Bacterial pneumonia pharmacology by Marc Imhotep Cray, M.D.

Marc Imhotep Cray, M.D.

Respiratory Infections Upper respiratory infection  Most are viral: common cold, pharyngitis, rhinitis, sinusitis etc. Lower respiratory infection  Frequently viral  Bronchitis (or) asthma: cough, wheezing, dyspnea  Pneumonia: cough, fever, (chills), rapid respiration, dyspnea

Marc Imhotep Cray, M.D.

Case 1 A 68-year-old man presents to the emergency department complaining of a fever, dyspnea, and a cough productive of green sputum. Physical examination reveals an ill-appearing man, breathing heavily. On lung examination, you note bronchial breath sounds and dullness to percussion over the right lower lung lobe. A chest x-ray demonstrates circumscribed opacity over the region of his right lower lung lobe. You obtain sputum and blood cultures and then admit this patient to the hospital for antibiotic treatment.

Marc Imhotep Cray, M.D.

Pneumonia: Overview  Pneumonia is a respiratory disease characterized by inflammation of lung parenchyma (excluding bronchi) caused by viruses, bacteria, fungi, or irritants  Treatment varies according to the situation  General clinical signs and symptoms of pneumonia include:  Fever, chills, muscle stiffness, pleuritic chest pain, cough, blood-tinged or rusty sputum, shortness of breath, rapid heart rate, and difficulty breathing

 Diagnosis is made by several laboratory methods and (or) diagnostic procedures, including:  Chest x-ray; Gram stain and culture (bacterial); bronchoalveolar lavage (Pneumocystis carinii pneumonia [PCP]); serodiagnosis (Mycoplasma)

 Classic laboratory findings associated with bacterial pneumonia are a neutrophilic leukocytosis with an increase in band neutrophils (left shift) Marc Imhotep Cray, M.D.

Pneumonia: Overview (2) ď ąThe four most common bacteria causing sinus and respiratory infections are: 1. Streptococcus pneumoniae 2. Hemophilus influenzae 3. Staphylococcus aureus 4. Mycoplasma pneumoniae ď ąThree common morphologic patterns of pneumonia are: 1. Lobar pneumonia 2. Bronchopneumonia and 3. Interstitial pneumonia Marc Imhotep Cray, M.D.

Pneumonias: Classification

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015) Marc Imhotep Cray, M.D.

Common causes of pneumonia Neonates (< 4 Wks.) Group B streptococci E. coli

Children (4 Wks.–18 Yrs.) Viruses (RSV) Mycoplasma C. trachomatis (infants–3 yr.) C. pneumoniae (school-aged children) S. pneumoniae

Adults (18–40 Yrs.)

Adults (40–65 Yrs.)

Elderly

Mycoplasma C. pneumoniae S. pneumoniae

S. pneumoniae H. influenzae Anaerobes Viruses Mycoplasma

S. pneumoniae Influenza virus Anaerobes H. influenzae Gram-negative rods

Redrawn and modified from: Le T and Bhushan V. First Aid for the USMLE Step 1 2015

Note: Most common pneumonias in childhood are Viral pneumonias Most commonly implicated viruses are Influenza, parainfluenza, respiratory syncytial virus, rhinovirus, and adenovirus Marc Imhotep Cray, M.D.

Common causes of pneumonia (2) Special groups Alcoholic/IV drug user

S. pneumoniae, Klebsiella, S. aureus

Aspiration

Anaerobes (e.g., Peptostreptococcus, Fusobacterium, Prevotella, Bacteroides)

Atypical

Mycoplasma, Legionella, Chlamydia

Cystic fibrosis

Pseudomonas, S. aureus, S. pneumoniae

Immunocompromised

S. aureus, enteric gram-negative rods, fungi, viruses, P. jirovecii (with HIV)

Nosocomial (hospital acquired)

S. aureus, Pseudomonas, other enteric gram-negative rods

Postviral

S. aureus, H. influenzae, S. pneumoniae

Redrawn from: Le T and Bhushan V. First Aid for the USMLE Step 1 2015 Marc Imhotep Cray, M.D.

Lobar Pneumonia ď ą S. pneumoniae most frequently, also Legionella, Klebsiella Intra-alveolar exudateď&#x192; consolidation (A) may involve entire lobe (B) or lung

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

Marc Imhotep Cray, M.D.

Bronchopneumonia  S. pneumoniae, S. aureus, H. influenzae, Klebsiella  Acute inflammatory infiltrates (C) from bronchioles into adjacent alveoli  patchy distribution involving ≥ 1 lobe (D)

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015) Marc Imhotep Cray, M.D.

Interstitial (atypical) pneumonia  Viruses (influenza, CMV, RSV, adenoviruses), Mycoplasma, Legionella, Chlamydia  Diffuse patchy inflammation localized to interstitial areas at alveolar walls; diffuse distribution involving ≥ 1 lobe (E)  Generally follows a more indolent course (“walking” pneumonia)

Marc Imhotep Cray, M.D.

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

Interstitial & Lobar Pneumonias Compared

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

Compare diffuse, patchy bilateral infiltrates of â&#x20AC;&#x153;atypicalâ&#x20AC;? interstitial pneumonia (A) with the localized, dense lesion of lobar pneumonia (B) Marc Imhotep Cray, M.D.

Companion Notes: 

MedPharm Digital Guidebook 2015, UNIT 10 Drugs Used In Infectious Disease  eNotes Infectious Diseases Pharmacology  Rapid Review Antimicrobial Drugs and Vaccines Marc Imhotep Cray, M.D.

Key Concepts  Antibiotics exploit differences between prokaryotic and eukaryotic cells to promote specificity and limit toxicity  For example, bacterial enzymes involved in DNA replication and RNA synthesis are different from those found in eukaryotic cells  bacterial ribosome is also significantly different, allowing selective targeting  One of major differences between bacteria and eukaryotic cells is peptidoglycan-containing bacterial cell wall whose synthesis is inhibited by several antibiotics Marc Imhotep Cray, M.D.

Antibiotics target bacteria by five major mechanisms 1. 2. 3. 4. 5.

Inhibition of cell wall synthesis Inhibition of protein synthesis Inhibition of nucleic acids Alterations of cellular membranes Antimetabolites

Marc Imhotep Cray, M.D.

Mechanisms of antibiotic action A: Schematic showing cell wallâ&#x20AC;&#x201C;active, membrane-active, & cytoplasm-active antimicrobial agents B: Antibiotics that inhibit protein synthesis by interacting with different ribosome subunits C: Antibiotics that inhibit nucleic acid synthesis

Marc Imhotep Cray, M.D.

Somers KD and Morse SA. Lange Flash Cards: Microbiology & Infectious Diseases. New York: McGraw-Hill, 2010

1. Inhibition of cell wall synthesis β-lactam antibiotics such as penicillin and cephalosporins target peptidoglycan cross-linking by binding to and inhibiting action of transpeptidase enzymes  Vancomycin inhibits cross-linking by binding terminal Dalanine- D-alanine precursor and preventing transpeptidation Cycloserine inhibits formation of D-alanine-D-alanine linkage Bacitracin inhibits transport of new peptidoglycan precursors through cell membrane  Isoniazid and ethionamide inhibit mycolic acid synthesis in mycobacteria

Marc Imhotep Cray, M.D.

2. Inhibition of protein synthesis Aminoglycosides such as gentamicin, neomycin, and kanamycin irreversibly bind and inhibit function of 30S ribosomal subunits  contrast to most inhibitors of microbial protein synthesis, which are bacteriostatic, aminoglycosides are bactericidal

Tetracyclines reversibly inhibits binding of aminoacyl-tRNA to 30S subunit Macrolides such as erythromycin, azithromycin, and clarithromycin attach to a 23S RNA on 50S subunit resulting in its inhibition Chloramphenicol blocks attachment of amino acids to nascent peptide chain on 50S subunit resulting in its inhibition Marc Imhotep Cray, M.D.

3.Inhibition of nucleic acids  Quinolones and fluoroquinolones such as ciprofloxacin inhibit DNA synthesis by blocking DNA gyrase  Rifampin binds strongly to DNA-dependent RNA polymerase and thus inhibits RNA synthesis  Metronidazole interacts with DNA, altering its helical structure and causing DNA fragmentation

Marc Imhotep Cray, M.D.

4. Alterations of cellular membranes ď ą Polymyxin targets cell membranes rich in phosphatidylethanolamine, causing an increase in cellular permeability

5. Antimetabolites ď ą Sulfonamides and trimethoprim inhibit folic acid metabolism

Marc Imhotep Cray, M.D.

Sites of Action of Major Antibacterials Summary Table Folate pathway

DNA

Antimetabolites Sulfamethoxazole Trimethoprim

Quinolones Ciprofloxacin

Marc Imhotep Cray, M.D.

RNA Inhibits RNA synthesis Rifampin

Ribosomal subunit 30S

50S

Aminoglycosides Gentamicin and Tetracyclines Doxycycline

Macrolides Erythromycin Lincosamides Clindamycin Chloramphenicol Oxazolidinones Linezolid Streptogramins Quinupristin/ dalfopristin

Cell wall Î˛-lactam antibiotics Penicillins Cephalosporin s Aztreonam Imipenem Vancomycin Polymyxin B

Antibacterials Summary Schematic

Marc Imhotep Cray, M.D.

Johannsen EC. & Sabatine MS. PharmCards, 4th ed. Lippincott Williams & Wilkins, 2010

Antibiotic Resistance Mechanisms

Marc Imhotep Cray, M.D.

Antibiotic Resistance Mechanisms  Bacteria have evolved a number of mechanisms to protect themselves from action of antibiotics Altered expression of proteins in drugresistant organisms  Often genes encoding antibiotic resistance are carried on transposons and plasmids, and are therefore easily transferred from one organism to another, creating bacteria resistant to multiple antibiotics  Drug resistance is mediated by a variety of mechanisms, such as:  alteration in antibiotic target site lowered penetrability of drug due to o decreased permeability o increased efflux of drug, or o presence of antibiotic-inactivating enzymes o modification of target sites Marc Imhotep Cray, M.D.

Four major mechanisms are involved 1. Inactivation of antibiotic through hydrolysis  An example is β-lactamases that cleave β-lactam ring of penicillins and cephalosporins 2. Chemical modification of antibiotic through acetylation, phosphorylation, or adenylylation  An example is chloramphenicol acetyl transferase that transfers an acetyl group from acetyl CoA to chloramphenicol, resulting in its inactivation

Marc Imhotep Cray, M.D.

Four major Ab resistance mechanisms cont. 3. Alteration of antibiotic targets through mutation  An example is alteration of a single amino acid in ribosomal protein S12 prevents streptomycin binding to 30S ribosome subunit without affecting protein synthesis (See next slide for more)

4. Alterations that affect permeability (ie, decrease intracellular concentration of antibiotic) are used by a variety of antibiotics  This can involve a decreased influx or an increased efflux from bacterial cell Marc Imhotep Cray, M.D.

Examples of bacterial resistance due to alterations of antibiotic targets ď ąPneumococcal resistance to penicillins is due to changes in chemical structures of target penicillin-binding proteins located in bacterial cytoplasmic membrane ď&#x201A;§ A similar mechanism underlies resistance of staphylococci to methicillin (MRSA strains)

ď ą A structural alteration in the d-Ala-d-Ala component of pentapeptide side chains of peptidoglycans is basis for a mechanism of resistance to vancomycin

Marc Imhotep Cray, M.D.

“An Admonition” Mild, kind , yet earnest reproof. Cautionary advice or warning. “Learning the characteristics of antibiotics simplifies learning infectious disease pharmacotherapy. Students and clinicians who attempt to learn the antibiotics of choice for different types of infections before knowing the characteristics of those drugs never truly understand the context of what they are attempting to learn. Once the characteristics of the antibiotics are known, making a logical choice to treat an infection is much easier.” Gallagher JC, MacDougall C. Antibiotics simplified. 2nd Ed. Jones & Bartlett Learning, 2012

Marc Imhotep Cray, M.D.

Pharmacology of Common Antibiotics Used to Treat Bacterial Pneumonia Penicillin Amoxicillin Amoxicillin/clavulanate Cefaclor Cefotaxime Ceftazidime Ceftriaxone Cefuroxime Cefuroxime axetil Marc Imhotep Cray, M.D.

Azithromycin Ciprofloxacin Clarithromycin Erythromycin Imipenem Metronidazole Rifampin Tetracycline 29

Penicillins EXAMPLES (in order of narrowest to broadest spectrum)  Natural penicillins – benzylpenicillin, phenoxymethylpenicillin  Antistaphylococcal penicillins – nafcillin, oxacillin  Aminopenicillins– ampicillin, amoxicillin MECHANISM OF ACTION (MOA)  β lactam moiety binds to and inhibits transpeptidase required for formation of peptidoglycan cross-links within bacterial cell wall results in defective bacterial cell wall synthesis and subsequent cytolysis  Nafcillin & oxacillin are relatively resistant to staphylococcal β lactamases  Aminopenicillins have enhanced activity against aerobic Gram-negative bacilli  Piperacillin when combined with tazobactam (a β-lactamase inhibitor) has good activity against Pseudomonas spp.  Augmentin (or) Co-amoxiclav is a combination of amoxicillin and clavulanic acid (a β lactamase inhibitor) Marc Imhotep Cray, M.D.

Penicillins cont.

SIDE-EFFECTS  Urticarial rash  Anaphylaxis INDICATIONS  GI disturbance  Pharyngitis/tonsillitis  Antibiotic-associated colitis  Pneumonia  Stevens–Johnson syndrome  Otitis media  Fever  Cellulitis  Joint pains  Meningitis  Rarely cholestatic jaundice w co Endocarditis amoxiclav  Rheumatic fever METABOLISM AND HALF-LIFE  Osteomyelitis Elimination is via kidneys and biliary tract  UTI CAUTIONS & CONTRA-INDICATIONS t½ for benzylpenicillin is ~30 min; t½ for flucloxacillin is ~50 min; t½ for amoxicillin  Hypersensitivity is ~1h (rashes, urticaria, angioedema, fever, arthralgia, acute interstitial nephritis (AIN) , MONITORING No specific drug anaphylaxis) monitoring required Marc Imhotep Cray, M.D.

Penicillins cont. DRUG INTERACTIONS  Reduced efficacy of OCP when taking penicillins Women should be warned of this and advised to use alternative contraceptive methods IMPORTANT POINTS  Benzylpenicillin (penicillin G) must be administered parenterally because it is inactivated by gastric acid secretions  Phenoxymethylpenicillin (penicillin V) has a similar spectrum of activity to benzylpenicillin but can be administered orally  Patients with infectious mononucleosis may get a diffuse, erythematous, maculopapular rash when treated with ampicillin or amoxicillin Marc Imhotep Cray, M.D.

Penicillins cont.  Pneumococcal isolates causing meningitis with a minimal inhibitory concentration (MIC) for penicillin G of greater than 2 mcg/mL are highly resistant  Such strains are not killed by concentrations of penicillin G or ampicillin that can be achieved in the cerebrospinal fluid  Nafcillin has minimal activity against penicillin-resistant pneumococci  piperacillin is mainly used for infections caused by gram-negative rods  Cefotaxime and ceftriaxone are the most active cephalosporins against penicillin-resistant pneumococci o addition of vancomycin is recommended in case of highly resistant strains

Marc Imhotep Cray, M.D.

Penicillin Antibacterials Summary Table

Marc Imhotep Cray, M.D.

Johannsen EC. & Sabatine MS. PharmCards, 4th ed. Lippincott Williams & Wilkins, 2010

Cephalosporins and other β-lactams EXAMPLES:  first-generation– cefalexin, cefradine  second-generation – cefuroxime  third-generation – cefotaxime, ceftriaxone, ceftazidime  carbapenems – imipenem, ertapenem MECHANISM OF ACTION:  MOA similar to penicillins except cephalosporins are relatively resistant to staphylococcal β lactamases o All beta-lactams share a MOA inhibition of transpeptidases (that is, penicillin binding proteins) in the bacterial cell wall  Penetrate CSF poorly unless meningeal inflammation is present

Marc Imhotep Cray, M.D.

Cephalosporins and other β-lactams cont. INDICATIONS  Pneumonia  Sepsis  Biliary tract infection  UTI  Peritonitis  Meningitis

SIDE-EFFECTS  Urticarial rash  Anaphylaxis  GI disturbance  Stevens–Johnson syndrome  Cholestatic jaundice (ceftriaxone)

CAUTIONS AND CONTRA-INDICATIONS  Hypersensitivity  Caution in renal impairment (dose adjustment required)

 Antibiotic-associated colitis Marc Imhotep Cray, M.D.

Cephalosporins and other β-lactams cont. METABOLISM AND HALF-LIFE Excreted via the kidneys  t½ for cefotaxime is ~1h  t½ for ceftriaxone is 6–9 h  t½ for imipenem is ~1h  t½ for piperacillin–tazobactam is 36–72 min MONITORING No specific drug monitoring required DRUG INTERACTIONS Reduced efficacy of OCP when taking cephalosporins women should be warned and advised to use alternative contraceptive methods IMPORTANT POINT  10% of patients who are hypersensitive to penicillins may have a similar reaction to cephalosporins and other β lactams Marc Imhotep Cray, M.D.

Beta-lactam Antibacterials (Other than PCN)

AP, anti-pseudomonal

Marc Imhotep Cray, M.D.

Johannsen EC. & Sabatine MS. PharmCards, 4th ed. Lippincott Williams & Wilkins, 2010

Macrolides EXAMPLES erythromycin, azithromycin, clarithromycin MECHANISM OF ACTION Inhibition of bacterial RNA-dependent protein synthesis by reversibly binding to 50S subunit of ribosomes within organism This affects bacterial growth and may be either bacteriostatic or bacteriocidal INDICATIONS Respiratory tract infections  Campylobacter enteritis  Urethritis (non-gonococcal)  Pertussis infection  Skin and soft tissue infections  Otitis media  Helicobacter pylori eradication Marc Imhotep Cray, M.D.

Macrolides cont. CAUTIONS & CONTRA-INDICATIONS METABOLISM & HALF-LIFE  Liver disease  Metabolized in liver and excreted via  Hypersensitivity biliary route  t½ is variable – t½ for erythromycin is SIDE-EFFECTS 1–1.5 h; t½ for azithromycin is 2–4  Nausea and vomiting days; t½ for clarithromycin is 3–7 h  Diarrhea  Hepatitis MONITORING No specific drug  Anorexia monitoring required  Pancreatitis  Headaches Marc Imhotep Cray, M.D.

Macrolides cont. DRUG INTERACTIONS  Enhanced anticoagulant effect of warfarin  Macrolides inhibit metabolism of theophylline thereby increasing plasma levels  Increased plasma levels of carbamazepine with concomitant use of macrolides  Increased risk of cardiac arrhythmias with amiodarone due to QT prolongation

Marc Imhotep Cray, M.D.

Macrolides cont. IMPORTANT POINTS  Erythromycin has similar bacterial sensitivity to penicillins and therefore can be used as an alternative in penicillin allergic patients  Helicobacter pylori eradication therapy consists of 2 antibiotics and a PPI o Current guidance suggest 1week of either amoxicillin or metronidazole and clarithromycin and a PPI  Macrolides are effective against community-acquired pneumonia caused by atypical organisms (Mycoplasma spp., Chlamydia spp., Legionella spp.)

Marc Imhotep Cray, M.D.

Macrolides cont. Erythromycin  Inhibition of liver cytochrome P450 by erythromycin has led to serious drug interactions  Erythromycin inhibits CYP1A2 form of cytochrome P450, which metabolizes methylxanthines  Consequently, cardiac and/or CNS toxicity may occur with excessive ingestion of caffeine  Unlike the tetracyclines, oral absorption of erythromycin is not affected by cations and drug does not cause photosensitivity  Because erythromycin undergoes biliary excretion, there is little reason to assess renal function before treatment

Marc Imhotep Cray, M.D.

Macrolides cont. Azithromycin ď ą Azithromycin has a half-life of more than 70 h, which allows for oncedaily dosing and a 5-d course of treatment for community-acquired pneumonia ď ą Unlike other macrolides, azithromycin does not inhibit cytochrome P450 enzymes involved in drug metabolism ď ą Depending on resistance patterns in community, it is possible to treat community-acquired pneumonia (CAP) with a single antibiotic, and azithromycin is one of the antibiotics commonly used

Marc Imhotep Cray, M.D.

Metronidazole MECHANISM OF ACTION Metronidazole possesses a nitro-group that becomes charged and trapped within intracellular compartment of anaerobes leads to bacterial DNA damage and ultimately strand breakage  cell death INDICATIONS  Surgical prophylaxis  Anaerobic infections (including dental and abdominal sepsis)  Aspiration pneumonia  Protozoal infections  Pelvic inflammatory disease CAUTIONS AND CONTRA-INDICATIONS  Known hypersensitivity to metronidazole Marc Imhotep Cray, M.D.

Metronidazole cont. SIDE-EFFECTS  GI disturbance  Metallic taste in mouth  Anorexia  Rarely hepatitis  Pancreatitis Peripheral neuropathy (with prolonged therapy) METABOLISM AND HALF-LIFE  t½ is ~8.5 h.  Metabolized to active compounds by the liver with 75% excreted in urine MONITORING No specific drug monitoring required Marc Imhotep Cray, M.D.

Metronidazole cont. DRUG INTERACTIONS  Alcohol should be avoided while taking metronidazole (see below)  Possible potentiation of anticoagulant therapy has been reported when metronidazole is used with warfarin IMPORTANT POINTS  Metronidazole is a potent inhibitor of obligate anaerobes and protozoa such as Trichomonas spp. and Entamoeba spp.  Patients should be advised to completely avoid alcohol during and for 48 h after a course of metronidazole due to the risk of a severe disulfiram-like reaction (flushing and hypotension)  Metronidazole can be used in chronic renal failure however, it is rapidly removed from plasma by dialysis

Marc Imhotep Cray, M.D.

Quinolones EXAMPLES Ciprofloxacin, levofloxacin, ofloxacin MECHANISM OF ACTION  Bactericidal action of ciprofloxacin results from inhibition of both type II (DNA gyrase) and type IV topoisomerases, required for bacterial DNA replication, transcription, repair and recombination INDICATIONS  UTI  Infections of the GI system  Bronchopulmonary infections  Typhoid fever  Gonorrhea and non-gonococcal urethritis and cervicitis  Anthrax Marc Imhotep Cray, M.D.

Quinolones cont. CAUTIONS AND CONTRA-INDICATIONS Patients with a history of tendon disorders related to quinolones Pregnancy, children and growing adolescents (due to risk of joint arthropathy) Avoid in patients with CNS disorders

SIDE-EFFECTS  GI disturbance  Headaches  Dizziness  Rashes

(e.g. epilepsy -can reduce seizure threshold)

 Tendon inflammation and damage  Confusion, anxiety and depression  Phototoxicity with excessive sunlight  Seizures

METABOLISM AND HALF-LIFE  t½ for ciprofloxacin is 3-6 h  Ciprofloxacin is excreted predominately unchanged in urine MONITORING No specific drug monitoring required Marc Imhotep Cray, M.D.

(including Stevens–Johnson syndrome)

Quinolones cont. DRUG INTERACTIONS  Increased risk of nephrotoxicity when quinolones given with cyclosporin  Possible increased risk of convulsions when quinolones given with NSAIDs or theophylline (also increases theophylline levels)  Ciprofloxacin enhances anticoagulant effect of warfarin  Increased risk of torsades de pointes with other drugs that also prolong the QT interval  Reduced efficacy when given with aluminum- or magnesium-containing antacids or iron preparations Marc Imhotep Cray, M.D.

Quinolones cont. IMPORTANT POINTS  Quinolones may impair performance of skilled tasks (e.g. driving); this effect is enhanced by alcohol  Discontinue if psychiatric, neurological or hypersensitivity reactions (including severe rash) occur  Ciprofloxacin is active against Gram-negative bacteria such as Salmonella spp., Shigella spp., Campylobacter spp., Neisseria spp. and Pseudomonas spp.

Marc Imhotep Cray, M.D.

Tetracyclines EXAMPLES Doxycycline, tetracycline, oxytetracycline MECHANISM OF ACTION  Active uptake into a susceptible organism results in inhibition of protein synthesis  Their bacteriostatic effect is achieved by binding to prokaryotic 30S ribosomal subunit and inhibiting aminoacyl tRNA and mRNA ribosomal complex formation  Additionally, topical tetracyclines are used in treatment of acne  This effect is mediated through inhibition of neutrophil activity and pro-inflammatory reactions, including those associated with o phospholipase A2 o endogenous nitric oxide and o interleukin-6 Marc Imhotep Cray, M.D.

Tetracyclines cont. INDICATIONS  Urogenital tract infections (e.g. salpingitis, urethritis caused by Chlamydia spp.)  LRTI (particularly Haemophilus influenzae infections in COPD patients)  Acne vulgaris and rosacea CAUTIONS AND CONTRA-INDICATIONS  Hypersensitivity to tetracyclines  Children under 12

SIDE-EFFECTS  GI disturbance  Dysphagia and esophageal irritation  Blood disorders  Hypersensitivity reactions (including Stevens–Johnson syndrome)

 Photosensitivity

(deposition in bone and teeth – risk of staining)

   

Pregnancy and breastfeeding Acute porphyria Chronic kidney disease Tetracyclines’ oral absorption is impaired by cations chelation

Marc Imhotep Cray, M.D.

Tetracyclines cont. METABOLISM AND HALF-LIFE t½ is variable depending on drug Tetracyclines are concentrated by liver in bile and excreted in urine and feces at high concentrations in a biologically active form MONITORING No specific monitoring required DRUG INTERACTIONS Tetracyclines can enhance effects of warfarin (due to enzymatic inhibition) Risk of idiopathic intracranial hypertension when tetracyclines used with retinoids Doxycycline can increase plasma concentrations of cyclosporine IMPORTANT POINTS  Patients are advised to use high-factor sun protection and avoid direct sun exposure when on doxycycline (due to photosensitivity)  Tetracyclines should be avoided in anyone taking potentially hepatotoxic drugs Marc Imhotep Cray, M.D.

Trimethoprim MECHANISM OF ACTION Binds to bacterial dihydrofolate reductase and irreversibly inhibits production of tetrahydrofolate  a precursor for synthesis of thymidine results in inhibition of bacterial DNA synthesis INDICATIONS UTI CAUTIONS AND CONTRA-INDICATIONS . Blood dyscrasias . Caution in patients with renal impairment SIDE-EFFECTS . GI disturbance . Pruritis . Rashes . Hyperkaliemia Marc Imhotep Cray, M.D.

METABOLISM AND HALF-LIFE Approximately 50% is bound to plasma protein t½ ranges from 8.6–17 h. Elimination is via kidneys MONITORING No specific drug monitoring required

Trimethoprim cont. DRUG INTERACTIONS  Increased risk of ventricular arrhythmias with amiodarone  Increased risk of nephrotoxicity when given with cyclosporine  Increased risk of hematological toxicity when given with azathioprine and methotrexate IMPORTANT POINTS  Commonly sensitive organisms include Gram-positive aerobes (Staphylococcus spp.) and Gram-negative aerobes (Enterobacter spp., Haemophilus spp., Klebsiella spp.)

Marc Imhotep Cray, M.D.

Co-trimoxazole  A combination of trimethoprim and sulfamethoxazole which inhibits an earlier stage of tetrahydrofolate synthesis o Drug of choice in the treatment of Pneumocystis jiroveci pneumonia

Marc Imhotep Cray, M.D.

Dale M M. , Haylett DG. Rang & Dales’ ‘Pharmacology Flashcards. Churchill Livingstone, 2014

Treatment of bacterial pneumonia First-line and second-line antibiotics for adults and children

Marc Imhotep Cray, M.D.

In Re of community acquired pneumonia (CAP)  It is often difficult to establish a definite cause of community acquired pneumonia (CAP)  More than 80% of cases are caused by typical pathogens such as S pneumoniae, H influenzae, or M catarrhalis, and 15% are due to nonzoonotic atypical pathogens such as Legionella species, Mycoplasma species, or C pneumoniae  Currently, monotherapy coverage of both typical and atypical pathogens in CAP is preferred to double-drug therapy  Preferred initial therapy includes a macrolide, doxycycline, or a quinolone active against respiratory pathogens  Ampicillin, clindamycin, and vancomycin have low activity against atypical pathogens in CAP Marc Imhotep Cray, M.D.

community acquired vs hospital-acquired pneumonia  In a community-acquired pneumonia, a wider spectrum cephalosporin (ceftriaxone) would cover typical organisms, and erythromycin would be active against the atypical organisms  Single antimicrobial drug therapy would be inadequate coverage in a hospital-acquired pneumonia that could include possible infection due to multidrug-resistant staphylococci as well as gram-negative bacilli such as Pseudomonas aeruginosa

 Vancomycin should cover gram positive organisms, and piperacillin plus a penicillinase inhibitor (tazobactam) would be active against most strains of likely gram-negative pathogens Marc Imhotep Cray, M.D.

Treatment of bacterial pneumonia Adults Type of infection  Community acquired and mild to moderate disease  No comorbidity

 S. pneumoniae, M. pneumoniae, C. pneumoniae, H. influenzae First-line antibiotics  Tetracycline, erythromycin Second-line antibiotics  Doxycycline, clarithromycin Marc Imhotep Cray, M.D.

Treatment of bacterial pneumonia cont. Type of infection  With comorbidity  Mixed infections with S. pneumoniae, H. influenzae, oral anaerobes, Gram negative bacilli, S. aureus, Legionella sp.

First-line antibiotics  Cefaclor, cefuroxime axetil, amoxicillin/clavulanate or any of these plus erythromycin or clarithromycin Second-line antibiotics  Trimethoprim/sulfamethoxazole plus erythromycin Marc Imhotep Cray, M.D.

Treatment of bacterial pneumonia cont. Type of infection  When community acquired severe disease in hospital, with or without comorbidity S. pneumoniae, H. influenzae, Legionella sp., M. pneumoniae, S. aureus, C. pneumoniae  Comorbidity pathogens: anaerobes, Gram negative bacilli

First-line antibiotics  Cefuroxime axetil, cefuroxime, cefotaxime, ceftriaxone, or any of these plus erythromycin or clarithromycin ± rifampin

Marc Imhotep Cray, M.D.

Treatment of bacterial pneumonia cont. Type of infection  With severe disease in ICU environment S. pneumoniae, H. influenzae, Legionella sp., Gram-negative bacilli, P. aeruginosa, S. aureus, M. pneumoniae, C. pneumoniae First-line antibiotics  Erythromycin ± rifampin plus either ciprofloxacin, imipenem, or ceftazidime

Marc Imhotep Cray, M.D.

Treatment of bacterial pneumonia cont. Type of infection  In institutionalized elderly patients with mild to moderate disease S. pneumoniae, H. influenzae, oral anaerobes, Gram negative bacilli, S. aureus, Legionella sp.

First-line antibiotics  Trimethoprim/sulfamethoxazole, cefaclor, cefuroxime axetil, amoxicillin/clavulanate, or any one of the above ± erythromycin or clarithromycin

Marc Imhotep Cray, M.D.

Treatment of bacterial pneumonia cont. Type of infection  With severe disease S. pneumoniae, H. influenzae, oral anaerobes, Gram negative bacilli, S. aureus, Legionella sp. First-line antibiotics  Cefaclor or cefuroxime axetil or amoxicillin/clavulanate or ceftriaxone or combinations, penicillin or amoxicillin plus ciprofloxacin Second-line antibiotics  Ciprofloxacin plus clindamycin Marc Imhotep Cray, M.D.

Treatment of bacterial pneumonia cont. Children Type of infection  With mild disease S. pneumoniae, S. aureus, streptococci Group A, M. pneumoniae, H. influenzae First-line antibiotics  Amoxicillin, erythromycin estolate Second-line antibiotics 

Trimethoprim/sulfamethoxazole, clarithromycin, erythromycin/sulfisoxazole, amoxicillin/clavulanate, cefixime, cefaclor, cefuroxime axetil chloramphenicol ± erythromycin or clarithromycin

Marc Imhotep Cray, M.D.

Treatment of bacterial pneumonia cont. Children Type of infection  With severe disease S. pneumoniae, S. aureus, streptococci Group A, M. pneumoniae, H. influenzae  First-line antibiotics  Cefuroxime ± erythromycin estolate or clarithromycin Second-line antibiotics 

Trimethoprim/sulfamethoxazole, clarithromycin, erythromycin/sulfisoxazole, amoxicillin/clavulanate, cefixime, cefaclor, cefuroxime axetil, chloramphenicol ± erythromycin or clarithromycin Marc Imhotep Cray, M.D.

Marc Imhotep Cray, M.D.

Further study: eLearning (IVMS Cloud Folders)  Pharmacology  Infectious Disease  Microbial biology & Immune System Textbooks:  Batchelder A. et al. Rapid Clinical Pharmacology- A Student Formulary. 1st ed. John Wiley & Sons, 2011  Carroll KC etal. Jawetz, Melnick, & Adelberg’s Medical Microbiology 27th Ed. New York: McGraw-Hill, 2016  Gallagher JC, MacDougall C. Antibiotics simplified. 2nd Ed. Jones & Bartlett Learning, 2012  Ryan KJ and Ray CG Eds. Sherris Medical Microbiology, 5th Ed. New York: McGraw-Hill, 2010 Marc Imhotep Cray, M.D.