Antibiotics, once the forefront and quintessence of modern medicine, are unfortunately progressing at a pace that has been superseded by the advent of new antibiotic resistance mechanisms poised by bacteria. Before the time of antibiotics, countless deaths occurred due to rampant infections caused by the myriad of diseases that people were often exposed to. Ancient civilizations would conjure up concoctions made from various medicinal herbs and/or invoke the power of greater deities to aid in then recovery of their affected. However, it wasn’t until 1928 that Alexander Fleming discovered penicillin adventitiously via a mold spore in a petri dish of bacteria. This was the most important milestone in the 20th century as we now officially had a surefire cure against gram-positive infections common to man. Thus, the road was paved for the exponential increase in the discovery and innovation of numerous new antibiotics of various mechanisms and classes. As part of this endeavor for a refresher course in antibiotics and their functions, I have designed this thread to encompass the topics of antibiotic classifications, antibiotic resistance, and the antibiotic usage guidelines established by the Infectious Diseases Society of America (IDSA).
To start off it is vital to know the mechanism by which antibiotics work. The primary target of antibiotics is to affect a unique characteristic of the bacteria cell that isn’t coincidentally also on the human cell; in this way, the potential of inhibiting or destroying the bacteria is maximized while also ensuring that the body isn’t harmed in that process. Usually, the most vital difference is the fact that bacteria have a cell wall that encapsulates all the necessary cell components necessary to bacteria survival. Next, the enzymes present in bacteria cells are slightly different compared to human cell enzymes, along with different ribosome sizes. Therefore, it would make sense for antibiotics to be designed to target these specific differences in cell components in order to avoid toxicity; and, as a result, antibiotics that aren’t as selective, as you’ll see later, will have unfavorable side effects to the body.
To simplify things a little bit, we will divide antibiotics into two major categories: bactericidal and bacteriostatic.
Bactericidal antibiotics impose a direct action on the bacteria by either killing or lysing the cell, resulting in complete cell destruction. To do so, they target biochemical pathways involved in cell wall assembly in order to produce a compromised cell wall with missing or altered components. Then, subsequent bacteria cell divisions will produce weaker cell walls that eventually lead to the complete failure of the cell wall to protect and uphold the integrity of the bacteria. These cells then lyse and die and can no longer replicate. Bactericidal antibiotics can then be divided further into those that utilize a concentration-dependent kill vs. those that utilize a time-dependent kill. We will talk more about this later on in the thread. These types of antibiotics are typically reserved for serious infections that need the effect of a bactericidal antibiotic in order to completely clear the infection, e.g. infections in the immunocompromised or meningitis.
Bacteriostatic antibiotics, on the other hand, do not directly kill the bacteria and instead only inhibit the bacteria from reproducing. These antibiotics are ones that you have to take for the full course of therapy, otherwise the potential for relapse will be high as the effects of bacteriostasis are reversible. These antibiotics target nucleic acid and protein synthesis, which are required in the replication process. By effectively slowing down bacterial growth, they allow the host immune system to ramp up enough to destroy the bacteria.
In this next part, I will list out the antibiotics belonging to each group.
References:
1) Calhoun C, Wermuth HR, Hall GA. Antibiotics. [Updated 2021 Jun 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from https://www.ncbi.nlm.nih.gov/books/NBK535443/
2) Ribeiro da Cunha B, Fonseca LP, Calado CRC. Antibiotic Discovery: Where Have We Come from, Where
Do We Go?. Antibiotics (Basel). 2019;8(2):45. Published 2019 Apr 24. doi:10.3390/antibiotics8020045
3) American Chemical Society International Historic Chemical Landmarks. Discovery and Development of
Penicillin. http://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html
To give an overview, this post will be going into the different types of antibiotics that are either bacteriostatic or bactericidal. Now theoretically, if one were to give a high enough concentration of a bacteriostatic agent, then they could become bactericidal.
Bactericidal Agents
· Aminoglycosides
· Bacitracin
· B-Lactams
· Daptomycin
· Glycopeptides
· Isoniazid
· Ketolides
· Metronidazole
· Polymyxins
· Pyrazinamide
· Quinolones
· Rifampin
· Streptogramins
Bacteriostatic Agents
· Chloramphenicol
· Clindamycin
· Ethambutol
· Macrolides
· Nitrofurantoin
· Novobiocin
· Oxazolidinones
· Sulfonamides
· Tetracyclines
· Tigecycline
· Trimethoprim
Now to delve deeper into the topic, we have to classify antibiotics even further. There are two other categories that physicians and pharmacists typically sort antibiotics out into: broad spectrum and narrow spectrum. These form the guiding principles of antibiotic stewardship, and they basically dictate what sort of antibiotic therapy should be utilized to give the most benefit while reducing the potential burden of adverse/unwanted effects.
Broad-spectrum antibiotics are used to treat many different types of infections as they are active against a wide range of bacterial species. They typically target structures or processes common to many different bacteria, e.g. the cell wall, bacterial DNA replication via gyrases, bacterial RNA synthesis, polypeptide-chain formation, and etc. Because of this non-selective targeting of numerous bacteria, it is relatively common to see that commensal (a.k.a. gut bacteria/good bacteria) can be wiped out by these antibiotics; this thereby can lead to a bacterial superinfection where the microbiome dynamic becomes unbalanced and shifted towards invasive bacteria. Now when someone goes to the hospital for an infection, a doctor would usually be able to diagnose it clinically via the general signs and symptoms present. Early intervention is crucial in these illnesses and a delay in giving any sort of antibiotic treatment could lead to worsening morbidity and mortality rates. Hence why doctors typically prescribe broad-spectrum antibiotics for empirical antibiotic therapy, where an antibiotic is given before the pathogen responsible for the particular illness or the susceptibility to a particular antimicrobial agent is known. However, these should be rapidly discontinued once the infectious agent is identified, and a narrower spectrum antibiotic can be used.
Now narrow-spectrum antibiotics are effective against a single or a few specific types of bacteria and are really only used when the causative infectious agent is identified and known. This is what’s called definitive therapy, were the pathogenic organism responsible for the illness is identified and now specifically targeted to be destroyed and rid from the body. These antibiotics target a specific molecule involved in bacterial metabolism, and this is often species specific for whichever type of bacteria they’re targeting. By using these antibiotics, there’s a sharp decrease in the incidence and likelihood of imposing a superinfection as they’re less likely to affect the gut microbiome. Moreover, they are less susceptible to antibiotic resistance due to their specificity.
We talked a bit briefly about how using broad-spectrum antibiotics could potentially be harmful. So now we’re going to delve into why specifically there’s an enormous concern for the misuse of antibiotics, and the reasoning behind it would be antibiotic resistance. In the next post, I’ll describe several ways bacteria have evolved to counteract antibiotics and why antimicrobial stewardship is so important.
References:
1) Calhoun C, Wermuth HR, Hall GA. Antibiotics. [Updated 2021 Jun 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK535443/
2) Loree J, Lappin SL. Bacteriostatic Antibiotics. [Updated 2021 Aug 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547678/
3) Noah Wald-Dickler, Paul Holtom, Brad Spellberg, Busting the Myth of “Static vs Cidal”: A Systemic Literature Review, Clinical Infectious Diseases, Volume 66, Issue 9, 1 May 2018, Pages 1470–1474, https://doi.org/10.1093/cid/cix1127
4) Pandey N, Cascella M. Beta Lactam Antibiotics. [Updated 2021 Sep 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK545311/