Anti Infective Agents: Principles PDF

Anti Infective Agents: Principles Thomas A. Panavelil, Ph.D., M.S., M.B.A.  Types of infections A. Bacterial infections B. Mycobacterial infections-bacterial, but classified separately - tuberculosis, Atypical infections, Leprosy (Hansen’s disease)...

Anti Infective Agents: Principles Thomas A. Panavelil, Ph.D., M.S., M.B.A.  Types of infections A. Bacterial infections B. Mycobacterial infections-bacterial, but classified separately - tuberculosis, Atypical infections, Leprosy (Hansen’s disease) C. Fungal Infections – Resistance to chemotherapy D. Helminthiasis (All Worm infections) E. Protozoal Infections (Example, Ameba) F. Viral Infections (Covid 19, Herpes, HIV, Influenza, HCV, HBV etc.)  Selection of Antimicrobial agents Sensitivity to the agent Severity and site of infection Safety of the agent: renal and hepatic function Patient factors like age, pregnancy etc. Cost of therapy (parenteral Vs oral for cost management if possible ) Antibiogram of the institution and specifically unit- specific antibiograms. As an example, the presence of VRSA at some hospital units. Home, nursing homes, hospital (nosocomial) can all carry bacteria that can cause infections.  Important Questions to ask the patients Do you have any other people sick at home? Do you have pets like pigeons or chickens at home? Eg: Histoplasmosis from chicken, cryptococcosis from pigeon, ornithosis from pigeon – Chlamydia infection causing pneumonia Where are you Employed? Infection by contaminated meat, infection from ICU atmosphere Where did you recently travel?  Points to Ponder Tuberculosis and lymphoma- cause increase in monocytes Drug allergy and metazoan infections can increase in eosinophils A bone and joint inflammation that is purulent could be due to an infection The presence of neutrophils in spinal fluid, sputum and urine could be a sign of bacterial infection Febrile patient with flank (back between ribs and hip) pain and dysuria (pain urinating) could be having an enteric E. coli infection Febrile patient with cough and sputum production could be having pulmonary infection by bacteria, mycobacteria, virus or mycoplasma  Identification of pathogens Identification is done by differential stains and molecular biological techniques Sensitivity is assessed using disc diffusion techniques and biochemical characteristics of the organism (such as glucose fermentation). There are many mechanized testing procedures. Infected body material should be collected before institution of antimicrobial therapy. Blood culture (collection at sharp elevation in temperature) is performed for acutely ill febrile patient. Collection to be done in aerobic and anaerobic bottles. Sample collection should be done before aspiration of abscesses because it may reduce microbial load. When taking cultures from skin, perineum, oropharynx, nose ears, eyes and throat, beware of colonization (pathogenic in certain settings only) Vs infection. Colonization by coagulase negative Staphylococcus (example S. epidermidis present on body surfaces), will give false results. Urine culture should be performed along with urinalysis for WBC, nitrite and esterase.  Host Factors Allergic reactions versus Adverse effects should be distinguished (An example is penicillin, and its GI effects). Conditions for prescribing cephalosporins to penicillin sensitive patients: Criteria: Delayed reactions (skin rash) vs immediate or accelerated reactions (anaphylaxis, laryngospasm). In delayed reactions cephalosporins can be given. If immediate-type reactions with penicillin occur, cephalosporins are not given. In Neonates Kernicterus can occur with sulfonamides and Gray baby syndrome can occur with Chloramphenicol In elderly patients, hepatic toxicity may manifest with administration of isoniazid. Prophylactic therapy in elderly to be determined based on the toxicity vs benefit. In Pregnancy: Teratogenic effects should be seriously weighed.  Host Factors… Pharmacokinetics: Penicillins, Cephalosporins, and Aminoglycosides are cleared rapidly due to increase in intravascular volume, increase GFR, and increase metabolism in pregnancy. Therefore, dosages may have to be increased. If the patient have an inherited metabolic abnormality such as G6PDH deficiency, drugs such as sulfonamides, nitrofurantoin, antimalarials, dapsone and chloramphenicol can cause hemolytic anemia! If the patient have an inherited metabolic abnormality such as slow acetylation, isoniazid can cause peripheral neuropathy. If the patient have a liver disease, the levels of drugs such as Chloramphenicol, Clindamycin, Erythromycin, Metronidazole and Rifampin have to be adjusted. If the patient has a renal dysfunction the levels of drugs such as Cefotaxime, Nafcillin, Piperacillin, and Sulfamethoxazole have to be adjusted.  Highest probabilities of infection causing organisms UTI: E. coli could be the organism Joint infection: S. Aureus could be the organism Community pneumonia: S. pneumoniae could be the organism Hospital acquired pneumonia: Enterobacter, Pseudomonas aeruginosa are possible organisms Bacteremia from urinary tract: Gram-negative bacilli are the possibility Bacteremia from IV catheter: Staphylococcus is the best possibility Patients taking immunosuppressive drugs or having immunosuppressive diseases: Staphylococcus, Enteric gram- negative bacilli and fungal infections are all possibilities. Meningitis in healthy adults: Meningococci (Neisseria meningitidis) is the most possible organism. Meningitis in lymphoma patients: Listeria monocytogenes is the most possible organism.  Other Drug factors Pharmacodynamics Pharmacokinetics If the Drug eliminated by kidneys, Creatinine clearance should be determined by Cockcroft and Gault equation. Consideration should be taken into post-antibiotic effect and concentration dependent killing (lectures on aminoglycosides and fluoroquinolones will deal with this area). Concentration dependent drugs can be given in large doses for long periods of therapeutic effects. Consideration should be taken into time-dependent killing (lecture on beta lactams will deal with this area). Frequent small doses are necessary for time dependent drugs. Tissue penetration: Drugs should reach the site of infection at effective concentrations. Therefore, considerations are made based on the tissue that is infected (brain, prostate, bone etc).  CSF penetration and Prostate Infections Blood brain barrier: Treatment of CNS infections depends on the ability of the drug to penetrate Blood brain barrier to reach CSF at proper therapeutic concentrations. Inflammation facilitates penetration of many antibiotics. Penetration of drugs in prostate and tissues harboring abscesses can change the treatment modalities. Bacterial prostatitis is difficult to cure, because of the inability of many antibacterial agents to cross the prostatic epithelium. Prostate also has a lower pH (6.4). Trimethoprim has the ability to reach proper concentrations in prostatic fluids due to its non-ionized state in the plasma. On the other hand, penicillin G which is ionized at plasma pH is ineffective in the treatment of prostatitis.  Toxicity CNS toxicity can be problem when dose is not adjusted for renal dysfunction. Examples for such drugs are Penicillins, Cephalosporins, quinolones, and imipenem. Hematological toxicity: The drugs are listed with hematological abnormality in parenthesis. Nafcillin (neutropenia), Piperacillin (platelet dysfunction), Cefotetan (hypoprothrombinemia), Chloramphenicol (bone marrow suppression), Trimethoprim (megaloblastic anemia) Nephrotoxicity is observed with aminoglycosides, vancomycin etc. Ototoxicity is observed with aminoglycosides, erythromycin etc. Photosensitivity with Azithromycin, Quinolones, Tetracyclines, Pyrazinamide, Sulfamethoxazole, Trimethoprim.  Empiric therapy Critically ill patients need immediate administration of drugs covering infections by both gram positive and gram-negative organisms. This is termed empiric therapy. The patient’s condition may require “empiric therapy” before the infective organism is known (Also called the “umbrella therapy” where a broad-spectrum antimicrobial or a combination of agents is used that will be effective against the most likely organisms). A simple detection of neutropenia may indicate a bacterial infection (neutropenia causes bacterial infection). A headache, rigid neck and sensitivity to lights may indicate symptoms of meningitis. Immediately after specimens for lab analysis are obtained (for culture and sensitivity) “empiric therapy” is initiated. The selection of drug is determined by site of infection and patient history (hospital of community acquired), travel history and age. Combination of drugs or a single drug covering gram-positive and gram-negative drugs used in this case.  Bacteriostatic vs. Bactericidal drugs Status of the patient such as immune system dysfunctions should determine if a bactericidal vs bacteriostatic drug should be used. Bacteriostatic drugs: They arrest the growth and replication of bacteria at serum levels achievable in the patient thus limiting the spread of infection. Body’s immune system attacks and eliminates the pathogens. Bactericidal: These agents kill the bacteria therefore the total number of viable organisms decrease. An antibiotic, as example chloramphenicol, may be bactericidal to one organism (pneumococci) and bacteriostatic to others (gram-negative rods).  Other Key factors Cost of therapy: Amoxicillin Vs Levofloxacin. Prophylaxis: Against potential risk.  Routes of administration Oral: Usually in outpatient therapy and in mild to moderate infections. Timing of intake is important if food impairs absorption Parenteral (all forms using needle): In serious infections when high serum levels are required. Also when the drug gets inactivated orally. Intra-thecal: For meningeal infections when the agent does not cross the blood brain barrier. Topical, Sublingual, Subcutaneous, Inhalational etc.  Antibiotic Spectra Narrow spectrum: Agents acting only on a single or a limited group of organisms. Extended spectrum: Active against gram-positive and a number of gram-negative bacteria (example, ampicillin). Broad spectrum: Drugs such as tetracycline and chloramphenicol is active against a wide range of organisms. These drugs may alter the nature of normal bacterial flora and can result in superinfections such as Candida infections.  Combination therapy Single agent therapy specific for the organism is the most appropriate. This increases spectra, reduces superinfections and reduces emergence of multidrug resistance. In situations such as tuberculosis multidrug therapy is of great benefit. Advantages of drug combinations are synergism (example beta lactams and aminoglycosides), broadening, and emergence of resistance. Major disadvantages of drug combinations: Some antibiotics act on growing organisms. Thus, if the second agent is bacteriostatic, it affects the action of the first drug that is bactericidal. Additive toxicity is another disadvantage (nephrotoxicity with aminoglycosides and vancomycin). Another example for disadvantage is beta-lactamase induction by one drug (Cefoxitin, Imipenem) inactivating penicillins, if used concomitantly.  Drug Resistance If the bacterial growth is still not halted when the maximal level of antibiotic tolerated by the host is used, bacteria are said to be resistant. Some organisms are inherently resistant to antibiotics. An example is vancomycin that is resistant to gram-negative organisms. Spontaneous mutations of DNA, DNA transfer of drug resistance, altered expression of proteins that include modification of target sites, decreased accumulation, enzymatic inactivation are all examples