methicillin sensitive (MSSA), methicillin resistant (MRSA), and community acquired MRSA (CA-MRSA).
For almost 40 years after the introduction of vancomycin into clinical use, drug-resistant strains (MIC >2 mcg/mL) were virtually non-existent. In 1996, the first vancomycin intermediate S. aureus (VISA) strain was described (MIC 4-8 mcg/mL) in Japan and four years later the first resistant strain (VRSA) with MICs ≥16 mcg/ml.
VISA strains are rare and typically arise after repeated or prolonged exposure to vancomycin.
VRSA strains, first identified in Michigan, are even rarer and are caused by the vanA gene complex acquired from VRE.
Case reports indicate this phenomenon occurs in patients treated with vancomycin with chronic underlying medical conditions, and who have MRSA or enterococcal colonization/infection.
Heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) are unique in that they exist as a subpopulation and can be difficult to identify in the microbiology lab.
hVISA are relatively uncommon in the US. Vancomycin is also a potent antibiotic against coagulase negative staphylococci (CoNS), including methicillin sensitive and resistant CoNS strains. Vancomycin is also highly active against streptococcus, including nutritionally variant streptococcus, penicillin-resistant viridans streptocococcus, and S. pneumonia.
Vancomycin is bacteriostatic against enterococcocus. While most isolates are sensitive, vancomycin resistance can develop in Enterococcus faecalis and faecium whereas E. casseliflavus and gallinarum have low level intrinsic vancomycin resistance.
United States surveillance data demonstrated a notable increase in vancomycin-resistant enterococci (VRE) isolates in the late 1990s.
VRE isolates had become very common in Europe twenty years earlier driven largely by the use of avoparcin, a glycopeptide, in agriculture.
Once this agent was banned from agriculture use, rates of VRE colonization in Europe fell precipitously. In the US the increase in VRE was driven by nosocomial acquisition, rather than agricultural antibiotic use, specifically in patients with long hospitalizations and antibiotic exposure.
Resistance is driven by changes to the target D-alanyl-D-alanine (D-ala-D-ala) precursor to D-alanine D-lactate (VanA, VanB, and VanD) or D-alanine D-serine (VanC, VanE, VanG, and VanL).
Enterococcal resistance to vancomycin is complex and can be plasma mediated or inducible. The VanA phenotype is the most common of the seven types of acquired resistance and results in high level vancomycin resistance.
As described earlier, during bacterial cell wall synthesis bacterial ligase in the cytoplasm joins D-ala residues to the peptidoglycan precursor and is transported across the cell membrane.
Vancomycin binds to the D-ala, interrupting cell wall synthesis, however, when the terminal residue is not alanine, vancomycin is not able to bind effectively.
Enterococcus faecium more commonly harbors VanA although it can be seen in E. faecalis and E. duran as well.
VanC resistance is found in all E. gallinarum and E. casseliflavus although these bacteria can concomitantly harbor other mechanisms of resistance. It is especially important to remember VanC resistance in these two enterococcal species when clinically evaluating rapid diagnostic results that only test for VanA and VanB.
Vancomycin is active against most anaerobic gram-positive bacilli and cocci, including Bacillus spp., Actinomyces spp., Clostridium spp., Finegoldia magna, Peptostreptococcus anaerobius, Corynebacterium spp., Listeria monocytogenes, Rhodococcus equi, and Propionibacterium acnes.
While not commonly found, there are some bacteria that are intrinsically resistant to vancomycin including Leuconostoc spp., Pediococcus spp. and select Lactobacillus spp.
Reduced binding to vancomycin due to a modification in the peptidoglycan precursor results in this resistance. Interestingly, although vancomycin is a gram-positive agents, there are occasionally sensitive Neisseria spp., a gram negative, strains in vitro.
Adverse Effects and Toxicity
Penicillin adverse effects are mostly dose dependent adverse drug reactions, associated with exceedingly high doses that are no longer used such as neurotoxicity and hemolytic anemia.
While many people report allergy to penicillin, less than 10% are truly allergic (Bourke 2015).
Vancomycin however can cause cutaneous adverse reactions and side effects including vancomycin hypersensitivity syndrome (known as red-man syndrome).
This syndrome, which includes itching or flushing of the skin (most often affecting the upper body), angioedema, hypotension, tachycardia, and infrequently muscle aches, is believed to be caused by a nonimmunologically mediated histamine release (Rothenberg, 1959).
Although the reaction can progress to angioedema and hypotension, bronchospasm is notably not included in the syndrome.
The reaction is related to the dose and rate of infusion and typically starts within 30 minutes of the initiation of the infusion and resolves quickly, either as the infusion is continued at a slower rate or within one hour of completion.
True IgE-mediated reactions associated with vancomycin are uncommon as are drug rash with eosinophilia and systemic symptoms (DRESS), IgA bullous dermatosis, exfoliative dermatitis, and cutaneous vasculitis.
Vancomycin elimination is primarily through renal clearance and has been associated with nephrotoxicity to varying degrees, however, it is clear that rates increase when it is administered with a concomitant nephrotoxic agent such as gentamicin.
Both intravenous vancomycin and penicillin, also primarily eliminated renally, should be dose adjusted for changes in renal function.
Ototoxicity is a rare side effect associated with vancomycin. In fact, early reports of ototoxicity were in patients treated with concomitant ototoxic antibiotics including aminoglycosides or erythromycin.
There is no age or serum concentration that correlates with increased risk (Sorrell and Collignon, 1985). It is postulated that vancomycin alone may not be ototoxic, rather it enhances the ototoxicity of ototoxic agents (Brummett 1990).
Even more uncommon are hematologic toxicities associated with vancomycin.
Neutropenia typically occurs after at least two weeks of vancomycin and resolves following discontinuation (Koo 1986).
As with ototoxicity, there is no serum level associated with an increased risk of neutropenia. Several case reports of thrombocytopenia are also in the literature.
Neither penicillin nor vancomycin are associated with adverse effects in pregnant or lactating women.
Penicillin comes in several formulations including the original formulation of Penicillin G as a sodium or potassium salt for injection.
A typical regimen for IV crystalline Penicillin G is 12-24 million units per 24 hours (continuous infusion or divided into 4-6 doses).
There are also less soluble salts that are administered intramuscularly providing activity over longer periods of time, the shorter acting is Procaine Penicillin G and the longer is Benzathine Pencillin G.
Absorption from the IM space continues for 24 hours after administration of Procaine Penicillin G whereas low level serum concentrations are maintained for 1-3 weeks following benzathine administration.
These long acting penicillins can not be injected IV.
Oral penicillin (penicillin V potassium) can be used for superficial streptococci infections, cutaneous anthrax, and prosthetic joint suppressive therapy.
Penicillin, as mentioned above, is a very effective therapy for group A and B streptococcal infections
Penicillin also exerts a significant post antibiotic effect (PAE), meaning bacterial killing continues after drug levels have declined against S. pyogenes which is very beneficial in invasive streptococcus infections and necrotizing fasciitis (Odenholt 1989).
Penicillin remains the drug of choice for the treatment of syphilis (Treponema pallidum) maintaining very low penicillin MICs.
Penicillin is no longer an empiric option for pneumonia, endocarditis, pelvic inflammatory disease, or meningitis, however, it is effective to treat sensitive pathogens causing infections in those locations.
Vancomycin is available for parenteral or oral administration.
Intravenous vancomycin remains an empiric option for coverage of gram positive organisms.
Vancomycin is also an effective treatment of susceptible organisms, as detailed above, involved in bone and joint infection, skin and skin structure infection, pneumonia, endocarditis, and meningitis.
Oral vancomycin is effective in treating C. difficile and S. aureus enterocolitis.
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