Bacterial and Fungal Infections Essay Assessment

1. Briefly, discuss the likely causative microorganisms contributing to this patient’s infection(s). Begin with the initial infection and the likely reasons for why the infection progressed to atypical pneumonia with the additional development of oral thrush.                                                                                   (10 marks)

Mrs. Brown’s initial infection was community-acquired pneumonia. The disease is known to be a respiratory tract infection that involves pulmonary parenchyma [1]. Amoxicillin was administered to cope with community-acquired pneumonia. Amoxicillin is considered to have a very high impact on the disease, which allows the bacteria not to evade more tissues, thus leading to less severe atypical pneumonia and the growth of oral thrush. Community-acquired pneumonia is characterized by coughing, which leads to the production of greenish-yellow sputum, high fever, chest pains, and painful breathing. Four different micro-organisms cause the disease. The Streptococcus pneumoniae, atypical bacteria; Mycoplasma pneumoniae and Chlamydia pneumoniae, viruses [1, p.139], and Hemophilus influenzae. Several risk aspects for community-acquired pneumonia are asthma, immunosuppressive therapy, smoking, functional impairment, oral steroids, age, previous community-acquired pneumonia infection, and chronic bronchitis. The most common way for the microbial agents to reach the alveoli is the oropharyngeal secretion. The microbes are inhaled from air droplets and exposed to the lung tissues. The microbes overcome the alveoli macrophages to cause pneumonia. If the alveoli fail to control the microorganism, the lungs develop an inflammatory response, which is a characteristic of the movement of the monocytes and white blood cells top the alveoli space.

2. Describe the antimicrobial action of clarithromycin. Include in your answer details of mechanisms of resistance towards this antibiotic. (15 marks)

Clarithromycin is used in the treatment of pneumonia. The drug is a protein synthesis inhibitor that prevents the bacteria in microbes from multiplying. Clarithromycin binds with the 23 rRNA from the 50s subunit in the ribosome, thus leading to inhibition of peptides translation [2, p.65]. Clarithromycin is acid-stable, therefore not affected by gastric acid. It is absorbed and diffuses to the tissues and phagocytes. The drug is transported to the infection site by the phagocytes. Clarithromycin is released during phagocytosis and has a refined concentration in the tissues compared to the plasma. The spectrum of activity of posaconazole includes Cryptococcus and Candida species. Posaconazole is used to treat oropharyngeal candidiasis, which provides for refractory infection to fluconazole. It also used as prophylaxis for candida infection, as hemopoietic stem cells in transplants, and patients with prolonged neutropenia. Posaconazole has a broad spectrum of activity that is fungistatic in its operation [3, p.1042]. Microbes acquire resistance towards antimicrobials. Some of the resistance mechanisms against clarithromycin are the modification of existing target, attainment of a target by-pass system, production of enzymes that inactivate drugs, removal of drugs from microbial cells, and reduction of cell permeability. Often, several resistance mechanisms can be observed at any time [4, p.375]. Ergosterol is essential in the fungal cell membrane as it stabilizes the membrane structure by bunding to the phospholipids. It regulates membrane fluidity, structure permeability, and enzyme activities bounded to the membrane.

3. Write down in detail the mechanism of action of meropenem. You should discuss key structural features in meropenem and their interactions with the bacterial target, which account for the antimicrobial activity. In comparison to amoxicillin, outline the unique chemical features of meropenem.

Following an IV administration, meropenem analogue 1 was found to display clinically effective antimicrobial activity. In contrast, analogue 2 showed no antimicrobial activity. Provide detailed mechanistic accounts for the above observations.

                                                                                                                                 (10 marks)

Meropenem is bactericidal but bacteriostatic in Listeria monocytogenes. Its action is felt through the inhibition of cell wall synthesis. In contrast to amoxicillin, meropenem is highly resistant to deprivation by β-lactamases or cephalosporinases. Resistance arises as a result of mutation of the penicillin-binding proteins and resistance to diffuse across the bacterial outer membrane. Meropenem is stable to dehydropeptidase-1, thus can be given without administering cilastatin.

Meropenem analogue 1 was administered as the right bacteria for the drug were present. The bacteria could not resist as the drug targeted their cell membrane, denatured it, and destroy the bacteria ready for removal. Meropenem analogue 2 was administered where the bacteria had already gained resistance to the drug; thus, the drug could not act on the bacteria. The effect may also be seen where the antimicrobial was not useful to the bacteria due to its low spectrum of activity.

4. You are required to design a new carbapenem analogue with antimicrobial activity that is equivalent or comparable to meropenem. e-Draw the chemical structure of your carbapenem analogue and provide a brief explanation of why your analogue would display clinically effective antimicrobial activity.  (5 marks)

Ertapenem is a bacterium producing ESBL. It is used in a variety of activities such as the treatment of severe infections of the lungs [5], pelvis, skin, and urinary tract. Ertapenem is used in the prevention of receiving certain types of surgery from being infected.

5. Posaconazole is available as an oral suspension. Explain why this formulation was chosen rather than an oral solution.  Considering the list of ingredients in the oral suspension formulation, discuss the function of each component.  (15 marks)

Posaconazole is an oral suspension as it is given with meals and beverages to people who eat a full meal. The ingredients used to make the medicine are: 1) polysorbate 80, which is used as a surfactant; 2) simethicone, which is used to treat gas symptoms; 3) sodium benzoate used as a food preservative; 4) sodium citrate dihydrate used to control pH; 5) citric acid monohydrate, which has antioxidant properties and sustains the stability of all lively ingredients; 6) glycerine, which is used as a moisturizer; 7) xanthan gum, which is used due to its additives; 8) liquid glucose, which is used as sweetener, 9) titanium dioxide, which is used for its pigment; 10) artificial cherry flavor used due to its fruity smell; 11) purified water used as a nonparental product – contact components [6

6. The table below lists some pharmacokinetic parameters for clarithromycin in a healthy 70 kg individual. The recommended regimen is 250 mg by oral tablet, every 12 hours for 7 days.

Oral bioavailability

55%

Apparent volume of distribution

240 L

Plasma protein binding

57%

Terminal half life

3.3 h

Renal clearance (as percentage of total clearance)

18%

Using the data supplied, describe the disposition of clarithromycin over the course of the regimen. Co-administration of clarithromycin with warfarin results in an increase in plasma concentration of warfarin.  What are the probable causes and consequences of this interaction?  (15 marks)

Posaconazole is used for antifungal prevention and treatment of immunosuppressed patients. Bioavailability of the drug includes gastric pH, lipid-rich food, and intermittent dosing, causing an increase in the bioavailability and pre-existing gut pathology, first pass-metabolism, interaction with H2 antagonists, and proton-pump inhibitors, potentially initiating reduction in the oral bioavailability. ADME represents the absorption, distribution, metabolism, and excretion. The four criteria impact the kinetics of drug acquaintance to the tissues, thus influencing the actions of the posaconazole drug [7, p.782]. Toxicity may also be considered. The compound is usually taken to the bloodstream before being absorbed by the target cell. The compound is then carried to its effector site via the bloodstream, where it then distributes into the muscles and organs. As the compound enters the body, its molecules begin to break down. The majority of metabolism is carried out in the liver, where the redox enzyme is used. Through excretion, the compounds are removed from the body. Discharge is done through the urine or faeces [7, p.786]. Midazolam is used before any surgery is conducted. It is used to help decrease anxiety, drowsiness, and reduce the memory of surgery procedure. Midazolam is used to sedate people with trouble breathing as well as those requiring tubes to enhance their breath. The drug is also used in the treatment of epilepsy. The interaction between midazolam and posaconazole is due to inhibition of CYP3A4 by posaconazole and the consequence of reduced elimination of midazolam with a rise in plasma concentration. The side effects of using midazolam include ataxia, respiratory depression, sedation, and euphoria.

7. When Noxafil® was launched in 2005 the BNF the monograph would have included the symbol ▼. What is this symbol?

Why would this symbol have been included in the early monographs for Noxafil®?

Include in your answer a description of what the system represents (15 marks)

The symbol is used to present any new medicine and is known as the black triangle. Medications with new active ingredients that are a combination of components or have a new route of being administered are considered unique and are represented by the given symbol [8]. Pharmacists working in clinics or providing dispensary services have an imperative role in supportive antimicrobial stewardship action. This includes responding to safety and following healthcare-associated infection standards. The essential functions are to provide information to the prescribers and review antimicrobial therapy. All pharmacists must have the said skills. Pharmacists intervention has helped reduce costs and improve appropriate antimicrobial use. The typical responses are the implementation of policies, therapeutic drug monitoring, and participation in ward rounds. Community pharmacists can also provide education to patients about using antimicrobial appropriately. Ward pharmacists may be involved in checking the results of the patients before and after administration of antimicrobial, and note down the changes [8, p.753]. They also prescribe an appropriate dose regimen and maintain proper timing for the duration of therapy. They recommend intravenous to oral switching. They monitor therapeutic drug administration. Providing information to the patient, their family, and carers on how an antimicrobial works and the appropriate way to use the antimicrobial is a critical procedure as well.