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Antibiotic Mechanism of Actions⁠⠀ ⁠⠀

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⭐ There are 5 basic antibiotic mechanisms of action against bacteria: ⁠⠀
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1) Inhibition of cell wall synthesis⁠⠀
2) Alteration of cell membranes⁠⠀
3) Inhibition of protein synthesis ⁠⠀
4) Inhibition of nucleic acid (DNA/RNA) synthesis ⁠⠀
5) Inhibition of folic acid synthesis ⁠⠀
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‼️ Due to increasing resistance to these antibiotics and their mechanisms, developing new antimicrobials and understanding their mechanisms of action are important. ⁠⠀
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 If you’re looking to learn more, check out our Youtube video for a full review! 

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Angiotensin Receptor Neprilysin Inhibitor (ARNI)

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Entresto® 

Angiotensin receptor-neprilysin inhibitors (ARNI) is a new class of heart failure medications. The first drug in this class is Entresto® (sacubitril/valsartan). It is a combination medication comprised of a neprilysin inhibitor (sacubitril) and an angiotensin II receptor blocker (valsartan). 

Mechanism of action: 

To understand the mechanism of action, you must first understand the following biological processes: 

Our body has natural enzymes and hormones that regulate blood pressure and fluid balance.

Natriuretic peptides help maintain sodium and water balance. When this balance is disturbed (say….due to heart failure), levels of natriuretic peptides rise in response to help restore homeostasis. Neprilysin is a naturally occurring enzyme that breaks down natriuretic peptides and prevents them from doing their job. 

Study Tip: Natriuretic sounds like the word diuretic, which is precisely what it is, a ‘natural diuretic’ peptide that helps your body get rid of excess sodium and fluid. Neprilysin ends in ‘-lysin’, hinting that it is an enzyme that lyses or breaks down other substances. 

Angiotensin is a protein hormone that causes vasoconstriction, leading to increased blood pressure and aldosterone synthesis, causing subsequent increases in water retention. 

Study Tip: the prefix ‘angio-‘ means vessel in Greek, so together angiotensin means a hormone that makes your blood vessels tense.

How the medications work (refer to the visual):

  • Sacubitril is a prodrug that inhibits neprilysin thus preventing it from breaking down natriuretic peptides. This mechanism leads to an increase in vasodilation and diuresis as levels of natriuretic peptides rise. 
  • Valsartan directly blocks angiotensin II receptors inhibiting angiotensin II from binding onto the receptors and causing vasoconstriction and aldosterone release.

Indications:

 

  • Reduce the risk of cardiovascular death and hospitalization in patients with chronic heart failure and reduced ejection fraction. 
  • Sacubitril/valsartan is to be used in place of an ACEI or ARB and in conjunction with other standard, heart-failure treatments (e.g., beta blocker, aldosterone antagonist).  

 

Side Effects:


A fun mnemonic to help you remember the side effects is PARCH.

  • Potassium increase
  • Angioedema 
  • Renal Failure
  • Cough
  • Hypotension
 

 Clinical Pearls/Education:

  • If the patient was previously on an ACEI, ensure that they are off of it for 36 hours before initiating sacubitril/valsartan to lower the risk of angioedema.
  • Brain natriuretic peptide (BNP) will not be a reliable marker of heart failure exacerbations in patients taking this drug because sacubitril/valsartan inhibits the breakdown of natriuretic peptide leading to an elevation in BNP.
  • Because neprilysin also breaks down angiotensin II, inhibiting neprilysin will result in an accumulation of angiotensin II. For this reason, a neprilysin inhibitor cannot be used alone; it must always be combined with an ARB (such as valsartan) to block the effect of the excess angiotensin II.
  • The recommended starting dose is sacubitril 49 mg/valsartan 51 mg twice per day. It should be doubled every 2 to 4 weeks as tolerated, up to the target dose of sacubitril 97 mg/valsartan 103 mg orally twice per day.
  • Reduce the starting dose to sacubitril 24 mg/valsartan 26 mg in patients with:
    • Renal impairment (eGFR < 30 mL/min)
    • Moderate hepatic impairment (Child-Pugh class B)
    • Previously on a low dose of on ACEI/ARB or not currently on an ACEI/ARB
  • Administer without regard to meals.
 

References: 

  • Entresto Package Insert (Link)
  • 2021 ACC Heart Failure Guidelines (Link)
  • Nicolas D, Kerndt CC, Reed M. Sacubitril/Valsartan. [Updated 2020 Dec 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. (Link

Check out our FREE Heart Failure Drug Guide here!

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Antibiotic-Resistant Bacteria: An Overview of the Major Superbugs

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Since Halloween is coming up, we have teamed up with @ideasinmykitchen to discuss a scary subject, antibiotic-resistant bacteria, with these sweet microbe cookies!

What are superbugs? 

Superbugs are bacteria that are genetically changed to withstand the effects of most antibiotics used to treat the infections they cause. Yet, the overuse of antibiotics continues to promote their growth. Each year, drug companies spend millions of dollars on research to develop new antibiotics that can combat these resistant strains of bacteria.

We will be reviewing 6 of the highest-ranked superbugs. The Center for Disease Control’s (CDC) Antibiotic Resistance Threats in the United States, 2019 (AR Threats Report), puts these superbugs at the top of their list for serious to urgent threats requiring immediate attention. Each year, at least 2 million people in the United States are reported to have antibiotic-resistant infections. An infection without an antibiotic to treat it can lead to poor prognosis and bad outcomes.

 

Methicillin-resistant Staphylococcus aureus (MRSA)

 

Staphylococcus aureus are gram-positive bacteria commonly found on the skin. The first-line antibiotic to treat staph infections was previously an anti-staphylococcal penicillin (methicillin) until the bacteria became resistant, hence the name methicillin-resistant Staphylococcus aureus. Methicillin resistance was developed by acquiring the mecA gene producing an altered penicillin-binding protein, PBP2a, with a lower affinity for beta-lactam antibiotics. The gene enables transpeptidase activity to continue in the presence of beta-lactam antibiotics, allowing the bacteria to replicate as normal.

Use of recreational IV drugs can increase the risk of developing severe and invasive MRSA infections, including endocarditis, bacteremia, and meningitis.

 

MRSA infections are divided into two categories by source: hospital-acquired (HA-MRSA) secondary to hospitalization, long-term care, dialysis, invasive device, surgery, etc. or community-acquired (CA-MRSA). The antibiotic of choice for MRSA infections varies by the type and site of infection.

 

Hospital-acquired MRSA

Community-acquired MRSA

Vancomycin

Daptomycin

Linezolid

Ceftaroline

Telavancin

Dalbavancin

Oritavancin

Sulfamethoxazole/Trimethoprim

Doxycycline

Minocycline

Clindamycin

Linezolid 

Vancomycin-resistant Enterococci (VRE)

Enterococci are gram-positive bacteria that include Enterococcus faecalis and Enterococcus faecium, typically found in the human intestines and female genital tract. E. faecium accounts for more than 70% of VRE strains. Enterococci resistance develops through the gene van A, and leads to resistance to vancomycin, the mainstay antibiotic for Enterococci infections.

 

The most common infections caused by VRE include wound infections, bacteremia, and urinary tract infections (UTIs). Other serious infections include endocarditis and meningitis. Antibiotic treatment options vary by severity, site of infection, and susceptibilities.

Primary Antibiotic Treatments

Alternative Antibiotic Treatments

Ampicillin

Gentamicin*

Linezolid

Daptomycin

Doxycycline

Nitrofurantoin+

Fosfomycin+

Chloramphenicol

Tigecycline

Quinupristin/dalfopristin
*used in combination with ampicillin for endocarditis. +for urinary tract infections

ESBL-producing Enterobacteriaceae

Enterobacteriaceae (also called Enterobacterales) is a family of gram-negative bacteria that commonly cause infections in the healthcare setting. Examples of bacteria in this family include Escherichia coli, Proteus mirabilis, and Klebsiella pneumonia.

 

Enterobacteriaceae can develop resistance by producing enzymes called extended-spectrum beta-lactamases (ESBLs) that break down and destroy commonly used beta-lactam antibiotics such as penicillins and cephalosporins. Treatment of ESBL-producing Enterobacteriaceae can be challenging and depends on the site and severity of infection and local resistance patterns.

Antibiotic Treatments

Clinical Notes

Carbapenems

Drug of choice*-ertapenem preferred

Piperacillin-tazobactam

Equivalent to carbapenems in UTI and biliary tract infections

Amoxicillin-clavulanic acid

Equivalent to carbapenems in UTI and biliary tract infections; convenient for oral switch

Ceftolozone-tazobactam

Reserved for multi-drug resistant P. aeruginosa infection
*Despite the preference for carbapenems in treating ESBL infection, use of other susceptible agents are suggested due to the rate of carbapenem resistance.

Carbapenem-resistant Enterobacteriaceae (CRE)

Resistance to carbapenems occurs through multiple mechanisms, including carbapenemase enzyme production (enzymes that break down antibiotics), efflux pump-action (carbapenem pumped out of bacteria), and decrease bacteria cell membrane permeability to carbapenem.

 

Treatment of CRE depends on the site of infection, the type of gram-negative pathogen, resistance profiles. It is essential to consult an infectious disease specialist to assist with appropriate antibiotic regimens as optimal CRE treatment is mostly unknown and based on small retrospective studies. Typical treatment includes an antibiotic backbone coupled with other susceptible antibiotics.

Isolate susceptibility

Drugs

Susceptible to a Beta-lactam

Backbone: ceftazidime-avibactam (preferred) or meropenem-vaborbactam; alternatively, meropenem (if MIC <8 mg/liter) or ceftazidime or aztreonam

PLUS

Accompanying drug: colistin, tigecycline, aminoglycoside, or fosfomycin (if isolate intermediate to the backbone drug, consider using 2 of these)

Resistant to all Beta-lactam

Backbone: colistin

PLUS

Accompanying drug: tigecycline, aminoglycoside, or fosfomycin

Resistant to all Beta-lactam and colistin

Backbone: tigecycline or aminoglycoside

PLUS

Accompanying drug: tigecycline, aminoglycoside, or fosfomycin

Pandrug-resistant or susceptible to only one drug

Meropenem plus ertapenem or ceftazidime-avibactam plus aztreonam; add any active drug; consider active investigational drug if available

Pseudomonas aeruginosa

Pseudomonas aeruginosa are gram-negative bacteria common in the community and hospital setting. It is a ‘water-loving’ bug as it is common in swimming pools, whirlpools, hot tubs, sinks, mops, hydrotherapy pools, and humidifiers. As an opportunistic pathogen, it can cause severe infections in critically ill patients in the hospital. Some strains of Pseudomonas aeruginosa may be highly resistant to many antibiotics, including carbapenems. P. aeruginosa can develop antibiotic resistance through lower outer membrane permeability coupled with adaptive genes or mutational processes.

Infections caused by Pseudomonas aeruginosa include pneumonia, bloodstream infections, urinary tract infections, and surgical site infections.

IV Antibiotic Treatments

Oral Antibiotic Treatments

Piperacillin/tazobactam (Zosyn)

Ticarcillin/clavulanate (Timentin)*

Cefepime

Ceftazidime

Meropenem

Imipenem

Tobramycin

Gentamicin

Amikacin

Ciprofloxacin

Levofloxacin

Aztreonam

Colistin

Ciprofloxacin

Levofloxacin

Fosfomycin+
*Not available in the United States + only for uncomplicated UTIs

Clostridioides difficile

Clostridioides difficile (also known as C. diff) are gram-positive toxin-producing anaerobes that commonly causes diarrhea and severe inflammation of the colon (colitis). It is a normal bacterium in the intestines and colon, but can lead to C. diff infections in patients taking antibiotics. Antibiotics disrupt the normal gastrointestinal flora by killing good bacteria leading to an overgrowth of harmful bacteria, such as C. difficile. Higher incidences of C. difficile infection have been associated with antibiotics such as ampicillin, amoxicillin, cephalosporins, clindamycin, and fluoroquinolones.

 

Other risk factors for C. difficile infections include age greater than 65 years old, recent hospitalization for an extended period, residence in a nursing home, immunocompromise patients, and previous exposure to C. difficile.

 

The rate of resistance to antimicrobials has significantly increased with this pathogen, limiting treatment options. With these new developments, the Infectious Disease Society of America (IDSA) guidelines updated their recommendation for the treatment of C. difficile in 2018.

Clinical Definition

Recommended Treatment

Initial episode, non-severe*

Vancomycin 125 mg 4 times a day x 10 days

OR

Fidaxomicin 200 mg twice daily x 10 days

Initial episode, severe+

Vancomycin 125 mg 4 times a day x 10 days

OR

Fidaxomicin 200 mg twice daily x 10 days

Initial episode, fulminant$

Vancomycin 500 mg 4 times a day by mouth or NG tube. If ileus, consider adding vancomycin rectally

PLUS

IV metronidazole 500 mg every 8 hours

First reoccurrence

Vancomycin 125 mg 4 times a day x 10 days if metronidazole was used for the initial episode

OR

Tapered and pulsed dose vancomycin regimen (e.g., 125 mg 4 times per day for 10-14 days; then 2 times per day for a week; and then every 2 or 3 days for 2-8 weeks)

OR

Fidaxomicin 200 mg twice daily for 10 days if vancomycin used for the initial episode

Second or subsequent reoccurrence

Vancomycin in a tapered and pulsed regimen

OR

Vancomycin 125 mg 4 times per day x 10 days followed by rifaximin 400 mg 3 times daily x 20 days

OR

Fidaxomicin 200 mg twice daily for 10 days

OR

Fecal microbiota transplantation
*Leukocytosis with a WBC count <15,000 cells/mL and a serum creatinine level <1.5 mg/dL +Leukocytosis with a WBC count >15,000 cells/mL and a serum creatinine level >1.5 mg/dL $Hypotension or shock, ileus, megacolon
Some patients are colonized with strains of antibiotic-resistant bacteria but do not develop any symptoms. Consider withholding antibiotics in patients who are clinically stable and monitor to decreased the possibility of resistance to the remaining antibiotic options. To prevent the emergence of these multi-drug resistant bacteria, it is important to optimize antibiotic treatments and deescalate as soon as cultures return.

Need to take a break from studying? Find this sugar cookie recipe from @ideasinmykitchen to create your own scary good superbugs!

For more antibiotic study material, check out our Antibiotics Pharmacology Coloring Book!

References and further reading suggestions

  • CDC. Antibiotic resistance threats in the United States, 2019. Accessed October 28, 2020. Link.
  • Palchak M, Sahni J, Desai N, Randhawa A, Mcginty L, Skirvin JA. Vancomycin-Resistant Enterococcus. USPharmacist. Published August 20, 2014. Link.
  • Lister PD, Wolter DJ, Hanson ND. Antibacterial-resistant Pseudomonas aeruginosa: clinical impact and complex regulation of chromosomally encoded resistance mechanisms. Clin Microbiol Rev. 2009;22(4):582-610. doi:10.1128/CMR.00040-09. Link.
  • Banawas SS. Clostridium difficile Infections: A Global Overview of Drug Sensitivity and Resistance Mechanisms. Biomed Res Int. 2018;2018:8414257. Published 2018 Feb 21. doi:10.1155/2018/8414257. Link.
  • Cho JM, Pardi DS, Khanna S. Update on Treatment of Clostridiodes difficile infection. Mayo Clin Proc. April 202;95(4):758-769. Link.
  • Ng K. Updates in the Management of Clostridium Difficile for Adults. USPharmacist. Published April 19, 2019. Link.
  • Smith H, Kendall B. Carbapenem-Resistant Enterobacteriacea. Statpearls. Updated July 31, 2020. Link.
  • Singleton A, Cluck D. The Pharmacist’s Role in the Treating Extended-Spectrum Beta-Lactamase Infections. USpharmacist. Published April 18, 2019. Link.

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It’s TEST LAUNCH DAY!

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We could not be more excited for this day to finally arrive. There’s been so much put into getting up to this point. But there’s not much time to celebrate; we’re still hard at work adding new products and features. Keep a lookout. We have even more exciting things to come!

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Antibiotic: Pharmacology Coloring Book Presale!

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We are excited to release the presale of our first Pharmacology Coloring Book on antibiotics! (Whoohoo!)

Learning antibiotics can be a daunting task, but we aim to make it fun in a creative way. There are so many antibiotics and bacterial organisms to remember and understand. Trust me, I have been there! With matching drugs to bugs to figuring out how to pronounce the names of the antibiotics and bacteria, it can become overwhelming.

We have created this fun coloring book as a supplement to help you learn the material! It has over 30 pages of illustrations, mind maps, humorous mnemonics, and labeling points to test your knowledge! We have also included space for you to incorporate your own notes and doodles! Research have shown that the style of doodle notes can help improve focus, retention, and creativity. 

If you are a visual learner, this coloring book will serve as the perfect supplement during your classes or rotations. 

We are having offering a promotional presale of 25% off. If you order now, you can buy it for $14.99 (originally $19.99) which includes FREE shipping. 

We would love your support! If you think we are doing something great, please share it with your family and friends!

Order Now

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