Chapter 39, Problem 1O

Summary Introduction

To discuss:

About the following antibiotics: aminoglycosides, quinolones, clindamycin, metronidazole, nitrofurantoin, vancomycin, and several other miscellaneous antibiotics.

Concept introduction:

Drugs that are used to treat bacterial infections are referred to as antibacterial agents. These antibacterial agents differ in their mode of action, which includes inhibition of cell wall, inhibition of protein and nucleic acid synthesis, and inhibition of essential metabolites synthesis. Antibiotics namely aminoglycosides, quinolones, clindamycin, linezolid, metronidazole, nitrofurantoin, and vancomycin are mostly reserved to treat highly potent infections. These drugs are mainly given through parenteral route. Thus, these drugs necessitate more through and skillful assessment of that particular drug and the patient.

Explanation of Solution

Important considerations when prescribing antibiotics for the treatment of particular infection include receiving an accurate diagnosis of the disease, knowing the distinction between definitive and empiric therapy, finding possibilities to change to narrow-spectrum drugs, affordability, dosage, knowing the characteristics specific to drugs, identifying adverse activities of drugs on the host, and finding the time when the therapy is no longer needed.

Identifying and initiating antibiotic-based treatment regimen:    

Receiving an accurate diagnosis of the disease:

• Most frequently, cellulitis is known to be caused by staphylococci or streptococci. Thus, treatment with antibacterial agents can be given and a positive culture is not mandatory.
• Community-acquired pneumonia: Can be treated empirically with antibiotics (fluoroquinolones or macrolide). Specific diagnostic analysis is not necessary.   

Definitive vs empiric antibacterial therapy:

• Bacterial meningitis is suspected in an otherwise healthy adult:
  • Most likely causative pathogen would be Neisseria meningitidis and Streptococcus pneumoniae.
  • As empiric therapy: Vancomycin and third-generation cephalosporin would be recommended.

Deciding chemotherapy and selecting a drug:

• Aminoglycosides:
  • Amikacin: Infections caused by tobramycin- and gentamicin-resistant gram-negative bacteria together with serious staphylococcal infections. Gentamicin and Tobramycin: Infections caused by gram-negative bacteria together with serious staphylococcal infections. Neomycin: Bowel cleansing (preoperative).
• Quinolones:
  • Broad-spectrum antibiotics with a potential bactericidal activity. Resistance becoming common. Ciprofloxacin: Widespread use; Resistance observed in Pseudomonas and Streptococcus spp. Anthrax, skin, respiratory and urinary tracts, GI, prostrate, bone, and typhoid fever. Levofloxacin: Potent than ciprofloxacin against gram-positive bacteria. Urinary and respiratory tracts. Moxifloxacin: Skin and respiratory infection and anaerobic infections. Norfloxacin: Prostatitis, UTIs, and STIs. Gemifloxacin: COPD exacerbation, CAP.
• Clindamycin:
  • Anaerobic pneumonia, chronic bone infection, septicemia (by staphylococci and streptococci), and intra-abdominal infection.
• Metronidazole:
  • Metronidazole that belongs to the drug class nitroimidazole is an antimicrobial agent active against anaerobic organisms. It is used in the treatment of gynecologic and intra-abdominal infections. Protozoal infections such as trichomoniasis and amebiasis can also treated using metronidazole. Similar to quinolones, metronidazole also obstructs the synthesis of microbial DNA. Gram-negative and anaerobic infections are observed in bone, abdominal cavity, skin, and GU and respiratory tracts.
• Nitrofurantoin:
  • UTIs caused by S. aureus and gram-negative bacteria.
• Vancomycin:
  • Serious staphylococcal infections; MRSA infections; other gram-positive infections; Streptococcal infections.
• Miscellaneous drugs:
  • Linezolid: Respiratory and skin infections caused by Staphylococcus and Streptococcus spp.; VRE infections.
  • Daptomycin: Complicated cases of skin and soft tissue infections.
  • Telavancin: Severe infections caused by gram-positive bacteria, including MRSA.
  • Colistimethate: For treating CRE-producing bacteria.
  • Quinupristin/ dalfopristin: Skin infections caused by Staphylococcus and Streptococcus spp.; VRE infections.

Interpretation of results of antibiotic sensitivity tests:

• Minimum inhibitory concentration (MIC) results will be reported; based on these results, it is interpreted as resistant, intermediate, or susceptible.

Bacteriostatic vs bactericidal therapy:

Some antibiotics may show bactericidal action on certain pathogens and can only have bacteriostatic effect on others, and sometimes vice versa.

• Bactericidal drugs: Kills pathogenic bacteria by disrupting the cell membrane, cell wall, or DNA.
  • Quinolones: Kills the bacteria by modifying their DNA, and this is accomplished by obstructing their topo-isomerase IV and DNA gyrase.
  • Clindamycin: Depending on drug concentration: bacteriostatic or bactericidal. Block synthesis of protein bacteria.
  • Metronidazole: Interfere with the biosynthesis of DNA of microorganisms.
  • Nitrofurantoin: Interfere with the formation of bacterial cell wall. Disrupts the activity of enzymes involved in the regulation of carbohydrate metabolism.
  • Vancomycin: Kills bacteria by inhibiting the biosynthesis of the cell wall.
  • Daptomycin: Complete mechanism unknown. Has the ability to bind with gram-positive cells (calcium-dependent process) and damage the potential of cell membrane.
  • Telavancin: Disrupt the function of bacterial membrane; inhibit the biosynthesis of bacterial cell wall.
  • Colistimethate: Penetrate and damage the cell membrane of bacteria.
• Bacteriostatic drugs: Block replication of the bacteria without destroying the pathogen.  
  • Aminoglycosides: Inhibit the synthesis of protein by binding to 30S ribosome.
  • Linezolid: Block the biosynthesis of bacterial protein.
  • Quinupristin/ dalfopristin: Inhibit synthesis of bacterial proteins.

Importance of antibacterial combinations:

• Synergistic effect: When two drug compounds are given simultaneously, the resultant chemotherapeutic effect is sometimes more than the effect of either drug administered alone; this phenomenon is known as synergism. A combination of penicillin and streptomycin is more effective than the effect of the drugs taken alone. The action of penicillin causes damage to the cell wall of bacteria, which makes the entry of streptomycin easy.
• Reduce emergence of resistant strains: A combination of drugs also possess broad spectrum activity and lessens emergence of drug-resistant strains to a great extent. Trimethoprim and sulfamethoxazole (TMP-SMZ), a widely used combination drug, involves in the inhibition of different steps in the synthesis of precursors of DNA, RNA, and proteins. Sulfamethoxazole is a structural analog of para-aminobenzoic acid (PABA), a folic acid precursor. This drug involves in the competitive inhibition of dihydrofolic acid synthesis from PABA. The second drug, trimethoprim, is structurally similar to a portion of dihydrofolic acid that involves in the competitive inhibition of tetrahydrofolic acid synthesis.
• Provide treatment till causative pathogen is identified: Synercid, a combination of quinupristin and dalfopristin (two cyclic peptides), is active against a broad range of gram-positive bacteria that are resistant to many other antibiotics. Synercid specifically acts at different points on the ribosome causing release of incomplete peptide chains. Dalfopristin inhibits an initial step, while quinupristin blocks a later step in protein synthesis. Such antibiotics are beneficial in providing treatment when the causative pathogen in a particular disease is not identified immediately. With an advantage of immediate treatment of disease, a combination of drugs saves valuable time.

Deciding an antibiotic: Factors related to host that need to be considered are as follows:

• Age.
• Renal and hepatic function.
• Genetic variation.
• Pregnancy.
• Lactation.
• History regarding intolerance or allergy.
• History regarding recent use of antibiotics.

Caution and contraindications:

• Quinolones: Caution: Nitrofurantoin antagonizes the activity of quinolones. In use with oral anticoagulants. Contraindications: Drug allergy.
• Clindamycin: In patients with pre-existing hypersensitivity, ulcerative enteritis and colitis, and infants (age: less than 1 month).
• Metronidazole: Drug allergy. Do not use during pregnancy (first trimester).
• Nitrofurantoin: Drug allergy; impairment of renal function.
• Vancomycin: Caution: Known hearing loss or renal dysfunction. Neonates and older patients. Contraindication: In patients with pre-existing hypersensitivity.
• Daptomycin: Drug allergy.
• Telavancin: Do not use in pregnant women. Contraindicated: concurrent use with unfractionated heparin.
• Colistimethate: Use in pregnant women: Can cross placenta, caution required.
• Aminoglycosides: Caution: Usage in full-term or premature neonates; Contraindications: Drug allergy; in pregnant women, it crosses through the placenta and harms the fetus.
• Do not use in lactating women: To prevent drug toxicity in infants (nursing).
• Linezolid: In patients with pre-existing hypersensitivity.
• Quinupristin/ dalfopristin: In patients with pre-existing hypersensitivity.

Intravenous vs oral therapy:

• In general, while opting for oral therapy for infections namely pneumonia, abscesses, and pyelonephritis, it is important to select an antibiotic with good bioavailability and absorption. For example, metronidazole, linezolid, and quinolones.
• For severe infections such as endocarditis or meningitis, much higher concentrations of drug compounds in the serum are required. Therefore, oral therapy is not usually recommended.

Considerations to continue the current antimicrobial therapy:

• Duration of the treatment.
• Analyzing the response to the current treatment.
  • Evaluated using both microbiological and clinical parameters.
  • Clinical parameters: Improvement of symptoms and signs, radiological findings, and laboratory values.
  • Microbiological parameters: In bacteraemia, bloodstream is devoid of pathogens.  
• Toxic and adverse effects: In some cases, antimicrobial agent administration results in allergic reactions. The adverse drug reaction occurs due to the interaction between the pharmacological agent and the immune system of human. These IgE-mediated hypersensitivity reactions are an undesirable characteristic of an antimicrobial agent. Production of hypersensitivity results as a consequence of host immune system recognizing a drug compound as a harmful pathogenic substance. Hypersensitivity refers to the increased adverse reactions, resulting in mild (nausea, pruritus, and vomiting) to severe (cardiovascular collapse) adverse effects in human.
  • Impaired clearance is seen in patients with deprived kidney or liver function using prolonged or higher doses of antibiotics.
  • Quinolones: Can cause a wide range of adverse effects. Long-term use: Bacterial over growth. Black box warning (FDA, US): Due to the risk of tendon rupture and tendinitis. In older adults: Causes liver damage.  
  • Clindamycin: GI tract adverse effects, including vomiting, diarrhea, abdominal pain, anorexia, and nausea.
  • Metronidazole: Headache, dizziness, nasal congestion, GI discomfort, thrombocytopenia, and reversible neutropenia. Increase toxicity of cyclosporine, lithium, calcium channel blockers, warfarin, antidepressants, and benzodiazepines.
  • Nitrofurantoin: Dizziness, GI discomfort, peripheral neuropathy (irreversible), ECG changes, skin reactions, headache, and hepatotoxicity.
  • Vancomycin: Nephrotoxicity and ototoxicity.
  • Daptomycin: Hypertension, hypotension, dizziness, headache, GI discomfort, rash, dyspnea, renal failure, and fungal infection.
  • Telavancin: Hypersensitivity reactions, headache, infusion reactions, anemia, and tachycardia. Red man syndrome: Increased liver functions, hypersensitivity reactions, and infusion reaction.
  • Colistimethate: Causes severe adverse effects: renal failure; neurotoxic effects: Dizziness, numbness, vertigo, paresthesia, speech impairment, and tingling. Administration: Inhalation form can cause acute failure of respiratory system.
  • Aminoglycosides: Ototoxicity; Nephrotoxicity.
  • Linezolid: Headache, diarrhea, vomiting, and nausea. Decrease platelet counts.
  • Quinupristin/ dalfopristin: At the infection site, edema, inflammation, pain, and thrombophlebitis are observed.

Conclusion

The aminoglycosides, quinolones, clindamycin, metronidazole, nitrofurantoin, vancomycin, and several other miscellaneous antibiotics are discussed.