An Overview of Antibiotics

To wrap this up, we’ll be delving into animal and human bite wounds last. To give a little bit of a background, approximately half of the United States population experiences an animal or human bite wound in their lifetime. With an estimated population of 330 million people in the U.S., this means that around 165 million people will suffer from some sort of bite wound that could potentially lead to a serious skin and soft tissue infection or even osteomyelitis. There are three main categories of bite wounds that are more frequently observed; that is dog bites comprise 80% of the total wounds and cat bites comprise the remaining 20%, with human bites sprinkled in that total as well. Of course, there are other animal bites, but these three categories make up the vast majority of what’s seen in practice.

The bacterial etiology can be a myriad of bacteria and organisms. The mouth flora of the animal or human biter and the victim’s skin flora can all be candidates/suspects to cause a possible infection. More precisely, dog and cat bites should primarily be tested for Pasturella species, Streptococcus species, Staphylococcus species, Neisseria species, and oral anaerobes. For human bites, it’s not as complicated, with an emphasis on Streptococcus species, Staphylococcus species, and oral anaerobes.

Now, how do we manage such bite wounds to prevent and/or treat infections? There are several steps and checks that need to be done in order to properly assess and tailor therapy for a patient. First and foremost, the bite wound should be irrigated with sterile water or saline. Then, the area should be washed with soap or povidone-iodine. If there’s extensive injury, especially one that goes deeper than the superficial layers of skin or more severe wounds, then surgical debridement and immobilization should be considered. Whilst doing so, the immunization record of the animal should be checked. If the animal wasn’t vaccinated against rabies, then rabies prophylaxis may be warranted. If in the case of a human bite, both the biter and the victim should be checked for HIV, herpes, hepatitis B, and hepatitis C, but this should be done on a case-by-case basis and based on patient history. Lastly, the tetanus immunization should be checked for the victim; this is because dogs and cats are known to be able to transmit tetanus through their bites. Therefore, if the victim hasn’t received a tetanus toxoid booster or vaccination within 10 years, then this option should be considered.

Prophylactic antibiotics for 3 to 5 days are recommended within the first 24 hours for patients who are either immunocompromised, asplenic, have advanced liver disease, have preexisting or resultant edema of the affected area, moderate to severe injuries of the hand or face, have injuries that may have penetrated the periosteum or joint capsule, and/or all human bites. The antibiotic treatment of choice for animal bite-related wounds is one that is active against both aerobic and anaerobic bacteria, such as amoxicillin-clavulanate at a dose of 875 mg/125 mg orally every 12 hours. If the patient is allergic to penicillins, then doxycycline or moxifloxacin could be used.

Lastly, primary wound closure is not recommended for animal bite wounds, with the only exception being wounds involving the face. If there is a face bite-wound, then it should be irrigated copiously, debrided cautiously, and started on preemptive antibiotics.

Hopefully this thread has given you a deeper look into the realm of antibiotics and their uses in numerous settings beyond the common bacterial infections. There is definitely so much more learn and seek out about the world of antibiotics, and it’s essentially an arms race against developing bacteria in our world. No one can really predict the future, but hopefully we, as humans, will be able to innovate and explore deeper into the realm of antibiotics and their numerous uses.

References:

1) Ramakrishnan K, Salinas RC, Agudelo Higuita NI. Skin and Soft Tissue Infections. Am Fam Physician. 2015 Sep 15;92(6):474-83. PMID: 26371732.

2) “Skin and Soft Tissue Infections (Sstis).” Expertinskin, https://expertinskin.com/en/down-to-basics/skin-and-soft-tissue-infections.

3) Stevens D, et al. Practice guidelines for diagnosis and management of skin and soft tissue infections: 2014 update by IDSA. Clin Infect Dise. 2014; 59: 10-52.

Necrotizing fasciitis, the scariest and most dangerous of the skin and soft tissue infections. It’s a rare but severe infection that is characterized by progressive destruction of the superficial fascia and subcutaneous fat. It’s associated with an extremely high mortality rate at 20-50% mortality for most patients due to the sheer severity and urgency of the disease; it’s no wonder that the other name for it is the “flesh-eating disease.” Any patient that comes into the hospital with anything resembling necrotizing fasciitis needs an immediate surgery consult to confirm and verify. The life-threatening nature of this disease adequately calls for extreme caution and prompt responsiveness to treatment, as patients could easily lose a limb(s) if actions aren’t taken rapidly. There are three types necrotizing fasciitis and they’re caused by different bacteria, with type 1 being the most commonly seen variant.

1) Type 1: polymicrobial, aerobic (Streptococcus, Enterobacteriaceae), and anaerobic (Bacteroides, Peptostreptococcus) bacteria; comprises of 80% of the cases of necrotizing fasciitis

2) Type 2: monomicrobial à group A Streptococcus, specifically Streptococcus pyogenes

3) Type 3: gas gangrene (muscle necrosis) caused by Clostridium perfringens

The clinical manifestations of necrotizing fasciitis can be described as the following:

· Fever

· Chills

· Leukocytosis

· Hot, erythematous edema without sharply demarcated regions

· Shiny, exquisitely tender, and painful lesions on skin

· Bullae filled with clear fluid

· Rapid progression into gangrene à at which point you have to cut the limb off to prevent further progression and damage

The management of necrotizing fasciitis requires prompt and decisive action taken every step of the way. First and foremost, aggressive and quick surgical debridement is required; studies have shown that there’s an increased rate of mortality associated with a delay of more than 14 hours in initial surgery. Then, blood and deep tissue cultures are required to determine the bacteria causing the infection and to determine which antibiotics to use. While the cultures are acquired, empiric broad spectrum antibiotics to cover methicillin-resistant Staphylococcus aureus (MRSA), pseudomonas, and anaerobes are required. For that reason, the combination of vancomycin and piperacillin/tazobactam is a prime choice for empiric therapy. The vancomycin component will cover for methicillin-resistant Staphylococcus aureus along with other gram-positive bacteria; and then the piperacillin/tazobactam will provide gram-negative coverage that also includes Pseudomonas and anaerobe coverage. When the cultures and sensitivities are completed, then definitive antibiotics are selected. If it turns out to be group A Streptococcus, then the antibiotic regimen should shift to just penicillin and clindamycin; the reason being that clindamycin not only gives MRSA coverage, but also suppresses the toxins produced by group A Streptococcus via ribosomal action.

After the initial therapy and management strategies are defined, then comes the follow-up portion for necrotizing fasciitis. Due to severity, some patients may require multiple debridement procedures to be done within 24 to 36 hours after the initial surgical debridement. Next, monitoring of renal function should be emphasized and prioritized due to the increased risk of acute kidney injury when combining vancomycin and piperacillin/tazobactam. This sort of antibiotic combination usually leads to antibiotic-induced kidney injury due to lack of monitoring and awareness. Therefore, a pharmacist’s job should always be to ensure that the patient is receiving the most optimal benefit from therapy while avoiding all of the possible risks and toxicities. Lastly, the antimicrobial therapy should be administered until these three criteria are met:

1) Surgical debridement is no longer needed

2) Clinical improvement is observed

3) Patient remains afebrile for 48 to 72 hours

Generally, patients with this disease are on 1-2 weeks of antibiotics before they are able to be taken off of them. Necrotizing fasciitis is an unbelievably serious disease that requires the utmost attention and keen medical knowledge to treat properly in order to prevent severe debilitating effects and especially death.

References:

1) Ramakrishnan K, Salinas RC, Agudelo Higuita NI. Skin and Soft Tissue Infections. Am Fam Physician. 2015 Sep 15;92(6):474-83. PMID: 26371732.

2) “Skin and Soft Tissue Infections (Sstis).” Expertinskin, https://expertinskin.com/en/down-to-basics/skin-and-soft-tissue-infections.

3) Stevens D, et al. Practice guidelines for diagnosis and management of skin and soft tissue infections: 2014 update by IDSA. Clin Infect Dise. 2014; 59: 10-52.

Next up, we will be discussing non-purulent skin and soft tissue infections (SSTIs). These non-purulent SSTIs can be further classified into the following:

1) Erysipelas – a superficial skin infection that only affects the outer layers of the skin

2) Cellulitis – an infection of the dermis/subcutaneous fat

3) Necrotizing fasciitis – an infection of the deep soft tissues that results in progressive destruction of the muscle fascia and subcutaneous fat

To start off, erysipelas is cellulitis involving the more superficial layers of the skin and lymphatics. These infections are most commonly associated with group A Streptococcus species, specifically Streptococcus pyogenes. The clinical presentation can be described as a bright red continuous, indurated, edematous area that spreads peripherally and is associated with high fever, chills, and general malaise.

Moving on, cellulitis initially infects the epidermis and dermis, and then it could potentially spread within the superficial fascia to lead into bacteremia. It’s also caused mainly by group A Streptococcus in addition to the less common Staphylococcus aureus species. It is usually associated with a history of a wound or trauma to the specific area. The clinical presentation can be described as erythema and edema of the skin that’s warm and painful to touch with lesions that are non-elevated with poorly defined margins; cellulitis can also be associated with drainage, exudates, and abscesses. The management of cellulitis involved elevation and immobilization of the area, alongside cold dressings for the pain and moist heat to aid in localization of the cellulitis. For more complicated cases, incision and drainage is also a very compelling option. The treatment strategies based on the severity of cellulitis are listed:

Mild: Oral penicillin V potassium, cephalexin, dicloxacillin, and clindamycin if the patient is allergic to penicillins

Moderate: IV penicillin, cefazolin, ceftriaxone, and clindamycin if the patient is allergic to penicillins

Severe: emergency surgery consult to rule out necrotizing fasciitis, then vancomycin + piperacillin/tazobactam

These agents all cover the range of methicillin-susceptible Staphylococcus aureus species as non-purulent skin and soft tissue infections are, in essence, not really at risk for MRSA species. To reiterate, mild cases can be treated with oral antibiotics while moderate cases require the need for IV antibiotics. However, when a severe case presents itself, broad-spectrum antibiotics are required, and MRSA coverage is also included in that empiric therapy as well. Once therapy is started, erysipelas and cellulitis cases usually respond quickly to the appropriately used antibiotics; improvements in systemic symptoms, along with redness and induration, can be seen in as little as 24 to 48 hours. However, it may take several weeks for the skin lesion(s) to resolve. The recommended treatment duration for non-purulent skin and soft tissue infections is 5 days, but the duration can be extended if there appears to be no improvement within that time period. Studies have shown that antibiotics can be discontinued in as little as 5 days from the start of therapy for non-purulent SSTIs as long as some improvement is seen. Decreasing then length of therapy for antibiotics has been shown to produce just as much benefit without the added risk of prolonged durations of antibiotic use.

References:

1) Hepburn MJ, Dooley DP, Skidmore PJ, Ellis MW, Starnes WF, Hasewinkle WC. Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulitis. Arch Intern Med. 2004 Aug 9-23;164(15):1669-74. doi: 10.1001/archinte.164.15.1669. PMID: 15302637.

2) “Skin and Soft Tissue Infections (Sstis).” Expertinskin, https://expertinskin.com/en/down-to-basics/skin-and-soft-tissue-infections.

3) Stevens D, et al. Practice guidelines for diagnosis and management of skin and soft tissue infections: 2014 update by IDSA. Clin Infect Dise. 2014; 59: 10-52.

Now onto the topic of purulent skin and soft tissue infections. These infections can be further broken down into the following 4 classifications:

1) Folliculitis – where there is superficial inflammation of the hair follicle and where pus is present in the epidermis only

2) Furuncles (boils) – a later stage that arises from preexisting folliculitis and involves inflammatory, draining nodules involving the hair follicles

3) Carbuncles – these form when adjacent furuncles coalesce to form a single inflamed and very painful area; they form deep masses that open and drain into multiple sinus tracts

4) Abscesses – collections of pus within the dermis and deeper skin tissue

To deal with these different stages of purulent skin infections, we’ll start with the most minor first. Folliculitis usually resolves spontaneously, but a warm, moist compress can be used with topical therapy, such as mupirocin, to help aid in the healing process. Furuncles, carbuncles, and abscesses require incision and drainage (I & D) as a primary measure. Antibiotics aren’t exactly necessary unless there’s significant fever and/or extensive cellulitis on an area of the body. If there’s a moderate to severe infection, empiric coverage against community-acquired methicillin-resistant Staphylococcus aureus (MRSA) is required. To sum it up, if pus is involved, you would use MRSA coverage; and, if there are no pus or boils, then MSSA coverage and topical mupirocin will do the trick. The main takeaway is that regardless of the severity of purulent skin and soft tissue infections, incision and drainage is the first and foremost option to utilize. Then, if it’s moderate to severe (constitutional symptoms), get cultures and sensitivities and then start antibiotics based on the results. We’ll always start with oral empiric MRSA coverage for moderate infections and then deescalate once the culture and sensitivity results come back. IV antibiotics are reserved for severe cases in which previous I & D has failed alongside the use of other antibiotics. A patient is classified as severe if they meet the aforementioned criteria and still present with constitutional symptoms such as fever, tachycardia, tachypnea, abnormal WBCs, or if they are immunocompromised.

Delving deeper, I will list out the proper empiric treatments based on the severity of the SSTI in a more organized manner.

Mild:

· Incision and drainage + adjunctive antibiotics if the abscess is > 5 cm

· Monitor for improvement in signs and symptoms of infection

Moderate:

· Incision and drainage +

o Doxycycline 100 mg orally every 12 hours

OR

o Sulfamethoxazole/trimethoprim 800/160 mg orally every 12 hours

· Monitor for nausea, vomiting, diarrhea, photosensitivity, age, and pregnancy status in doxycycline

· Monitor for rash, hyperkalemia, renal function, photosensitivity, and hematologic toxicities in sulfamethoxazole/trimethoprim

Severe:

· Incision and drainage +

o Vancomycin 15 mg/kg IV every 12 hours

OR

o Daptomycin 4-6 mg/kg IV every 24 hours

OR

o Linezolid 600 mg PO or IV every 12 hours

OR

o Ceftaroline 400 mg IV every 12 hours

· Monitor for levels, red man syndrome, and renal function in vancomycin

· Monitor for elevated creatinine phosphokinase levels in daptomycin

· Monitor for platelets and drug interactions with selective serotonin reuptake inhibitors in linezolid

· Monitor for hypersensitivity and diarrhea in ceftaroline

Empiric treatment should be streamlined based on culture and sensitivity results, alongside the antibiogram specific for that region/practice/hospital. Treatment duration for purulent skin and soft tissue infections depends on clinical improvement and can range from 7 to 14 days typically. Antibiotics may be discontinued once clinical improvement is noted, meaning that they are not required to be continued until there’s full resolution of skin lesions. Lastly, patients should be educated on appropriate wound care to avoid recurrent infections.

References:

1) Kishimoto E, Ota L, Solomon C. Daptomycin and Incidence of Elevated Creatinine Phosphokinase (CPK) Levels: A Case Report and Case Series Review. Hawaii J Med Public Health. 2013;72(8 Suppl 3):42.

2) Martin E. Stryjewski, Henry F. Chambers. Skin and Soft-Tissue Infections Caused by Community-Acquired Methicillin-Resistant Staphylococcus aureus. 2008. Clinical Infectious Diseases; 46:S368–77.

3) “Skin and Soft Tissue Infections (Sstis).” Expertinskin, https://expertinskin.com/en/down-to-basics/skin-and-soft-tissue-infections.

4) Stevens D, et al. Practice guidelines for diagnosis and management of skin and soft tissue infections: 2014 update by IDSA. Clin Infect Dise. 2014; 59: 10-52.

Now that we’ve covered the bare basics of antibiotics and their uses, we will now go into the topic of skin and soft tissue infections (SSTs).

Now the most common infections seen in the community and hospital settings are skin and soft tissue infections. They may involve any or all layers of the skin, e.g. epidermis, dermis, and subcutaneous fat, fascia, and muscle. These infections may spread far from the initial sit of infection and could lead to more severe complications, such as endocarditis or gram-negative sepsis. Another example could be some simple cellulitis on the leg that could then potentially spread into the blood and cause bacteremia.

The bacterial etiology of skin and soft tissue infections can be separated by those above the waist and those below the waist. A majority of SSTI’s are caused by the gram-positive organisms present on the skin. Normal flora above the waist includes primarily gram-positive organisms, like coagulase-negative Staphylococcus species, Corynebacterium, Staphylococcus aureus, or Streptococcus pyogenes. Normal flora below the waist includes both gram-negative and gram-positive organisms, like Enterobacteriaceae, Enterococcus, and the organisms listed above for flora above the waist. Nosocomial pathogens can also cause SSTIs, and they include Pseudomonas aeruginosa and MRSA.

Now let’s go into the types of SSTIs and their classifications:

1) Impetigo: bullous vs. non-bullous

2) Purulent: furuncle vs carbuncle vs abscess

3) Non-purulent: erysipelas vs cellulitis vs necrotizing infection

4) Animal and human bites

5) Necrotizing fasciitis

Impetigo is a superficial skin infection seen most commonly in children during hot, humid weather. It occurs on exposed skin, especially on the face, and it initiates from minor trauma like a scratch or an insect bite. It’s extremely communicable and readily spreads through close contact with other children. Usually, when a child is diagnosed with impetigo, they shouldn’t return back to school until it’s cured. There are two different classifications for impetigo. Non-bullous impetigo is the most common and it’s caused by B-hemolytic Strepococcus and/or Staphylococcus aureus. It’s characterized by small, fluid-filled vesicles or pustules that then rupture with a golden yellow crust. Bullous impetigo is caused by the toxin produced by Staphylococcus aureus. It’s characterized by vesicles/bullae with clear yellow fluid that then rupture with a thin, light brown crust due to enlarged lymph nodes. Now the management of impetigo is quite simple. For mild cases, topical mupirocin applied twice daily on the lesions for 5 days is sufficient. However, if it looks severe with multiple lesions or if it involves the face, then oral antibiotics are needed for a 7-day course of therapy. The empiric antibiotics used for impetigo can be the following:

1) Dicloxacillin 250 mg by mouth four times daily (adult dose)

2) Cephalexin 250 mg by mouth four times daily (adult dose); 25-50 mg/kg/day by mouth in three to four divided doses (pediatric dose)

3) Erythromycin 250 mg by mouth four times daily (adult dose); 40 mg/kg/day by mouth in three to four divided doses (pediatric dose)

4) Clindamycin 300-400 mg by mouth four times daily (adult dose); 20 mg/kg/day by mouth in three divided doses

5) Amoxicillin-clavulanate 875/125 mg by mouth twice daily (adult dose); 5 mg/kg/day of the amoxicillin component by mouth in two divided doses (pediatric dose)

All of these are effective for impetigo caused by methicillin-susceptible Staphylococcus aureus (MSSA). However, if impetigo is caused by methicillin-resistant Staphylococcus aureus, then clindamycin, sulfamethoxazole-trimethoprim, or doxycycline should be used instead. Lastly, the crusts could be removed by soaking in soap and warm water for symptomatic relief.

References:

1) Hartman-Adams H, Banvard C, Juckett G. Impetigo: diagnosis and treatment. Am Fam Physician. 2014 Aug 15;90(4):229-35. PMID: 25250996.

2) Stevens D, et al. Practice guidelines for diagnosis and management of skin and soft tissue infections: 2014 update by IDSA. Clin Infect Dise. 2014; 59: 10-52.

Moving on, some bacteria have even gone one step further from just inactivating/destroying the antibiotic. In fact, these bacteria have even started requiring that antibiotic for growth! It’s truly a bizarre happenstance and a sign of how quickly and how scary they evolve as they’re not only resistant, but they’re even feeding off of antibiotics. To give an example, Enterococcus is a species of bacteria that easily develops a resistance to vancomycin through the mechanisms listed above, which already makes it a very scary bug to deal with. This being that vancomycin is generally regarded as the last line therapy in gram-positive infections, and there aren’t many other options left after vancomycin has been deemed useless by vancomycin-resistant Enterococci (VRE). Despite all of this, Enterococcus goes one step further to develop vancomycin-requiring strains after prolonged exposure to the antibiotic. This calls for improved resistance testing protocols and especially good antimicrobial stewardship strategies, as this could potentially be disastrous if strains of this bacteria break out.

Next, there’s a mechanism that reduces the affinity of the antibiotic to the target site, e.g. 30S ribosome, 50S ribosome, or cell wall. This is caused by specific point mutations in the target and also in the activating enzymes that the antibiotics require to go from prodrug to active drug. For example, fluoroquinolone resistance is caused by the mutation of the natural target, which are DNA gyrase and topoisomerase IV. For macrolides and tetracyclines, there’s target modification that results in ribosomal protection from the antibiotics. Lastly, there’s acquisition of a resistant form of the native, susceptible target, which is seen in staphylococcal methicillin resistance caused by production of a low-affinity penicillin-binding protein.

Furthermore, there’s resistance due to enhanced excision of the incorporated antibiotic. This is more specific to viruses but is still relevant here. Enhanced excision basically means that they chop the antibiotic or antiviral drug in half, rendering them useless. For example, various point mutations in the reverse transcriptase gene in HIV causes phosphorolytic excision of the incorporated chain-terminated nucleoside analog. This basically leads to an ineffective antiviral drug that essentially doesn’t get to the target site, doesn’t exert any active mechanisms, and just gets excreted out as an inactive and ineffective molecule.

Hetero-resistance is when a subset of the total microbial population is resistant, despite the total population being considered susceptible on testing. In bacteria, hetero-resistance has been described especially for vancomycin in S. aureus, vancomycin in Enterococcus faecium, colistin in Acinetobacter baumannii-calcoaceticus, rifampin, isoniazid, and streptomycin in M. tuberculosis, and penicillin in S. pneumoniae. In essence, only a few species are resistant, but they will continue to grow despite a majority of the species being susceptible. This is akin to a class having 25% of students pass, while the other 75% fail.

It’s also good to note that there are viral quasispecies, which are a population structure that are comprised of numerous variant genomes that continue to develop mutations at extreme rates. Many have actually studied the genomic evolution frequency and patterns observed in COVID-19, showing that quasispecies were differing daily and that the observed mutation dynamics were something that definitely require more research into. In essence, viral replication is more error prone than bacteria and fungi replication due to the nature of their processes.

Lastly, there is the development of alternative pathways to those inhibited by the antibiotic. This is pretty self-explanatory as it’s just the bacteria finding a way to thrive by diverting its metabolic pathways to ones other than those affected by the antibiotic. This can be seen in sulfonamide antibiotic-resistant strains overproducing PABA that then antagonizes those said antibiotics. Moreover, resistant strains to vancomycin would produce D-ala-D-lactate instead of D-ala-D-ala, leading to significantly reduced affinity to vancomycin.

As you can see, the evolutionary bases of resistance are either vertically through mutations or horizontally through external acquisitions of genetic elements via plasmids.

Before ending off this post, I will go into how combination antimicrobial therapy is one of the options employed to combat antibiotic resistance. The purpose of combination antimicrobial therapy is as follows:

1) to provide broad-spectrum empiric therapy in seriously ill patients

2) to treat polymicrobial infections (such as intra-abdominal abscesses)

3) to decrease the emergence of resistant strains (the value of combination therapy has been clearly demonstrated in tuberculosis)

4) to decrease dose-related toxicity by using reduced doses of one or more components of the drug regimen

5) to obtain enhanced inhibition or killing

Synergism is where two antibiotics work much better together as they would individually. This can be the blockade of sequential steps in a metabolic sequence, like what we see in trimethoprim-sulfamethoxazole (Bactrim). Additionally, synergism can be the inhibition of enzymatic inactivation, such as the inhibition of B-lactamase by B-lactamase inhibitor drugs, like sulbactam, that results in improved ampicillin efficacy (Unisyn). Moreover, there is the enhancement of antimicrobial agent uptake; this can be seen when using penicillins and other cell wall-active agents to increase the uptake of aminoglycosides by a number of bacteria, including staphylococci, enterococci, streptococci, and P. aeruginosa.

Antagonism is essentially the opposite of synergism, and these are the combinations that should never be used in antimicrobial therapy. This can be seen in the inhibition of bactericidal activity by static agents or the induction of enzymatic inactivation, where some antibiotics induce the production of B-lactamase that thereby makes other penicillins ineffective.

References:

1) Acar JF. Antibiotic synergy and antagonism. Med Clin North Am. 2000 Nov;84(6):1391-406. doi: 10.1016/s0025-7125(05)70294-7. PMID: 11155849.

2) Domingo E, Perales C. Viral quasispecies. PLoS Genet. 2019 Oct 17;15(10):e1008271. doi: 10.1371/journal.pgen.1008271. PMID: 31622336; PMCID: PMC6797082.

3) Higgins PG, Fluit AC, Schmitz FJ. Fluoroquinolones: structure and target s3ites. Curr Drug Targets. 2003 Feb;4(2):181-90. doi: 10.2174/1389450033346920. PMID: 12558069.

4) Jary A, Leducq V, Malet I, Marot S, Klement-Frutos E, Teyssou E, Soulié C, Abdi B, Wirden M, Pourcher V, Caumes E, Calvez V, Burrel S, Marcelin AG, Boutolleau D. Evolution of viral quasispecies during SARS-CoV-2 infection. Clin Microbiol Infect. 2020 Nov;26(11):1560.e1-1560.e4. doi: 10.1016/j.cmi.2020.07.032. Epub 2020 Jul 24. PMID: 32717416; PMCID: PMC7378485.

5) Said MS, Tirthani E, Lesho E. Enterococcus Infections. [Updated 2021 Dec 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK567759/

To delve a little more into how bacteria resist annihilation via antibiotics, these next two posts will be dedicated to the specific mechanisms that they employ in order to do so.

These mechanisms can be listed as such:

1) Reduced entry of antibiotic into pathogen

2) Enhanced export of antibiotic by efflux pumps

3) Release of microbial enzymes that destroy the antibiotic

4) Alteration of microbial proteins that transform pro-drugs to the effective moieties

5) Alteration of target proteins

6) Development of alternative pathways to those inhibited by the antibiotic

Now let’s elaborate on these mechanisms further. Reduced entry of the antibiotic into the pathogen, namely the bacteria, is caused by changes in the porin channels of the outer membrane of the bacteria. Porin channels are water-filled pores in the outer membrane of bacteria and they allow hydrophilic molecules, like antibiotics, to passively diffuse across the membrane. Thus, porin modification is the major bacterial resistance strategy that resists the permeation of antibiotics through their fundamental protection structure. These modifications can come in the form of mutations, decreases, or even absences of porin channels in outer membrane. This is especially important for antibiotics with an intracellular target as this completely shuts off their access point to reach those targets.

Next up, enhanced export of the antibiotic by efflux pumps is something that has been developed by bacteria as a result of antibiotics. These efflux pumps include: multidrug and toxic compound extruders (MATE), major facilitator superfamily (MFS) transporters, small multidrug resistance (SMR) systems, resistance nodulation division (RND) exporters, ATP-binding cassette (ABC) transporters). More specifically, the ABC transporter is encoded by the Plasmodium falciparum multidrug resistance gene 1 (Pfmdr1). These pumps are specific to different types of bacteria and to different types of antibiotics they are exposed to. They act as a secondary defense mechanism in case an antibiotic is able to get past the outer membrane or cell wall and into the bacteria, despite porin channel mutations.

Then, in case these efflux pumps don’t work and the antibiotic is still wreaking havoc inside the bacteria, then this is where the microbial enzymes are released to break down and destroy the antibiotics. To go into detail, B-lactam antibiotics are inactivated by B-lactamases via hydrolysis. Aminoglycosides are altered by acetylation, phosphorylation, and/or adenylation. Chloramphenicol is inactivated by chloramphenicol acetyltransferases. These are just a few of the inactivation/destruction methods developed and employed by bacteria to combat the advent of these new antibiotics. This mechanism is especially concerning as they can completely dismantle an entire line of antibiotics against that bacteria species, rendering us scrambling for alternative options among the already sparse amount of antibiotics. To add on, the lack of incentive and innovation to develop new antibiotics is a growing concern as our options against these resistance mechanisms continue to dwindle.

References:

1) Locher KP. Review. Structure and mechanism of ATP-binding cassette transporters. Philos Trans R Soc Lond B Biol Sci. 2009;364(1514):239-245. doi:10.1098/rstb.2008.0125

2) Pagès, JM., James, C. & Winterhalter, M. The porin and the permeating antibiotic: a selective diffusion barrier in Gram-negative bacteria. Nat Rev Microbiol 6, 893–903 (2008). https://doi.org/10.1038/nrmicro1994

With the advent of antibiotics, humanity as a race had advanced forth several more spaces in the power paradigm of organisms. With antibiotics, they were practically almost impermeable to numerous infections that would have originally brought them down. However, as we moved forth, so did the bacteria that were targeted. After being wiped out again and again by antibiotics, bacteria are able to mutate as they divide and generate one immune to that certain antibiotic mechanism; thereby making them insusceptible furthermore to any means used to destroy them. To give a general outline of how fast resistance is observed once a new antibiotic is introduced, I’ve tabulated the time frames as follows:

As one can clearly see, it only takes a maximum of 5 to 10 years for the resistance to a specific antibiotic to develop in bacteria. Since they replicate incessantly and unfalteringly, they are able to produce mutations that can accommodate this sort of resistance and pass it on. To clarify a little more, there are innumerable bacteria living in the human body at any given time; and during an infection, there exists also the presence of harmful bacteria. Now, once the signs and symptoms of an infection are present, antibiotics are usually prescribed and taken by the host. These antibiotics kill the bacteria causing the illness, as well as the good bacteria protecting the body from infection. However, a select few of the harmful bacteria have a genetic mutation that makes them impervious to the antibiotic used. And so, once the antibiotic wipes out the susceptible harmful bacteria and the beneficial commensal bacteria, then the antibiotic-resistant bacteria are now allowed to grow and take over. What’s worse is that some of these resistant bacteria can give their resistance horizontally, instead of vertically, to other bacteria and this can cause a superinfection with numerous resistant bacteria. This is precisely why antimicrobial stewardship is so deathly important as improper use of antibiotics could ultimately lead to the cultivation of a super-infectious bacteria that can comfortably wipe out the human race without much to stop it in its tracks. The estimated minimum number of illnesses and deaths caused by antibiotic resistance in 2019 was around 3 million illnesses and roughly 50,000 deaths! And to make matters worse, the trend that we’re seeing is a largely upward model of growth, meaning that every year, more and more people suffer and die from antibiotic resistance. So, in summary, choosing the right therapy and regimen to combat microbes is extremely essential for the sake of preserving what little firepower we have left against our ever-mutating and advancing adversaries that are the bacteria that pose a threat to us.

In the next post, I will delve into how synergism and antagonism work with antibiotics and other medications, as well as the different resistance mechanisms that bacteria develop against antibiotics.

References:

1) Centers for Disease Control and Prevention. (2019). Antibiotic/Antimicrobial Resistance (AR/AMR). https://www.cdc.gov/drugresistance/biggest-threats.html#:~:text=More%20than%202.8%20million%20antibiotic,people%20die%20as%20a%20result. January 26, 2022.

2) Nature Reviews Drug Discovery 12, 371–387 (2013) doi:10.1038/nrd3975

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/