------------------------------------------------------------------------------- TITLE: ANTIMICROBIALS IN OTOLARYNGOLOGY SOURCE: Dept. of Otolaryngology, UTMB, Grand Rounds DATE: May 3, 1989 RESIDENT PHYSICIAN: Ronald G. Morton, M.D. FACULTY: Francis B. Quinn, M.D. DATABASE ADMINISTRATOR: Melinda McCracken, M.S. ------------------------------------------------------------------------------- "This material was prepared by resident physicians in partial fulfillment of educational requirements established for the Postgraduate Training Program of the UTMB Department of Otolaryngology/Head and Neck Surgery and was not intended for clinical use in its present form. It was prepared for the purpose of stimulating group discussion in a conference setting. No warranties, either express or implied, are made with respect to its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and should not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion." I. Commonly Useded Antibiotics A. Penicillins Common nucleus Thiayolidine ring Beta lactam ring Connects to a variable side chain. Natural penicillins extracted from Penicillium chrypogenum. Synthetic penicilllins prepared by incorporating precursors in mold culture, by modifying a natural penicillin, or by adding side chains to 6-aminopenicillanic acid. 1. Mechanism of Action: Penicillins exert their action on actively dividingcells by causing abnormal cell wall development. They inhibit the 3rd stage of cell wall synthesis i.e. the crosslinking of peptidoglycan polymers via peptide bonds. 2. Development of Resistance: a) Alterations in Penicillin binding proteins. b) Inability to penetrate into bacterial cell wall. c) Enzymatic hydrolysis klof the penicillin molecule. 3. Antibacterial Spectrum a) Penicillin G (benzylpenicillin) - Gram (+) cocci: group A,B, and non Enterococcus D, Pneumococcus, few Staph. - Gram (-) bacilli: Bacillu anthracis, C. Diphtheriae, Listeria monocytogenes. - Gram (-) cocci: Neisseria gonorrheae, N. meningitidis. - Gram (-) bacilli: Pasteurella multocida, Streptobacillium moniliformis, spirilium minor. - Anaerobes: Clostridium sp., Bacteroides sp., except B. fragilis, Fisobacterium, Peptostreptococcus. - Miscellaneous: Treponema pallidum, Leptospira. c) Penicillin V (phenoxypenicillin) - Essentially the same antibacterial spectrum as penicillin G. c) Penicillinase-resistant Penicillins: - These include Methicillin Nafcillin,Dicloxacillin, Oxacillin. - Active against most all Strep and Staph except for MRSA. d) Aminopenicillins - These include Ampicillins, Amoxicillin, Bacampicillin Cyclocillin. - Similar antibacterail spectrum to penicillinG but more active against Enterococcus and Listeria. - Broken down by beta-lactamase. e) Antipseudamonal Penicillins - Ticarcillin, Carbenicillin - Active against P. aeruginosa and indole positive Proteus, Enterobacter, and Acinetobacter. f) Extended Spectrum Penicillins - Mezlocillin: similar in activity to ticarcillin but more active against B. fragilis and Enterococcus. - Piperacillin: identical spectrum to mezlocillin, but more active against pseudomonas. g) Clavulanic acid: - Produced by fermentation of Streptomyuces clavuligerus. - A beta-lactam structurally related to penicillins that inactivates a wide variety of beta-lactamases by blocking active sites of these enzymes. 4. Adverse Reactions a) Hypersensitivity reactions (1 - 5 %) b) Irritant properties primarily effect the peripheral nervous system. c) Nephropathy: allergic reaction manifested by interstitial nephritis. d) Hypokalemia. B. Cephalosporins - Common nucleus: beta-lactam ring dihydrothiazine ring Connected to a side chain. - Derived from Cephalosporium acremonium. 1. Mechanism of Action: - Inhibits third step in bacterial wall synthesis and bind to specific proteins on cell membranes, altering permeability, inhibiting protein synthesis and releasing autolysins. 2. Development of Resistance - Decrease permeability of bacterial cell to antibiotics. - Production of beta-lactamase. 3. Antibacterial Spectrum: a) FIRST GENERATION cephalosporins - These include Keflin, Kefzol, Ancef - Highest degree of activity against gram positive organisms: including Strep. and Staph, but not MRSA. Not effective against Enterococcus. - Same spectrum of coverage as PCN-G against gram(+) anaerobes and aerobic bacilli. b) SECOND GENERATION cephalosporins - These include Mandol, Mefoxin, Ceclor,Zinacef. - Less active against gram(+) bacteria. - Their clinical advantage is against H. influenzae, and some aerobic gram(-) bacilli (i.e. Proteus and Enterobacter. c) THIRD GENERATION cephalosporins - These include Cefotaxime, Moxalactam, Cefoperazone. - Greatest activity against gram(-) aerobes with variable activity against Pseudomonas. 4. Adverse Reactions: a) Hypersensitivity reaction: highest incidence those allergic to PCN. b) Hematologic -neutropenia,leukopenia, thrombocytopenia. c) Gastrointestinal -nausea, vomiting, anorexia, diarrhea. d) Reversible renal impairment. C. Erythromycin - Produced by Streptomyces erythreus 1. Mechanism of Action: - Inhibits bacterial protein synthesis by binding to the 50S ribosomal unit. 2. Development of Resistance: a) Alteration in protein component of 50S ribosomal subunit. b) Plasmid mediated resistance. 3. Antibacterial Spectrum - Similar activity to PCN-G - Also effective against Mycoplasma, Legionella, and Actinomyces. - Used in combination with Sulfisoxazole in pediatric population -effective against H. influenzae. 4. Adverse Reactions: a) Gastrointestinal -nausea, vomiting,diarrhea. b) Hypersensitivity reactions c) Cholestatic hepatitis - especially seen with erythromycin estolate. D. Clindamycin - Semisynthetic derivative of Lincomycin. 1. Mechanism of action: - Binds to 50S ribosomal subunit, thus inhibiting protein synthesis. 2. Development of resistance: - Similar to that as seen with erythromycin, developing in a stepwise fashion. 3. Antibacterial spectrum: - Active against most gram(+) organisms, aerobic and anaerobic; anaerobic gram(-) organisms. Some staph have developed resistance. 4. Adverse reactions: a) AAPMC - Estimated to occur in less than 1% to as many as 10% in the elderly. This can be fatal with symptoms of crampy pain, watery and at times bloody diarrhea. Plaque like lesions in colon that histopathologically are composed of WBC's, epithelial debris and fibrin. Caused by enterotoxigenic Clostridium difficille. Treat with Vancomycin. b) Mild nausea and diarrhea c) Hypersensitivity reactions d) Leukopenia e) Transient increase in LFT's and rarely hepatotoxicity. II. Indications for Antimicrobial Treatment A. Otitis Media 1. Acute Otitis Media - both viral and bacterial etiologies - major pathogens include Pneumococcus H. influenzae B. catarrhales. - less commonly casused by: Group A Strep. Staph. Anaerobes a) Diffusion of antimicrobials into middle ear fluid i) Penicillin V + G levels of 13-22% that of serum. ii) Ampicilliin levels of 50% that of serum. iii) Amoxicillin levels higher than ampicillin. iv) Erythromycin/Sulfa 30-60% of the serum levels. v) Keflex middle ear levels felt to be inadequate for most pathogens. vi) Ceclor good middle ear levels observed. vii) Clavulanic acid reaches levels sufficient to inhibit beta- lactamase. viii)SXT also reaches therapeutic middle ear levels b) Treatment i) Amoxicillin - most common agent used - 30-50 mg/kg/day ii) Pediazole - effective against many beta- lactamase producers. iii) Ceclor - effective - 40 mg/kg/day. iv) Augmentin - very effective - same dosage as amoxil - effective against many beta- lactamase producers. v) Most recommend 7-10 days of treatment 2. Recurrent Otitis Media - Children experiencing three or more episodes in a 6 month period. Treatment options: a) Treat each acute episode with standard agents b) Prophylaxis c) Polyvalent pneumococcal vaccine d) BM + Tubes 3. Otitis Media with Effusion - Special considerations given because of possible cause of developmental delay. - It is recommended by some to treat the asymptomatic patients with a standard antibiotic course and if not resolved, treat with one of the above medical regimens prior to surgical treatment. 4. Chronic Suppurative Otitis Media - Most common isolates are Staph, Pseudomonas, occasional aerobic gram(-) bacilli and anaerobes. a) Topical treatment - often use aminoglycoside preparation - ototoxicity from use of these not fully elucidated. b) Systemic Treatment - requires use of anti- staphylococcal and other broad spectrum antibiotics. - Psuedomonas infection may require parenteral treatment. 5. Malignant External Otitis - Seen in elderly diabetics with persistent external otitis who develop severe pain, persistant discharge, swelling, tenderness, and external canal granulation tissue is seen. - Caused by Pseudomonas aeurginosa - Cartilage and bone invasion, osteomyelitie, possible brain abscess, cranial neuropathies. - May be fatal a) Treatment - antipseudomonal antibiotics e.g. ticarcillin and tobramycin for 4-6 weeks. May also use 2nd and 3rd generation cephalosporins - HBO - Surgical debridement - Control diabetes B. Sinusitis Common pathogens Pneumococcus, non-typable H. influenzae, and less commonly, oral anaerobes. Staph, strep, B. cattarhalis and some gram(-) bacilli. 1. Diffusion of Antimicrobial agents into sinuses - most antimicrobials diffuse into sinuses, but dose is non-therapeutic; concentrations when relatively low doses used to treat pharyngitis are used. - Amoxil, SXT and Bacampicillin provide adequate sinus tissue levels. - Oral cephalosporins, except ceclor, do not. 2. Recommended treatment - Aminopenicillins in maximum doses - Ceclor 500 mg 3-4 times per day - Bactrim 160mg/800mg BID. 3. Fungal Sinusitis a) Aspergillus may cause sinusitis; usually seen in diabetics whose mucosa is damaged by previous bacterial infection. - treatment usually debridement and drainage. Few use brief systemic treatment. b) Phycomycosis rare rhinocerebral mycosis caused by such organisms as Mucor. - treatment = aggressive surgical debridement systemic antifungal agents, and HBO. C. Pharyngitis - Streptococcus, Group A is the most common and important pathogen encountered, but numerous other organisms produce pharyngeal inflammation. 1. Penetraation of antimicrobial agents in tonsillar tissue : all commonly used antibiotics penetrate the tonsillar tissue well. 2. Treatment: a) Group A Strep: 1.2-2.4 million units IM or 25,000 units/kg in children under 60 lbs. and/or 10 day course of p.o. PCN. b) Group B Strep: same treatment c) Syphilis: seen in secondary stage, usually in homosexual males. treat with 2.4 million units of PCN IM per week for three weeks. d) Gonococcal pharyngitis: treat with 4.8 million units PCN IM and one gram of Probenecid. More difficult to eradicate than cervical or urethral GC. e) Diphtheria: rare due to immunizations. treat with PCN or erythromycin and antitoxin. f) There is increasing recognition that those with large tonsillar tissue are more prone to recurrent tonsillitis and relapses after treatment. Felt to be due to anaerobes in tonsillar crypts and tissue destruction of PCN by beta lactamase produced by B. melaninogenicus. Treat with Clinda mycin. 3. Peritonsillar Abscess - caused by Group A Strep and oral anaerobes. - treat with PCN or Clindamycin and drainage. 4. Ludwig's Angina - caused by oral anaerobes amd micro aerophiles. - treat with drainage, airway protection and IV PCN or Cleocin. D. Epiglottitis and Pseudocroup Acute epiglottitis caused by H. influenzae type B in children and by H. influenzae, pneumococcus, Staph and Group A Strep in adults. - Treatment now with cefuroxime or cefataxime, formerly treated with ampicillin and chloramphenicol. Pseudocroup much more common than epiglottitis, caused by parainfluenza viruses types 1,2, and 3 and RSV. E. Orofacial and Odontogenic Infection - Due to oral flora. - Most are self limited, but may deepen, spreading along the path of least resistance. - Range from simple dental infections to facial cellulitis, Ludwig's angina, and spreading to deep neck space infections. - Treat with drainage and IV PCN or Cleocin; possible add aminoglycoside. F. Neck Infection Following Surgery 1. Parotitis - much less frequent with better attention to hydration. - caused by Staph aureus. - treat with anti-staph antibiotics (Nafcillin) 2. Wound Infections - usually polymicrobial with gram(-) organisms of unknown significance. - treat with drainage as necessary and multi-antibiotic regimen. III Antibiotic Prophylaxis in Otolaryngologic Surgery A. Otologic Surgery - studies of the effect of antibiotics on the presence of pathogens in the ear showed that they did not eradicate those already present before surgery or prevent their development post operatively. - found no significant difference in infection rates post operatively between those treated with prophylactic antibiotics and those not. B. Tonsillectomy It appears antibiotics used in tonsillectomy patients are well tolerated and help minimize post-operative symptoms of paun, fever, foul oral odor and poor p.o. intake. C. Facial Fractures -in a study using Kefzol and placebo prophylactically in mandible, zygoma and LeFort fractures,results showed over 42% of placebo group developed infection while less than 9% of the treated group developed infection. D. Nasal and Sinus Surgery -most all use perioperative antibiotics for these procedures. -there have been reports of toxic shock syndrome after nasal surgery. -found no studies that report differences in infection rate between treated and untreated patients. E. Non-contaminated head and neck surgery -retrospective studies of thyroid, parotid and submandibular gland surgery demonstrate no efficacy in giving prophylactic antibiotics to these patients. F. Contaminated Head and Neck Surgery 1. Studies of bacteriology of wound infections reveal 96% to be polymicrobial. Value of post-operative wound cultures is still unclear. Johnson states infections appear to be unrelated to antibiotic used prophylactically and to the particular surgery performed. The presence of gram (-) organisms in cultures is of unclear significance. 2. Choice of antibiotic - Burke has shown that maximal effectiveness of prophylaxis is achieved when given prior to contamination and if given 3 or more hours after contamination they are of no benefit. Multiple studies investigating various treatment regimens of cephalosporins Clindamycin with or without aminoglycosides have found Clindamycin alone to be the most efficacious. There is no evidence that gram (-) prophylaxis is of benefit. 3. Duration of treatment - studies comparing one day, two day and five day courses of treatment show 24 hour treatment as effective as more prolonged courses. 4. Other factors -previous radiation therapy does not effect incidence of postoperative wound infection. -previous tracheotomy does not effect the incidence of post-operative wound infection. -patients undergoing laryngectomy with or without neck dissection had a lower incidence of infection compared to those undergoing resection of oropharyngeal tumors. -patients requiring pectoralis major flap reconstruction had higher incidence of postoperative infection than those who did not. 5. Cost effectiveness of prophylaxis -studies show that hospitalization of those patients who develop post-operative wound infections is two to three times that of those who do not. -the average increase in the cost of hospital stay is greater than $10,000 per patient comparing those developing infections and those who do not. -------------------------------------------------------------------------------- BIBLIOGRAPHY 1. Neu, Harold; Contemporary antibiotic treatment in Otolaryngology. Otol Clinics of No Amer. Nov 1984. 2. Johnson, J. et al. Antiobiotic Use During Major Head and Neck Surgery. Annals of Surg. Jan 1988. 3. Johnson, J. et al. Antibiotic Prophylaxis in High Risk Head & Neck Surgery - 1 vs. 5 day treatment. Otol - Head and Neck Surg. Dec 1988. 4. Johnson, J. et al. An Assessment of the Need for Gram-negative Bacterial coverage in Antibiotic Prophylaxis for Oncological Head and Neck Surgery. Jour Inf Dis. Feb 1987. 5. Johnson, J. et al. Antimicrobial Prophylaxis for Contaminated Head and Neck Surgery. Laryngoscopr 94:Jan 1984. 6. Mandell-Brown, et al. Cost effective4ness of Prophylactic Antibiotics in Head and Neck Surgery. Otol - Head and Neck Surgery. Vol 92:1984. 7. Telian, et al. The Effect of Antibiotic Therapy on Recovery After Tonsillectomy in Children. Arch Otol. Vol 112.June 1986. 8. Jackson, J. et al. Antimicrobial Prophylaxis in Ear Surgery. Laryngoscope, Oct, 1988. 9. Rubin et al. Bacteriologic analysis of Wound Infection following Major Head and Neck Surgery. Arch Otol. Sep 1988. 10. Saginur, R. et al. Antibiotic Prophylaxis in Head and Neck Surgery. Jour Otol. April 1988. 11. Kircher, et al. Use of Topical Oral Antibiotics in Head and Neck Prophylaxis: is it justified. Laryngoscope, Jan 1988. 12. Chole, et al. Antibiotic Prophylaxis for Facial Fractures: A Prospective Randomized Clinical Trial. Arch Otol. Oct. 1988. 13. Johnson, J. et al. Infection Following Contaminated Head and Neck Surgery. Arch Otol. Apr 1984. 14. Jahn et al. Medical Management of Chronic Otitis Media. Otol Clin No Amer Nov. 1984. 15. One vs. Two Days of Prophylactic Antibiotics in Patients Undergoing Major Head and Neck Surgery. Fee, W. Laryngoscope, May 1984. ----------------------------------END------------------------------------------