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once the forefront and quintessence of modern medicine, are unfortunately progressing at a pace that has been superseded by the advent of new antibiotic resistance mechanisms poised by bacteria.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
Skin and soft tissue infections (SSTIs) encompass a range of conditions caused by bacterial invasion of the skin, subcutaneous tissue, and muscles. Common SSTIs include cellulitis, impetigo and abscesses. These infections are primarily caused by gram-positive bacteria, such as Staphylococcus aureus (including MRSA) and Streptococcus pyogenes. A minor local skin trauma such as a cut or abrasion can be the event that triggers the event and lead to a deeper infection. “Primary SSTIs result from the invasion of otherwise healthy skin; secondary SSTIs result from infection of already-damaged skin, such as from trauma or an underlying disease. Infections are often localized but they can also spread via the blood stream or lymphatic flow” (NIH). SSTIs can range from mild infections requiring minimal intervention to life-threatening conditions necessitating aggressive treatment. They can be categorized as superficial infections, such as impetigo, carbuncles and furuncles, or infections that penetrate the subcutaneous tissue such as cellulitis. They can be purulent or non-purulent. Purulent infections like an abscess contain pus. “The severity of the infection (mild, moderate, or severe) impacts the choice of antibiotics and the route (topical, PO, or IV)” (UWorld RxPrep) A mild infection does not have systemic signs present, a moderate infection has systemic signs present. Severe infections has systemic signs along with deeper signs of infection like fluid filled blisters, skin sloughing, hypotension, or evidence organ dysfunction. During a severe infection, patients can also be immunocompromised or have failed oral antibiotics with incision and drainage for purulent infections. Impetigo is common in children and spreads quickly. It presents as a blister like rash that may be painful or itchy and found anywhere on the skin, typically around the nose, mouth, hands, and arms. The pustules rupture and a thick yellowish clear fluid dries up and forms honey colored crusts around the area. It can be treated with a local antibiotic like mupirocin if the lesion are limited and localized. For more numerous and extensive lesions, it can be treated with cephalexin 250-500 mg by mouth four times a day. Some other measures that can be taken are using a warm wet compress to help remove dried crusts. Folliculitis is a superficial infection of the hair follicles and it looks like red pimples. Furuncles are purulent infections of the hair follicles and carbuncles are a group of infected carbuncles. These may only require warm compresses to reduce inflammation and help with drainage. Incision and drainage is what is recommended for large furuncles. Antibiotics like SMX/TMP and doxycycline may be used. Cellulitis is a diffuse bacterial infection of the dermis and subcutaneous tissues characterized by redness, warmth, swelling, and pain. It often results from skin breaches, such as cuts or ulcers. Treatment involves antibiotics like cephalexin. Clindamycin or dicloxacillin for can also be used for cellulitis. Abscesses are localized infections involving pus collection. They often require incision and drainage, and antibiotics can also be used. The antibiotic used should cover MSSA and MRSA, so SMX/TMP and doxycycline would be appropriate options, but if cultures show MSSA, cephalexin should be used. Proper wound care, hygiene, and timely medical attention can prevent SSTIs. Early recognition and treatment are vital in reducing complications and ensuring recovery.
UWorld RxPrep NAPLEX Review 2025 Chapter 22 Infectious Diseases II Page 351
www.ncbi.nlm.nihgov/books/NBK545311/
Beta lactams, such as penicillins, cephalosporins, and carbapenems, work by inhibiting bacterial cell wall synthesis. They “inhibit the last step in peptidoglycan synthesis by acylating the transpeptidase involved in cross-linking peptides to form peptidoglycan. The targets for the actions of beta-lactam antibiotics are known as penicillin-binding proteins (PBPs). This binding, in turn, interrupts the terminal transpeptidation process and induces loss of viability and lysis, also through autolytic processes within the bacterial cell” (NIH), making them bactericidal. The chemical structure that characterizes beta lactams are their beta lactam ring. Penicillins and cephalosporins are available in multiple formulations, including child friendly oral formulations like chewable tablets and suspensions. Carbapenems, are available only in parenteral form and are reserved for resistant infections to mitigate the risk of antimicrobial resistance. Penicillins are not active against MRSA or atypical organisms. They are active against gram positive cocci and gram-positive anaerobes and show no appreciable gram negative activity. Penicillin VK is a first line treatment for pharyngitis (strep throat). Amoxicillin is used as first line treatment for otitis media with a pediatric dose of 80-90mg/kg/day. Amoxicillin is also the drug of choice for infective endocarditis prophylaxis before dental procedures. They are also used in H.pylori treatment regimens. Amoxicillin-clavulanate is used as first line treatment for acute otitis media and bacterial sinusitis if antibiotics are indicated. Using the lowest dose of clavulanate decreases the risk of diarrhea. Dicloxacillin is a penicillin that covers MSSA and does not require renal adjustment. Zosyn is a parenteral penicillin that is active against pseudomonas. Cephalosporins are another class of beta lactams that can be further categorized into five generations. First generation cephalosporins like cefazolin and cephalexin target Gram positive cocci like staphylococcus and streptococcus, with limited gram negative activity. Second generation agents like cefuroxime and cefotetan add coverage for anaerobes and more gram-negative bacteria like H. influenzae. Third generation cephalosporins like ceftriaxone and ceftazidime improve gram-negative activity and cross the blood brain barrier. Fourth generation agents like cefepime provide broad spectrum coverage, including pseudomonas. Fifth generation like ceftaroline uniquely cover multidrug resistant gram positive pathogens, including MRSA, while retaining gram negative activity. Carbapenams are highly resistant to most beta lactamases, making them effective against multidrug resistant organisms. Examples include imipenem, meropenem, and ertapenem. Carbapenems cover a wide range of Gram positive, Gram negative, and anaerobic bacteria. However, ertapenem lacks activity against Pseudomonas aeruginosa and Acinetobacter. They are commonly used for severe or high risk infections, such as intra abdominal infections, sepsis, pneumonia, and complicated UTIs. Despite their potency, they do not cover MRSA or Stenotrophomonas. Common uses of carbapenems include “polymicrobial infections, empiric therapy when resistant organisms are suspected, ESBL positive infections, resistant pseudomonas or Acinetobacter infections (except ertapenem)” (UWorld RxPrep). Carbapenems interact with other drugs like valproic acid and leads to it being decreased which then leads to a loss of seizure control. It is important to be mindful of patients and avoid beta lactams in those who might have a beta lactam allergy to avoid hypersensitivity reactions such as a rash and in rare cases anaphylaxis.
UWorld RxPrep NAPLEX Review 2025 Chapter 22 Infectious Diseases I Page 322
www.ncbi.nlm.nih.gov/books/NBK545311/
An Overview of Hospital Acquired Pneumonia (HAP):
Hospital-acquired pneumonia (HAP) is defined as pneumonia that develops more than 48 hours after a patient is admitted to the hospital. This category includes both hospital acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP).
Some risk factors include older age, chronic lung disease, depressed consciousness, aspiration, agents that increase gastric pH (H2 blockers, antacids, proton pump inhibitors, previous antibiotic exposure (especially broad spectrum), prolonged intubation, paralysis, total opioid exposure, etc. Furthermore, additional risk factors include immunosuppressive populations such as those with AIDS, organ transplant recipient, chronic steroid usage, and hyperglycemia with blood glucose >180 mg/dL in hospitalized patients.
Most common pathogens include streptococcus pneumoniae, haemophilus influenzae, enteric gram-negatives (E.Coli, Klebsiella, Proteus), ESBL- producing organisms, and pseudomonas species. Risk factors for MDR pathogens (including Pseudomonas aeruginosa, other gram-negative bacilli and methicillin-resistant S. aureus (MRSA) include intravenous (IV) antibiotic use within the previous 90 days, septic shock at the time of VAP, acute respiratory distress syndrome (ARDS) preceding VAP, >5 of hospitalization prior to the occurrence of VAP, and acute renal replacement therapy prior to VAP onset.
Additionally, risk factors for MRSA include treatment in a unit in which >20% of S. Aureus isolates associated with HAP are methicillin resistant, treatment in a unit in which the prevalence of MRSA is not known, colonization with and/ or prior isolation of MRSA on culture at any body site (especially the respiratory tract).
A clinical presentation of Hospital Acquired Pneumonia (HAP) can be described as fever, cough, shortness of breath and increased sputum production and an elevated white blood cell count. Clinical manifestations vary based on the causative pathogen and patients health status. Lab abnormalities include leukocytosis (WBC >11,000 cells/uL or leukopenia (WBC < 4,000 cells/uL), bandemia (>10% bands or immature white blood cells), and septic shock (may cause multi-organ dysfunction (elevated BUN, creatinine, liver enzymes, INR, acidosis, thrombocytopenia). Imaging may convey new or progressive consolidation or infiltrates, sputum cultures for bacterial pneumonia portray moderate WBC counts with positive Gram stain and culture results, two sets of blood cultures are recommended for VAP; 15% of patients may have bacteremia, and bronchoscopy or other invasive cultures should be considered for severe pneumonia not responding to empiric regimens.
Treatment Overview:
The selection of therapy for hospital-acquired pneumonia (HAP) is based on several criteria, including the patient's history of colonization with or prior isolation of multidrug-resistant (MDR) gram-negative bacilli. Patients without such a history may be treated with Piperacillin-tazobactam or Cefepime. Additionally, if MRSA risk factors are present, anti-MRSA therapy should be initiated. For patients without a history of colonization with or prior isolation of MDR gram-negative bacilli and no prior culture history of carbapenemase-resistant pathogens, options include Ceftazidime-avibactam, Ceftolozane-tazobactam, Impipenem-cilastatin-relebactam, and Meropenem-vaborbactam. Patients with no prior culture history of carbapenamase- resistant pathogens may also be treated with Meropenem or Imipenem-cilastatin.
To continue with the treatment for HAP, patients with risk factors for mortality and no prior culture history of carbapenemase-resistant pathogens can be treated with Meropenem or Imipenem-cilastatin, in addition to one of the following: Vancomycin or Linezolid. On the other hand, patients presenting with risk factors for mortality and carbapenemase-resistant pathogens may be treated with Ceftazidime-avibactam, Ceftolozane-tazobactam, Imipenem-cilastatin-relebactam, or Meropenem-vaborbactam, along with one of the following Vancomycin or Linezolid. Typically, Vancomycin therapy involves administering 15-20 mg/kg every 8 to 12 hours for most patients with normal kidney function, while Linezolid is typically administered at 600 mg IV every 12 hours.
Supportive Care & Conclusion:
Supportive care is crucial in the management of hospital-acquired pneumonia (HAP). This includes maintaining proper hydration, ensuring adequate nutrition, and providing supplemental oxygen as needed to maintain optimal oxygen levels.
As pharmacists, it is essential to spread education and awareness regarding pneumococcal and influenza vaccinations. Pneumococcal vaccination is recommended for all patients aged 65 years and older, as well as those with specific risk factors, such as chronic heart, lung, and liver diseases, immunocompromised conditions, and impaired splenic function. Additionally, encouraging smoking cessation and fall prevention are key strategies in reducing the risk and severity of HAP.
References:
BrozekHospital-acquired and ventilator-associated pneumonia (HAP/VAP). https://www.idsociety.org/practice-guideline/hap_vap/
UpToDate. (n.d.). UpToDate. https://www.uptodate.com/contents/treatment-of-hospital-acquired-and-ventilator-associated-pneumonia-in-adults
Community-acquired pneumonia (CAP) stands as a significant contributor to global morbidity and mortality. The clinical manifestation of CAP varies across the spectrum, spanning from mild symptoms such as fever to productive cough and more severe symptoms such as respiratory distress and sepsis. The type of pneumonia one is diagnosed with is based upon the site of acquisition: community-acquired pneumonia (CAP) refers to a sudden infection of the lung parenchyma acquired outside the hospital, whereas hospital-acquired pneumonia refers to infection of the lung parenchyma within hospital settings. CAP is one of the most prevalent and serious conditions, accounting for over 4.5 million outpatient and emergency room visits annually in the United States alone. Furthermore, CAP is also the second leading cause of hospitalization and the primary infectious cause of mortality. Some common risk factors that increase a person’s chance of acquiring CAP are older age, chronic comorbidities, smoking and alcohol overuse, etc.
In terms of microbiology and pathogenesis, streptococcus pneumoniae and respiratory viruses stand out as the most commonly identified pathogens in patients diagnosed with community-acquired pneumonia. The most commonly identified causes of CAP can grouped into three primary categories:
Typical bacteria such as S. pneumoniae, Haemophilus influenzae, Group A streptococci
Atypical bacteria (bacteria that are inherently resistant to beta-lactams) such as legionella spp, chlamydia pneumoniae, chlamydia psittaci
Respiratory viruses such as Influenza A and B, rhinoviruses, respiratory syncytial virus and adenoviruses.
For the majority of patients diagnosed with CAP, the exact cause is unknown at the time of diagnosis. Therefore, antibiotic therapy is often initiated empirically, targeting the most probable pathogens. The specific pathogens implicated in CAP vary depending on the patient’s severity of illness, local epidemiological factors and individual patient characteristics that may increase the risk of infection with drug-resistant organisms. In other words, in mild cases of CAP, the potential range of causative pathogens is typically narrow and limited. However, in patients with severe CAP that necessitates hospitalization, the spectrum of potential pathogens is more diverse, leading to a broader-spectrum antibiotic treatment choice.
In the outpatient setting, initial treatment strategies to manage CAP depends on whether or not the patient has any comorbidities. For patients with no comorbidities or no risk factors for MRSA and P. Aeruginosa, amoxicillin 1 gram three times daily, doxycycline 100 mg twice daily or a macrolide such as Azithromycin 500 mg on the first day then 250 mg daily or Clarithromycin 500 mg twice daily are recommended. However, for patients who present with comorbidities including chronic heart, lung, liver or renal disease, diabetes mellitus, alcoholism, and/or asplenia, the initial antibiotic regimens that are recommended are Amoxicillin/clavulanate 500mg/125mg three times daily or amoxicillin/clavulanate 875/125 mg twice daily. If a patient cannot take Amoxicillin/clavulanate, a cephalosporin such as Cefpodoxime 200 mg twice daily or Cefuroxime 500 mg twice daily. In addition to the amoxicillin/clavulanate or the cephalosporin, the patient typically is prescribed a macrolide such as Azithromycin 500 mg on the first day then 250 mg daily or Clarithromycin 500 mg twice daily (this is considered combination therapy). In the case of monotherapy for these patients, a respiratory fluoroquinolone such as Levofloxacin 750 mg once daily or Moxifloxacin 400 mg daily may be used.
On the other hand, in patients who are treated in the inpatient setting for the treatment of CAP, the choice of antibiotic regimens differ and choice is based on whether the patient presents with risk factors for MRSA and P. Aeruginosa. For adults with CAP with no risk factors for MRSA and P. Aeruginosa, the preferred initial empiric regimen typically includes combination therapy with a beta-lactam (ampicillin+sulbactam 1.5-3 g every 6 hours) OR a cephalosporin (Cefotaxime 1-2 g every 8 hours, Ceftriaxone 1-2 g daily) AND a macrolide antibiotic (Azithromycin 500 mg daily or Clarithromycin 500 mg twice daily). If a patient is not able to tolerate or has contraindications to combination therapy, monotherapy with a respiratory fluoroquinolone is recommended (Levofloxacin 750 mg daily or Moxifloxacin 400 mg daily). In the case that a patient is found to present with risk factors for MRSA or P. Aeruginosa, it is recommended that antibiotic coverage is extended to cover a broader range of bacteria. Additional empiric treatment options in these patients include Vancomycin 15 mg/kg every 12 hours or Linezolid 600 mg every 12 hours (for MRSA) and Piperacillin-tazobactam (4.5 gram every 6 hours), Cefepime 2 gram every 8 hours, Aztreonam 2 gram every 8 hours, or Meropenem 1 gram every 8 hours (for P. Aeruginosa). Regarding the duration of therapy with these antibiotics, the patient’s clinical response is the key determinant for this. Typically, patients are treated with antibiotics until they have been afebrile and clinically stable for at least 48 hours and for a minimum of five days. Patients with a mild infection typically have to take an antibiotic for 5 to 7 days, whereas patients with a more severe infection may have to take the antibiotics longer, typically for 7 to 10 days.
Resources:
Metlay JP, Waterer GW, Long AC, et al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200(7):e45-e67. doi:10.1164/rccm.201908-1581ST
Ramirez JA. Overview of community-acquired pneumonia in adults. UpToDate. April 5, 2024. Accessed May 2, 2024. https://www.uptodate.com/contents/overview-of-community-acquired-pneumonia-in-adults#H2683461669.
1. Diagnosis and Susceptibility Testing: Before initiating antibiotic therapy, it's essential to accurately diagnose the infection and identify the causative pathogen. This often involves collecting specimens for culture and sensitivity testing to determine which antibiotics are effective against the specific bacteria or fungi causing the infection. Rapid diagnostic tests may also be utilized to expedite the identification of pathogens and guide antibiotic selection.
2. Empiric Therapy: In many cases, antibiotic treatment must be initiated empirically based on clinical suspicion before microbiological results are available. Empiric therapy aims to cover the most likely pathogens based on the patient's clinical presentation, site of infection, and local epidemiology. Antibiotic choice should consider factors such as the severity of illness, risk factors for antibiotic resistance, and potential adverse effects.
3. De-escalation and Targeted Therapy: Once microbiological data becomes available, antibiotic therapy should be reassessed, and adjustments made based on susceptibility results. De-escalation involves narrowing the antibiotic spectrum to the most appropriate agent(s) based on susceptibility testing, minimizing unnecessary broad-spectrum antibiotic use. Targeted therapy allows for more precise treatment of the identified pathogen, optimizing efficacy while reducing the risk of antibiotic resistance and adverse effects.
4. Duration of Therapy: The duration of antibiotic therapy varies depending on factors such as the type and severity of infection, the patient's clinical response, and the presence of complicating factors (e.g., immunocompromised status, foreign bodies). Antibiotic courses are typically tailored to the individual patient, with a focus on achieving clinical resolution while minimizing the development of antibiotic resistance and adverse effects. Shorter courses of antibiotics are often preferred when appropriate to reduce the risk of complications and antibiotic-associated adverse events.
5. Intravenous versus Oral Therapy: In severe infections or when the patient is unable to tolerate oral medications, intravenous (IV) antibiotics may be administered initially. Once the patient's condition stabilizes and oral intake is feasible, transitioning to oral antibiotics can facilitate early discharge from the hospital and reduce the risk of complications associated with prolonged IV therapy. Oral antibiotics with bioequivalent IV formulations are often preferred to streamline the transition from parenteral to oral therapy.
6. Antibiotic Stewardship: Antibiotic stewardship programs play a crucial role in optimizing antibiotic use in the hospital setting. These programs promote judicious antibiotic prescribing practices, monitor antibiotic use and resistance patterns, provide education and feedback to healthcare providers, and implement interventions to improve antibiotic prescribing practices. By promoting appropriate antibiotic use, stewardship programs help mitigate the development of antibiotic resistance, reduce healthcare costs, and improve patient outcomes.
In summary, treating infections with antibiotics in a hospital setting requires a systematic approach that integrates diagnostic testing, empirical therapy, targeted therapy, and antibiotic stewardship principles. By following evidence-based guidelines and optimizing antibiotic use, healthcare providers can effectively manage infections while minimizing the emergence of antibiotic resistance and reducing the risk of adverse effects for patients.
Antibiotics, once hailed as the pinnacle of modern medical advancement, are now facing a challenge posed by the emergence of new bacterial resistance mechanisms. Before their advent, societies grappled with countless deaths due to rampant infections. Ancient civilizations resorted to herbal remedies and divine intervention for healing. However, it wasn't until 1928 when Alexander Fleming serendipitously discovered penicillin, marking a transformative milestone. This discovery paved the way for a surge in antibiotic innovation, offering a reliable solution against common gram-positive infections. As part of an exploration into antibiotics and their roles, this discussion thread aims to cover antibiotic classifications, resistance mechanisms, and usage guidelines set by the Infectious Diseases Society of America (IDSA).
Understanding the mechanism of antibiotics is crucial. They target unique bacterial characteristics while sparing human cells, usually focusing on disparities like cell wall structure and enzyme composition. This specificity minimizes harm to the body, as non-selective antibiotics can lead to adverse effects.
Antibiotics can be broadly categorized as bactericidal or bacteriostatic. Bactericidal antibiotics directly kill bacteria by disrupting cell wall assembly, leading to cell lysis and death. They can be further classified based on concentration or time-dependent killing mechanisms. Reserved for severe infections, they are crucial in cases such as immunocompromised individuals or meningitis.
Bacteriostatic antibiotics, on the other hand, inhibit bacterial reproduction without killing them. They target nucleic acid and protein synthesis, slowing bacterial growth to allow the immune system to eliminate them. Compliance with the full course of therapy is essential to prevent relapse.
Antibiotics, crucial tools in modern medicine, are categorized into various classes based on their chemical structure, mechanism of action, and spectrum of activity. Understanding these classes is fundamental for effective treatment and combating antibiotic resistance. Here, we'll delve into some of the major antibiotic classes:
Penicillins:
Penicillins, discovered by Alexander Fleming in 1928, inhibit bacterial cell wall synthesis by targeting enzymes involved in peptidoglycan cross-linking.
Common examples include penicillin G, amoxicillin, and ampicillin.
These antibiotics are effective against a wide range of gram-positive bacteria but have limited activity against gram-negative bacteria due to their inability to penetrate the outer membrane.
Cephalosporins:
Cephalosporins share a similar mechanism of action to penicillins, targeting bacterial cell wall synthesis.
They are classified into generations based on their spectrum of activity and resistance to β-lactamases.
Examples include cephalexin (first generation), ceftriaxone (third generation), and ceftaroline (fifth generation), which exhibit increased activity against gram-negative bacteria and resistance to β-lactamases.
Macrolides:
Macrolides inhibit bacterial protein synthesis by binding to the 50S subunit of the bacterial ribosome.
They are effective against a wide range of gram-positive bacteria and some gram-negative bacteria.
Common examples include erythromycin, clarithromycin, and azithromycin, which are often used to treat respiratory tract infections and sexually transmitted diseases.
Tetracyclines:
Tetracyclines inhibit bacterial protein synthesis by binding to the 30S subunit of the bacterial ribosome.
They have a broad spectrum of activity against both gram-positive and gram-negative bacteria.
Examples include tetracycline, doxycycline, and minocycline, which are used to treat a variety of infections, including acne, respiratory tract infections, and Lyme disease.
Fluoroquinolones:
Fluoroquinolones inhibit bacterial DNA synthesis by targeting DNA gyrase and topoisomerase IV enzymes.
They have a broad spectrum of activity against both gram-positive and gram-negative bacteria.
Common examples include ciprofloxacin, levofloxacin, and moxifloxacin, which are often used to treat urinary tract infections, respiratory tract infections, and skin infections.
Sulfonamides and Trimethoprim:
Sulfonamides inhibit bacterial folate synthesis, while trimethoprim inhibits dihydrofolate reductase, both essential for bacterial DNA synthesis.
Trimethoprim-sulfamethoxazole (co-trimoxazole) is a combination antibiotic that synergistically targets folate synthesis at two different points.
They are used to treat urinary tract infections, respiratory tract infections, and certain bacterial skin infections.
Glycopeptides:
Glycopeptides inhibit bacterial cell wall synthesis by binding to the D-alanyl-D-alanine terminus of nascent peptidoglycan chains.
Vancomycin and teicoplanin are examples of glycopeptides used to treat serious infections caused by gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA).
Understanding the characteristics and mechanisms of action of these antibiotic classes is essential for prescribing appropriate treatment regimens and combating the challenge of antibiotic resistance. Additionally, proper antibiotic stewardship practices are crucial to preserve the effectiveness of these life-saving medications for future generations.
Overview Of Antibiotics: Fluoroquinolones
Fluoroquinolones are group of broad-spectrum antibiotics that have been used widely as therapy of respiratory and urinary tract infections. These antibiotics are active against a wide range of aerobic gram- positive and gram- negative organisms. Fluoroquinolones are mechanism of action is believed to be act by inhibition of type II DNA topoisomerases that are required for synthesis of bacterial mRNAs and DNA replication. Overall, fluoroquinolones are indicated for treatment of several bacterial infections, some being first line and others being alternate options. The fluoroquinolones that are available on the market in the US are; ciprofloxacin, Gemifloxacin, levofloxacin, moxifloxacin, norfloxacin and ofloxacin.
Fluoroquinolones do not have the best side effects profile. In fact, they have a few black boxes warnings. The black boxed warning of increased risk of tendinitis and tendon rupture. The rate of this side effect was higher for people over 60, people who had received kidney, heart or lung transplants and people taking steroid treatment. Later on a new black boxed waring was added for the risk of worsening symptoms for those with myasthenia gravis. A new black boxed warning was instated in 2013, for the potential risk for irreversible peripheral neuropathy (serious nerve damage). These warning are not common, however do pose a serious risk in patients who may experience them, therefore, it was put as a black boxed warning. However, the most common side effects of fluoroquinolones are, nausea, vomiting, CNS reactions, dizziness, insomnia and headaches.
A less common side effects that is seen in fluoroquinolones but does in fact effect the skin is phytotoxicity. Phototoxicity is defined as a toxic response that is elicited after the initial exposure of skin to certain chemicals and subsequent exposure to light, or that is induced by skin irradiation after systemic administration of a chemical substance. The most common clinical representation of phototoxicity is presented as irritation or exaggeration like sunburn, erythema, pruritis and edema. Drug-induced photosensitivity can also look like lupus like reactions due to their scaling, annular and psoriasiform characteristics.
The most common Fluoroquinolone that causes phototoxicity is lomefloxacin, which is not marketed in the US. However, it is caused by oxidative stress. Treatment for this is relatively simple in most cases, being discontinuation of antibiotic. In addition to this patient should be avoiding the sunlight exposure as best as they can. These two practices usually will allow the reaction to go away and heal on its own. However, if the reaction is severe and the skin is more irritated the use of topical or systemic corticosteroids may be appropriate for symptom relief.
Besides phototoxicity fluoroquinolones do not have many other side effects on the skin that are so common. These broad-spectrum antibiotics are extremely beneficial to the world of antibiotics and treatment in infections. Understanding their interactions to the body and their side effects are a key component in properly utilizing them.
References:
Kowalska, Justyna et al. “Molecular and Biochemical Basis of Fluoroquinolones-Induced Phototoxicity-The Study of Antioxidant System in Human Melanocytes Exposed to UV-A Radiation.” International journal of molecular sciences vol. 21,24 9714. 19 Dec. 2020, doi:10.3390/ijms21249714
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Fluoroquinolones. [Updated 2020 Mar 10]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547840/
Tanne, Janice Hopkins. “FDA adds "black box" warning label to fluoroquinolone antibiotics.” BMJ (Clinical research ed.) vol. 337,7662 a816. 15 Jul. 2008, doi:10.1136/bmj.a816
Kowalska, Justyna et al. “Drug-Induced Photosensitivity-From Light and Chemistry to Biological Reactions and Clinical Symptoms.” Pharmaceuticals (Basel, Switzerland) vol. 14,8 723. 26 Jul. 2021, doi:10.3390/ph14080723
The skin is colonized with a multitude of microbes that usually do not harm a healthy host. Skin breaks due to trauma can create an opening for these microbes to penetrate deeper into the skin layers, which results in the infection. Skin and soft tissue infections consist of infections that vary highly in severity. These range from uncomplicated cellulitis, manageable with oral antibiotics in an outpatient setting, to life-threatening infections such as necrotizing fasciitis, requiring immediate surgical intervention.
Skin and soft tissue infections are characterized into purulent and nonpurulent infections, which is a classification based on the type of bacteria that is causing the infection and whether there is a presence of purulent exudate (also known as pus) or not. Some purulent infections are cutaneous abscess, carbuncles, and furuncles, meanwhile nonpurulent infections consist of impetigo, erysipelas, and cellulitis. The bacteria that causes most SSTIs are S aerus or β-haemolytic streptococci, most commonly Streptococcus pyogenes, also referred to as Group A streptococcus. In impetigo and cellulitis, or nonpurulent SSTIs, methicillin-susceptible S aureus alone or in combination with β-hemolytic streptococci is responsible for infection.
Risk factors for developing SSTIs include compromised epidermis, inadequate personal hygiene, overcrowded living conditions, underlying health issues, and close proximity to individuals with SSTIs. Additionally, skin conditions like eczema and psoriasis, which create small fissures, contribute to SSTI susceptibility. Conditions such as venous stasis and lymphedema, often associated with obesity, can predispose individuals to SSTIs by compromising bacterial filtering mechanisms, leading to elevated microbial counts. Surgical procedures also pose a risk for SSTIs due to the breach in the skin they entail.
According to the guidelines, disease severity is classified as mild, moderate, or severe under each type of SSTI. This is based on systemic signs of infection, immunodeficiency, or failure of outpatient therapy. For instance, in mild purulent SSTI, incision and drainage of the abscess alone, without antibiotics, can be curative, as this eliminates the bacterial source of infection. For animal bite wounds, an antimicrobial agent active against aerobic and anaerobic bacteria should be used.
For nonpurulent SSTIs, beta-lactams are used. This includes penicillins such as penicillin G, penicillin VK, and piperacillin/tazobactam, as well as cephalosporins, such as cephalexin and ceftriaxone. The antimicrobial therapy for purulent SSTIs include cephalosporins like cefatroline, lipopeptides like daptomycin, oxazolidinones such as linezolid or tedizolid, sulfonamides like Trimethoprim-sulfamethoxazole, tetracyclines like doxycycline and minocycline, glycopeptides like vancomycin, and lipoglycopeptides like telavancin, oritavancin, and dalbavancin. For individuals who are immunocompromised, the differential diagnosis for skin lesion infections should encompass bacterial, fungal, viral, and parasitic agents. In pregnant women, β-lactam antibiotics are typically considered safe and should be the preferred choice whenever feasible. In cases of purulent SSTIs in pregnancy, vancomycin is a suitable treatment option.
Regarding monitoring and follow-up, patients should undergo evaluation 48 to 72 hours after starting antibiotic therapy. In most SSTIs, noticeable improvement in clinical symptoms is expected within 3 days of appropriate treatment. If a patient shows no response during this period, further culture and sensitivity testing is necessary, and treatment should be adjusted based on the identified pathogen. A lack of or delayed response to treatment may suggest the requirement for surgical intervention to address the infection's source. Healthcare providers should be assessing systemic signs of an infection such as a fever, an increase in erythema, swelling, or tenderness, and the spread of infection to other areas of the body. Timely assessment and adaptation of therapeutic approaches are crucial for effective management of SSTIs.
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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/