Pneumonia infects between three and four million people in the US every year, with one million patients being hospitalized. It has an age-adjusted mortality rate of 22% (Arcangelo, Peterson, Wilbur et al., 2017). Community acquired pneumonia (CAP) is an infection of the lungs affecting individuals with no recent history of stay in the hospital or nursing home. Majority of CAP cases are caused by viral or bacterial infections, with Streptococcus pneumonia known to be the leading causative agent, with prevalence in up to 65% of the cases. However, initial diagnosis of CAP makes attribution to viral or bacterial infection difficult; hence, most doctors opt to treat it with antibiotics (Drug.com, 2018). According to Arcangelo et al. (2017), other pathogens that can cause CAP include mycobacteria, mycoplasma, and fungi. In addition, systemic infections such as influenza A or B and measles or varicella can cause pneumonia in adults and children respectively. It is important to note that pathogens that cause pneumonia in people with compromised immune systems are different from those seen in other types of pneumonia.
Types of Dugs Available for Treatment
Empiric therapy is common in the management of CAP cases because diagnosis often reveals multiple pathogens that cannot be effectively cleared by a single regimen. The goal of pharmacotherapy in CAP is to rid the body of the pathogen through selection of antibiotic therapy. Arcangelo et al. (2017) advised that the empiric treatment for CAP should always be active against S. pneumonia , the most commonly identified pathogen. Therapeutic regimens for CAP vary depending on age and condition of patient and comorbidities. There are over 150 drugs for treatment of pneumonia, but the most commonly used include macrolide (clarithromycin or azithromycin) or doxycycline,), a beta-lactam (high-dose amoxicillin, amoxicillin-clavulanate, or a second- or third-generation cephalosporin) plus a macrolide or an antipneumococcal fluoroquinolone (levofloxacin, moxifloxacin, gemifloxacin), and Ciprofloxacin.
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The most commonly described macrolide antibiotics in the treatment of pneumonia are erythromycin, clarithromycin, or azithromycin. The pharmacokinetics of these drugs is dependent on their chemical structure. For instance, erythromycin is degraded in the stomach environment where the pH is low. The 8, 9-anhydro-6, 9-hemiketal intermediate is inactive as an antibiotic but may cause the gastrointestinal adverse effects that have been associated with erythromycin. Further metabolism of the intermediate transforms it into the inactive anhydroerythromycin, erythromycin-6, 9; nine, 12-spiroketal. Clarithromycin is more acid stable and is not degraded as fast in the stomach. Azithromycin is even more stable at low pH, resulting in comparatively longer serum half-life and increased concentrations in tissues. Due to their stability in low pH, azithromycin and clarithromycin have an oral bioavailability of 37% and 55% respectively, compared to an oral bioavailability of 25% for erythromycin. However, peak serum concentrations of azithromycin and clarithromycin are lower than for erythromycin of the same dose.
The absorption of these drugs in the stomach is thought to be restricted by P-glycoprotein (ABCB1) efflux transporters, which are encoded by the ABCB1 gene. The transported are also thought to mediate the excretion of drug metabolites into the bile. The involvement of P-glycoprotein (ABCB1) in the transportation of many other drugs implies the macrolides are involved in drug-drug interactions. Macrolides are widely distributed into the blood and body tissues because they are lipophilic. In the blood stream, they preferentially bind alpha-1-acid glycoprotein (AGP) (encoded by the gene ORM1). The binding protein is only second to albumin in concentration. Erythromycin mostly binds to AGP in the plasma, while azithromycin is 93% unbound in the plasma, but only 16% unbound in liver tissue. Macrolides are transported to the site of infection by phagocytes. Clarithromycin and azithromycin have 400- and 800-times higher concentration in phagocytes than in the serum, while tissue concentration is 50 higher than plasma concentration. They are found in the peritoneal fluid and milk but low levels partition in the brain.
Erythromycin is extensively degraded by CYP3A4 in the liver, and 80% of it is inactivated through demethylation before 60% and 40% are excreted in the bile and urine respectively. The major metabolite from erythromycin is N-desmethylerythromycin. Similarly, Clarithromycin is believed to be metabolized by CYP3A4 into the inactive metabolite N-desmethylclarithromycin and the active metabolite 14-(R)-hydroxyclarithromycin. On the other hand, azithromycin does not seem to interact with SLCO1B1 or SLCO1B3, and is weak substrate for CYP3A4. As a result, only about 6% if it is recovered in urine as most is excreted unchanged in the bile via both MRP2 (encoded by the gene ABCC2 ) and ABCB1.
The basic mechanism of action of macrolides on bacterial is the inhibition of protein synthesis. The drugs specifically target the translation phase of protein synthesis by blocking it through reversible binding to the 50S subunit of the 70S bacterial ribosomes. The mechanism of action makes macrolides effective against actively dividing pathogens. Depending on their concentration, macrolides may also be bacteriostatic or bactericidal. Efficacy is dependent on the interval of time of dosing with percentage concentration above the minimum inhibitory concentration. The mechanism of action of macrolides create a low barrier for bacteria developing resistance in instances where ribosomal structure or affinity of the drug changes.
On rare occasions, macrolides can cause damage to the liver resulting to inability to secrete bile and inflammation. While risk factors for the side effect are unknown, the mechanism of action is thought to be immunological reaction. Concomitant infection of the liver may result from the production of hepatotoxic metabolites, or indication of cell signaling pathways leading to death of liver cells. Hepatotoxicity is common in patients taking erythromycin that those on azithromycin. It is important to note that Clarithromycin performs better against gram-positive bacteria than azithromycin, which has better activity against gram-negative bacteria. Greater stability and tissue concentrations of azithromycin allow it to penetrate lowly permeable cell walls of gram-negative bacteria and stop gene translation and growth.
Influence of Behavior on Effectiveness and Efficiency of Drugs
Behavior is an important factor in the development of drug resistance pathogens. According to Arcangelo et al. (2017), methicillin-resistant S. aureus (MRSA) has emerged as the most common pathogen isolated in community-acquired skin and soft tissue infections and is increasingly recognized as a cause of CAP. The 2010 Global Burden of Disease report asserted that for sub-Saharan Africa, for example, 15 of the top 20 health risk factors are predominantly behavioral, and the other five are highly influenced by behavior (Shelton, 2013). Lifestyle behaviors such as tobacco and alcohol use, and risky sexual behavior can act as antecedents towards reduced efficacy of pneumonia drugs. In addition, care-seeking behavior determines the progression of disease, and it may be too late for drugs to be effective when an individual visits the hospital for checkup. Client adherence and collaboration is a major contributor to drug resistance because many of the cases stem from failure to complete the dosage or collaborate with the physician during treatment.
Measures for Reduction of Negative Side Effects
Addressing the role of behavior in influencing the efficacy of treatment is dependent on policy and priority setting. For instance, for patients above 60 years, they must be admitted and only released once the therapy has been completed. This would reduce instances of failure to take the drug as prescribed. Public education is instrumental in cultivating pro-social behavior towards healthcare initiative. Such programs must be embraced to ensure individuals are aware of the existing frameworks for accessing health services. Encouraging early visits to the hospitals is crucial for early diagnosis to arrest the disease at its initial stage of development. Fox and Obregón (2014) advocated for population-level behavior change as the best strategy for improving health outcomes in all settings.
References
Arcangelo, V. P., Peterson, A. M., Wilbur, V., & Reinhold, J. A. (Eds.). (2017). Pharmacotherapeutics for advanced practice: A practical approach (4th ed.). Ambler, PA: Lippincott Williams & Wilkins.
Drugs.com. (2018). Pneumonia: What is it? Retrieved from https://www.drugs.com/health-guide/pneumonia.html.
Fox, E., & Obregón, R. (2014). Population-level behavior change to enhance child survival and development in low-and middle-income countries. Journal of Health Communication , 19 (sup1), 3-9.
Shelton, J. D. (2013). The 6 domains of behavior change: the missing health system building block. Health Sci Pract., 1, 137-140 . doi: 10.9745 .
