Antimicrobial Therapy in Otolaryngology—Head and Neck Surgery

Bacteriology Basics


Main Bacterial Functions

  • Bacterial DNA is made via folic acid production with p-aminobenzoic acid (PABA) as an intermediate.

  • Bacterial genome is unwound by DNA gyrase and helicase allowing it to be read.

  • DNA is transcribed forming mRNA.

  • mRNA combines with the bacterial 70S ribosome (composed of 50S and 30S components) and translation occurs, forming proteins including cell wall components.

  • Penicillin-binding proteins (PBPs) catalyze construction of cell wall peptidoglycan including transpeptidase, which binds d-Ala-d-Ala chain of peptidoglycan for cross-linking.

  • Gram-negative (GN) bacteria have an outer cell wall, whereas gram positive (GP) do not have.

  • Porins (outer membrane proteins [omps] of different subtypes) allow entry of particular molecules of various sizes, charges, and shapes through the cell wall.

  • Efflux pumps (with different subtypes) are ATPase pumps that expel molecules from within the cell.

Main Bacterial Resistance Mechanisms

  1. Enzymatic inhibition—modification of the antibacterial material

    1. Beta-lactamase—hydrolysis of beta-lactam—affects penicillins and cephalosporins.

      1. Number one resistance pattern

      2. Many with particular beta-lactamase are coresistance to tetracyclines, sulfonamides, aminoglycosides, even fluoroquinolones (GN only)

    2. Aminoglycoside modifying enzymes reduce affinity for 30S ribosome.

  2. Penicillin-binding proteins (PBPs) modification—changing binding site of beta-lactam, decreasing its affinity for PBP

    1. Low affinity for binding beta-lactam antibiotic requiring clinically unattainable drug concentrations to overcome inhibition.

    2. PBP2a—confers penicillin and cephalosporin resistance via plasmid gene mecA in methicillin-resistant Staphylococcus aureus (MRSA).

    3. Use of d-Ala-d-Lactate instead of d-Ala-d-Ala confers resistance to cephalosporins and vancomycin.

  3. Porin (omp) modification

    1. Decreased porin production—Pseudomonas aeruginosa—decreased susceptibility to beta-lactams

    2. Loss of porin type—may confer particular or multidrug resistance

  4. Efflux pump in GN organisms

    1. Increased production—Escherichia coli—may produce major facilitator tetracycline transporter (tetB) for tetracycline only versus small multidrug resistance (SMR) emrE-gene transport protein which provides resistance against broad range of antibiotics.

  5. Modification of antibiotic target

    1. Ribosome—antibiotic binding site may be altered.

      1. Point gene mutation

      2. Methylation

    2. Cell wall—modification of cell phospholipid bilayer leads to repulsion of daptomycin-calcium molecule.

    3. Mutated DNA gyrase and topoisomerase IV genes confers resistance to fluoroquinolones.

    4. RNA polymerase—rifampicin cannot bind.

    5. Biofilm production—production of extracellular polymeric substance which may account for nine times greater mass than the bacteria itself. Reduced penetration of antibiotic.

      1. Bacteria enter slow growth state.

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Classification Name Spectrum Mechanism of Action Side Effects
Quinolones (bactericidal) Ciprofloxacin GN bacilli, Pseudomonas, atypicals, no anaerobic or GP coverage Inhibit DNA gyrase and bacterial topoisomerase IV that promotes DNA strand breakage  Stevens-Johnson syndrome, QTc prolongation, arthropathy, tendonitis, tendon rupture  
Levofloxacin MSSA, Streptococcus sp., GN bacilli, atypicals
Moxifloxacin MSSA, Streptococcus sp., anaerobes, atypicals    
Nitrofuran Nitrofurantoin (bacteriostatic, can be bactericidal at high concentrations) Broad spectrum—GP and GN: E. coli and S. saprophyticus Damages bacterial DNA Pulmonary fibrosis, hemolytic anemia, neuropathies
Nitroimidazole (bactericidal) Metronidazole Anaerobes, GN—Bacteroides fragilis, C. difficile, protozoa; penetrates blood-brain barrier Binds to cellular proteins and DNA Headache, nausea, vaginitis, metallic taste, disulfiram-like reaction with alcohol, peripheral neuropathy
Folic acid inhibitors (bactericidal) Trimethoprim Broad spectrum—GP and GN: MSSA, CA-MRSA Inhibits reduction of dihydrofolic acid to tetrahydrofolic acid Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), urolithiasis, cytopenias, hepatitis, hyperkalemia, increases warfarin levels
Sulfonamides (bacteriostatic) Sulfamethoxazole Broad spectrum—GP and GN: MRSA Inhibits enzymatic conversion of pteridine and p-aminobenzoic acid (PABA) to dihydropteroic acid Nausea, vomiting, diarrhea, hypersensitivity, hematologic effects (anemia, aganulocytosis, thrombocytopenia)

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Classification Drug Spectrum Mechanism of Action Side Effects
Pseudomonic acid Mupirocin (bacteriostatic; bactericidal at high concentrations) Mostly GP Inhibits RNA and protein synthesis Contact dermatitis
Antimycobacterial (bactericidal) Rifampin Broad spectrum—GP + GN: Pseudomonas, Mycobacterium tuberculosis Blocks RNA transcription Liver enzymes, rash, discoloration of teeth, urine, saliva, sweat, tears

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Ribosome – 50S

Classification Drug Spectrum Mechanism of Action Side Effects
Macrolides (bacteriostatic)   Broad spectrum: Streptococcus sp., Corynebacterium, Chlamydia sp., Legionella, Moraxella, Helicobacter pylori Irreversible binding to 50S ribosome to inhibit protein synthesis; prevent continuation of protein synthesis QTc prolongation, reduces birth-control effectiveness, drug-drug interactions
Erythromycin     Avoid in liver disease, increases GI motility
Clarithromycin Haemophilus influenzae   Adjust for CKD
Azithromycin Mycoplasma, Mycobacterium avium complex, H. influenzae   Avoid in hepatic disease
Lincosamide Clindamycin (bacteriostatic; bactericidal at high concentrations against staphylococci, streptococci, anaerobes such as B. fragilis) Streptococcus sp., MSSA, CA-MRSA, anaerobes Irreversible binding to 50S ribosomal subunit C. difficile infections, adjust with liver dysfunction
Oxazolidinone (bactericidal) Linezolid Resistant GP organisms Binds to 50S ribosomal subunit Cytopenias, serotonin syndrome, altered taste, tongue discoloration, optic neuritis
Phenicol (bacteriostatic) Chloramphenicol Broad-spectrum—GP + GN: Streptococcus pneumoniae, N. meningitidis, H. influenzae, Enterococcus faecium Binds 50S subunit Irreversible aplastic anemia, myelosuppression, neuritis, glossitis, gray baby syndrome

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Ribosome – 30S

Classification Drug Spectrum Mechanism of Action Side Effects
Aminoglycosides (bactericidal) Listed most to least vestibulotoxic Aerobic GN bacilli: Pseudomonas, Klebsiella, Serratia, Proteus, Acinetobacter, and Enterobacter Binds to 30S ribosomal subunit Vestibulocochlear toxicity (hair cell death in cristae ampullaris, utricle, and saccule; see below) high > low frequency, dose dependent. Mitochondrial susceptibility, reversible nephrotoxicity
Gentamicin Synergy with beta-lactam to treat Enterococcus sp. infections; not as effective against Pseudomonas
Tobramycin More active against Pseudomonas
Amikacin Reserve for resistant Pseudomonas and Acinetobacter infections Most cochleotoxic
Vestibulotoxicity: streptomycin > gentamicin > tobramycin > amikacin—most cochleotoxic
Tetracyclines (bacteriostatic)   Broad: GP (MSSA, MRSA), GN, protozoa, spirochetes, mycobacteria, and atypical species Binds reversibly to 30S ribosomal subunit Hepatotoxicity, photosensitivity, tinnitus, pseudotumor cerebri, teeth discoloration. Avoid in children, pregnancy. Expired medication can cause Fanconi syndrome.
Tetracycline Adjust for CKD
Glycycline Tigecycline (derivative of minocycline) Very broad spectrum—reserve for ID or MDR organisms Binds reversibly to 30S ribosomal subunit to inhibit protein synthesis Nausea, vomiting, diarrhea, photosensitivity, teeth discoloration, fetal damage

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Cell Wall Synthesis

Classification Drug Spectrum Mechanism of Action Side Effects
Penicillins (bactericidal) PCN G, PCN V GP cocci and rods, GN cocci, most anaerobes; Not GN bacilli Binds PBPs inhibiting cell-wall synthesis  Interstitial nephritis, cytopenias. Adjust for CKD 
Antistaphylococcal Nafcillin, oxacillin, dicloxacillin MSSA   Nafcillin and oxacillin metabolized by liver
Broad-spectrum, second generation Ampicillin, amoxicillin Above plus GN bacilli: E. coli, Proteus mirabilis, Salmonella, Shigella, H. influenzae   30% incidence of rash in those with infectious mononucleosis (EBV)
Anti-pseudomonal, third generation Carbenicillin, ticarcillin GN organisms, indole-positive Proteus, Enterobacter, Pseudomonas    
Fourth generation Piperacillin Same as above plus Klebsiella, enterococci, B. fragilis, Pseudomonas    
PCN with beta-lactamase inhibitor Amoxacillin/clavulanate Ticarcillin/clavulanate Oxacillin-sensitive S. aureus, H. influenzae, beta-lactamase producing Enterobacteriaceae   Beta-lactamase inhibitors cause increased diarrhea
Ampicillin/sulbactam Same plus anaerobes (B. fragilis), Acinetobacter baumannii  
Piperacillin/tazobactam Similar to above  
Cephalosporins (bactericidal)     Binds PBPs inhibiting cell wall synthesis Cytopenias, anaphylaxis, pseudomembranous colitis, adjust for CKD
First generation Cefazolin, cephalexin, cefadroxil Most GP cocci, E. coli, P. mirabilis, K. pneumoniae    
Second generation Cefaclor, cefuroxime, cefprozil Less active against staphylococci; greater activity against GN bacilli – H. influenzae, Moraxella catarrhalis    
Cephamycin subgroup Cefotetan, cefoxitin E. coli, P. mirabilis, Klebsiella, Bacteroides    
Third generation Cefdinir, cefixime, cefotaxime, cefpodoxime, ceftazidime, ceftriaxone, cefditoren Therapy of choice for GN meningitis, less active against most GP; E. coli, P. mirabilis, Proteus, Klebsiella, Enterobacter, Serratia, Citrobacter, Neisseria, H. influenzae    
Cefotaxime, ceftriaxone Usually active against pneumococci with intermediate susceptibility to penicillin; Lyme disease, meningitis due to H. influenzae    
Ceftazidime Above plus P. aeruginosa; poor GP coverage    
Fourth generation Cefepime Pneumococci, MSSA, Neisseria, H. influenzae, Enterobacter, indole-positive Proteus, Citrobacter, Serratia, P. aeruginosa    
Fifth generation Ceftaroline Similar to ceftriaxone with improved GP activity: MRSA, VISA    
Beta-lactamase inhibitor combination, new generation Ceftolozane/tazobactam Broad spectrum against GN bacilli: P. aeruginosa, most ESBL; limited GP    
Ceftrazidime/avibactam Broad spectrum: most Enterobacteriaceae, P. aeruginosa, Actinobacter    
Carbapenems (bactericidal)   Broad spectrum: GN, anaerobes (B. fragilis), P. aeruginosa, GP (including MRSA) Binds PBPs inhibiting cell wall synthesis C. difficile, seizures in high doses; adjust for CKD
Imipenem/cilastin, meropenem, doripenem      
Ertapenem Narrower spectrum: no Pseudomonas, Acinetobacter coverage, MRSA    
Monobactam (bactericidal) Aztreonam GN: Pseudomonas, Enterobacter; no anaerobe or GP coverage Inhibits mucopeptide synthesis of cell wall Rare: toxic epidermal necrolysis, eosinophilia; adjust for CKD
Glycopeptides (bactericidal) Vancomycin MSSA, MRSA, MRSE, Streptococcus sp., Corynebacterium, Enterococcus faecalis and faecium; oral: C. difficile Inhibits late-stage cell wall synthesis Vancomycin-induced renal failure, red man syndrome; adjust for CKD
Lipoglycoprotein (bactericidal) Telavancin (derivative of vancomycin) Useful in vancomycin intermediate resistant bacteria Inhibits late-stage cell wall synthesis and causes cell membrane depolarization  
Cyclic peptides Bacitracin (bacteriostatic, -cidal depending on organism/concentration) GP Inhibits peptidoglycan transport Contact dermatitis

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Apr 30, 2020 | Posted by in OTOLARYNGOLOGY | Comments Off on Antimicrobial Therapy in Otolaryngology—Head and Neck Surgery

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