TITLE: Antibiotics in Head and Neck Surgery
SOURCE: UTMB Dept. of Otolaryngology Grand Rounds
DATE: January 28, 1998
RESIDENT PHYSICIAN: Karen L. Stierman, M.D.
FACULTY PHYSICIAN: Ronald W. Deskin, M.D.
SERIES EDITOR: Francis B. Quinn, M.D.

|Return to Grand Rounds Index|

"This material was prepared by physicians in partial fulfillment of educational requirements established for Continuing Postgraduate Medical Education activities and was not intended for clinical use in its present form. It was prepared for the purpose of stimulating group discussion in a interactive computer mediated 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 subscribers or other professionals and should not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion."

INTRODUCTION

The topic of antibiotics in head and neck surgery is a broad topic. This presentation attempts to review classification of wounds, the commonly used antibiotics, and the major head and neck surgical conditions that require perioperative antimicrobial therapy. Wound infections make up the largest single group of postoperative infectious complications of surgery. They are the second most frequent type of nosocomial infection. In the United States, at least 920,000 of the 23 million surgical patients develop a wound infection each year.

The need for prophylactic antibiotics in contaminated head and neck surgery is generally accepted. In contaminated cases, it has been shown that the wound infection rate with placebo approaches 100% through many prospective randomized clinical trials. When considering use of any antibiotic therapy, cost must be considered. Johnson, et al. in a retrospective analysis found that the cost per infection per person was $12,155.05 (1987 dollars). In a study by Blair in 1992, the excess cost to each patient who developed a wound infection was $36,000 (1992 dollars). The cost of administrating antibiotic prophylaxsis was much less than the cost of treating the infection. Wound infections are usually polymicrobial and treatment is with appropriate drainage and multi-antibiotic regime. In addition to cost,. One must also consider other issues associated with antibiotic therapy such as side effects and development of resistant strains.

Virtually all bacterial pathogens have the ability to acquire resistance to antibiotic therapy. This problem is more common in nocosomial pathogens such as VRE and MRSA. More recently, community acquired pathogens, such as Strept. pnuemoniae have developed resistant strains. Resistance to penicillin is found in 30-70 % of isolates depending on the hospital. Some strains are also found to be resistant to one of the following: cephalosporins, Bactrim, chloramphenicol, or a macrolide. Children are more likely than adults to be infected with strains resistant to chloramphenicol, erythromycin, or Bactrim.

CLASSIFICATION OF WOUNDS

Wounds are classified as clean, clean contaminated, contaminated and dirty. By classifying them, one can assess the potential for development of post-operative infections. Clean wounds usually imply an elective case. Contamination from the lumen of the respiratory, alimentary, and GU tracts is not encountered. There is no associated inflammation or break in aseptic technique. They may be closed primarily and are associated with an infection rate of 1-5 %. Clean contaminated wounds result from operations where the oropharyngeal cavity, respiratory, alimentary or GU tract is entered under controlled conditions. Most otolaryngology/head and neck surgery cases fall under this description. The infection rate is 8-11 %, although a 28-87% infection rate has been demonstrated in major head and neck cases. Contaminated wounds result after spillage from the GI tract, acute nonpurulent inflammation is encountered, or there is a major break in sterile technique. Fresh traumatic wounds are in this group, which carries an infection rate of 15-17 %. Dirty wounds are those in which the organisms causing the postoperative infection are present prior to the operation. These include wounds associated with old trauma, an abscess, or a perforated viscus. Their infection rate is greater than 27%. As a rule, traumatic wounds are considered to be contaminated. However, it is the amount of bacteria present that determines the development of infection. The number of bacteria necessary to infect tissue is estimated to be 100,000 organisms per gram of tissue. Host factors and local wound factors also play a role in determining the need for antibiotic therapy.

TIMING AND ROUTE

The effectiveness of antibiotic therapy is dependent upon the time at which the drug is administered, the route of administration, the agent used. Using an animal model, Burke found that antibiotics were most effective when given before the bacteria enters the blood or tissue and have no effect if given 3 hours after inoculation occurs. This study was corroborated by Classen et. al who found surgical wound infection rates in clean and clean contaminated cases to be 1.4% when antibiotics were given within three hours of surgical incision and 3.3% if antibiotics were given later.

Parenteral administration of antibiotics in head and neck surgery is the traditional route. Alexander and Alexander demonstrated that IV administration achieves the earliest level of antibiotic coverage in wound fluid. However, IM injections achieve the highest sustained level. Therefore it is recommended in contaminated cases to administer IV and IM loading doses followed by continuous IV or intermittent IM injections. The efficacy of topical antibiotics in contaminated head and neck surgery is still under investigation. Many studies show that the number of bacteria in the wound are reduced when using topical antibiotics however it has not been shown that this reduction is associated with a reduced number of wound infections.

COMMONLY USED ANTIBIOTICS

Penicillins

The penicillin groups are as follows: natural penicillins, penicillinase resistant penicillins, aminopenicillins, antipseuomonal penicillins, and extended spectrum pencillins. These groups are generated on the basis of their antimicrobial activity.

Penicillins work by causing abnormal cell wall development in actively dividing bacterial cells. Drug resistance is achieved by alterations in penicillin binding proteins which hinders the ability of the drug to penetrate into the bacterial cell wall.

Natural penicillins are extracted from Penicillium chrypogenum. Penicillin G is the major natural penicllin. It has a half life of 30 minutes . However, penicillin G may be combined with procaine or benzathine to make a longer acting repository penicillin. Penicillin is the drug of choice for the treatment of St.pyogens and St. pneumoniae. However, 30% of isolates of St. pneumoniae are penicillin resistant. In penicillin resistant St. pnuemoniae, erythromycin or pediazole is used. It also has a good anaerobic spectrum and is the drug of choice for Clostridia perfringens. It does not have good activity for B. fragilis. Penicillin V is the oral form and has in general the same spectrum of activity.

The synthetic penicillins are prepared by mixing precursors in mold culture, by modifying a natural penicillin, or by adding side chains to 6-aminopenicillanic acid. The parenteral semi-synthetic penicllins are nafcillin, oxacillin, and methicillin. These drugs are used when S. aureus is suspected as they are resistant to staphlococcal B-lactamase. They also have good activity against St. pyogenes and St. pneumoniae. The most active pencillins are nafcillin and oxacillin. However, these drugs may cause interstitial nephritis, leukopenia, and reversible hepatic dysfunction. Methicillin carries the greatest potential for producing interstitial nephritis. Cloxacillin and dicloxacillin are the oral forms of synthetic penicillins.

The aminopenicillins include ampicillin(oral or iv form) and amoxicillin(oral form only). The aminopenicillins are not effective in the presence of B-lactamase. They are the antibiotics of choice for Enterococcus sp. and are active against some gram negative rods(E.coli and P. mirabilis). They are less active than PenG against Strept. species.

The antipsuedomonal penicillins include carbenicillin and ticarcillin. These are also susceptible to B-lactamase. These drugs have a similar gram negative spectrum of activity however are more active against Pseudomonas sp., Enterobacter sp. Serratia sp. and strains of B. fragilis group. They have poor activity against Klebsiella sp. They are synergistic with aminoglycosides against Ps. aeruginosa and some enterobacteriaccae. Ticarcillin is more active than carbenicillin. Side effects include sodium loading and platelet dysfunction.

The extended spectrum penicillins include mezlocillin and piperacillin. These drugs have sensitivities and side effects similar to the anti-psuedomonal penicillins. However, in vitro they are more active against the Streptococcus species and the Klebsiella species.

Cephalosporins

The cephalosporins are derived from Cephalosporium acremonium. They inhibit the third step of bacterial wall synthesis by binding to proteins on the cell membrane. Once bound, they alter the membranes permeability and inhibit protein synthesis and release autolysins. Resistance to cephalosporins is achieved by a decrease in the bacterial cell wall permeability to the antibiotics. The cephalopsporins have been divided into first, second and third generation agents.

The first generation agents include cephalothin, cephapirin, cephradine, and cefazolin. They are active against Streptococcus sp. and Staph. aureus and Staph. epidermidis. They have limited gram negative activity but are active against E. coli, Klebsiella sp., and Proteus mirabilis. Associated adverse effects include allergic reactions, drug eruptions, phlebitis, and diarrhea. Large amounts of B-lactamase will inactivate cefazolin. The rest of the first generation cephalosporins are more resistant to B-lactamase.

The major second generation cephalosporins are cefoxitin, cefotetan, and cefuroxime., They have increase activity against the gram negative organisms. Cefoxitin and cefotetan are more active against the anaerobes. In one study by Maier et al. cefuroxime was found to have an advantage of better tissue penetration in the parotid gland, sinuses, and soft tissue of the neck when compared to other second generation cephalosporins.

The third generation cephalosporins include cefotaxime, ceftizoxime, ceftriaxone, ceftazidime, and cefoperazone. They are less active against Gram positive organisms but are more active than the enterobacteriaceae. Cefotaxime, ceftizoxime, and ceftriaxone are called the triplets and are very resistant to B-lactamase. They also have good activity against the Gram positive organisms with the exception of Enterococcus sp. They have good activity against Gram negative organisms except Pseudomonas sp. Ceftazadime has similar but less activity against the Enterobacter sp when compared to the triplets. It has superior activity against Pseudomonas sp. However, for serious Psuedomonas infections it should be combined with an aminoglycoside. Adverse reactions to cephalosporins include hypersensitivity reaction, hematological disturbances, GI complaints and reversible renal impairment.

Macrolides

Erythromycin is produced by Streptomyces erythreus. It inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit. Resistance to this drug is achieved when there is an alteration in the protein component of the 50S ribosomal subunit. Resistance is mediated by plasmids. Erythromycin is effective against a similar spectrum of bacteria as penG. It is also effective against Mycoplasma, Legionella, Actinomyces, and H flu. It is used in combination with Sulfisoxazole in Pediazole. Adverse reactions include nausea, vomiting, diarrhea and cholestatic hepatitis.

Other antibiotics

Clindamycin is a semisynthetic derivative of Lincomycin. It binds to the 50S ribosomal subunit and inhibits protein synthesis of bacteria. Resistance is gained to this drug by the same mechanism as for erythromycin.. It is active against most Gram positive organisms(both aerobic and anaerobic) and anaerobic Gram negative organisms. It has good penetration into bones and abscesses. Adverse reactions include psuedomembranous colitis, mild nausea and diarrhea, leukopenia, and hepatotoxicity.

Vancomycin has great activity against Staphlococcus aureus Staph. epidermidis, and Enterococcus. It is the antibiotic of choice for methicillin resistant Staph. aureus. It can be associated with nephrotoxicity or ototoxicity especially when given along with an aminoglycoside. Vancomycin use is also associated with the emergence of vancomycin resistant enterococcus which is often seen in immunocompromised patients in the ICU.

Metronidazole is a good antibiotic for the treatment of anaerobic organisms. It acts by producing toxic oxygen radicals that are lethal for anaerobic organisms. It is well absorbed into abscesses. Side effects are rare but include seizures, cerebellar dysfunction, disulfiram reaction with alcohol, and psuedomembranous colitis.

Aminoglycosides

Aminoglycosides include gentamycin, tobramycin, amikacin and netilmicin. These antibiotics are the standard for treatment of aerobic Gram negative infections. They are used mostly in head and neck surgery against mixed microbial abscesses and when microbes from the GI tract are suspected as the cause of infection(i.e. aspiration pneumonia). They have poor activity against Gram positive organisms. They are very effective against Psuedomonas aeruginosa and enterobacteriaceae. They are inactivated by enzyme modification and amikacin is less susceptible to this. Therefore, if resistant Psuedomonas sp. is suspected, amikacin should be used. These antibiotics are associated with ototoxicity and nephrotoxicity.

Sulfonamides

Bactrim or Trimethoprim-sulfamethoxazole is an antimicrobial agent that is active against gram negative bacteria including. H. influenza, E. coli, P. mirabalis. It is very active against Gram negative aerobic organisms. but some Gram positive organisms such as Staph. aureus, Strept. pyogens and Strept. pnuemoniae,. It should not be used in the last month of pregnancy.

Flouroquinolones

Flouroquinolones include nofloxacin, levofloxacin, ciprofloxacin, and ofloxacin. This class of antibiotics has good efficacy against gram negative organisms. It is also sensitive to some staph. sp. Children and adolescents should not be given quinolone drug therapy due to bone growth problems found with their use in animal studies.

INDICATIONS FOR ANTIMICROBIAL TREATMENT

Otologic Surgery

The perioperative instillation of ototopical antimicrobial drops seems to reduce the incidence of otorrhea after tympanostomy tube insertion. Studies show a statistically significant decrease in post-tympanostomy otorrhea from 16.4% to 8% when cortisporin otic drops are used from 1 to 5 days. It has also been shown that perioperative use of antimicrobial ear drops after myringotomy and tube insertion does prevent the colonization of the tube by microbial organisms. The most common pathogens are those found in acute otitis media and otitis externa. These include Steptococcus pneumoniae, Hemophilus influenza, and Moraxella catarrhalis which were isolated in 40% of the patients studied and Pseudomonas and Staphylococcus aureus which were also isolated in 40% of patients studied.

Recently, increasing concern has emerged over the development of resistance of Pseudomonas to many commonly used antimicrobial ear drops. In a study done at the Childrens Hospital in Pittsburgh, only 17% of the aural isolates of Psuedomonas were found to be sensitive to neomycin. Further studies need to be carried out in the area.

In other otologic surgery, there has been no significant difference shown in infection rates post-operatively between those patients treated with peri-operative antibiotics and those who have not been treated. In the surgical treatment of ears with chronic drainage by tympanomastoidectomy, pathogenic microorganisms may remain in the middle ear even after surgery and may cause recurrent infection. One study showed that the postoperative secretions from a tympanostomy tube placed after mastoid surgery was still colonized by bacteria. Even with prophylaxis, the isolates remained. The bacterial isolates found were Psuedomonas and Staph. epidermidis. Studies to date show no statistically significant influence upon post-operative otologic infection or colonization rates as a result of using prophylactic antibiotics. Although studies show that there is a higher incidence of infection and graft failure in those ears infected preoperatively, the use of preoperative antibiotics did not alter this outcome.

When placing prosthetic devices, especially cochlear implants, there is always temptation to use prophylactic antibiotics. However, according to studies to date, infection resulting in removal of the implant does not seem to be dependent on prophylactic antibiotic use. Therefore, aside from otologic drops, prophylactic antibiotic use does not appear useful in otologic surgery. Wound infection is prevented more effectively by starting with a dry ear and observing good surgical technique.

Neurotological procedures that are long in duration and often require exposure of the dura and CNS are associated with a risk of CSF leak, meningitis, and wound infection. In a study by Kartush, et al., the result suggested that bacitracin irrigation intraoperatively alone is sufficient to prevent infectious complications however further studies need to be performed.

Tonsillar surgery

The most common cause for tonsillitis is Group A Streptococcus and penicillin is the drug of choice. For those patients with recurrent tonsillitis refractory to penicillin, clindamycin may be used. Peritonsillar abscesses can also be treated with iv or oral clindamycin or penicillin after appropriate drainage.

Several studies show that antibiotics given for 5-7 days post-operatively from a tonsillectomy are beneficial. Dysphagia, fever, pain, mouth odor and poor oral intake in the post-operative period can be reduced by giving a therapeutic regime of ampicillin or amoxicillin in children and ampicillin plus a beta lactamase inhibitor in adults. The duration of antibiotic treatment is unknown, and currently a 7 day course is recommended.

Odontogenic infections

Odontogenic infections are most commonly caused by oral flora. Most are self limited, but they have the tendency to deepen often forming a neck space abscess or facial/neck cellulitus. After appropriate drainage, treatment is recommended with IV penicillin or Cleocin. This can be augmented with Cleocin mouthwash.

Neck Abscess

The usual organisms are Staphlococcus aureus, hemolytic streptococci(including Strept. pnuemoniae), and anaerobes. Antibiotics recommended include penicillinase-resistant penicillin, clindamycin or metronidazole, and a third generation cephalosporin or aminoglycoside. There is a high incidence of B-lactamase resistant organisms in head and neck abscesses. Usually, antibiotic therapy is combined with surgical or needle drainage if there is no clinical improvement after 24 hours of antibiotic therapy alone.

Facial fractures

Facial fractures deserve consideration of antibiotics. In the considering operative reduction of mandible fractures, perioperative treatment with clindamycin or penicillin is appropriate in reducing the incidence of infection from oral flora in open mandible fractures. In one study there was a 43% incidence of infection in mandible fractures not treated with antibiotics perioperatively versus a 13% infection rate in those treated with appropriate antibiotics. In displaced maxillary sinus fractures requiring repair through an intraoral approach, prophylactic antibiotics is reasonable to prevent infection from oral flora. Therefore, antibiotics covering the oral flora are recommended in open mandible fractures and in any surgical procedures where the wound will be contaminated by oral flora.

Facial lacerations/Soft Tissue injuries

The decision to use antibiotics is based on the mechanism of injury of the facial laceration and how long the wound has been contaminated, patient factors such as diabetes and age. The type of antibiotic required is based on the suspected organisms. Soft tissue injuries of the head and neck involving crush injuries, wounds contaminated with body secretions, pus, or soil, wounds with devitalized tissue, and those patients receiving treatment of their injury three hours after it occurs should receive antibiotics

For animal bites, the antibiotic therapy is based on the type of animal. For example, 5% of dog bites usually result in infection with Strept. viridans, P. multocida, S. aureus, E. correndens, Bacteroides, Fusobacterium, and Caphocytophaga and is treated with Augmentin. Human bites usually result with infection with S.viridans, S. epidermidis, cornnebacterium, S. aureua, eikenella, bacteroides, and peptostrep and treatment is based on the length of time of contamination as well as the etiology. Studies show conflicting results on the use of antibiotics in animal bites reducing the incidence of wound infection. Some studies suggest that there is a strong correlation of amount of devitalized tissue and would infection. Current recommendations are to give empiric therapy to all human bites to the head and neck. Empiric antibiotic therapy is also recommended in animal bites where debridement of devitalized tissue is insufficient.

Nasal and Sinus Surgery

Nasal bacterial flora consist of diptheroids, coagulase-negative cocci, and enterobacteria. Approximately 50% of patients undergoing nasal surgery will have coagulase-positive Staphlococcus residing in their nasal cavities. Keflex is useful in preventing toxic shock syndrome after nasal surgery where packing in the nasal cavity has been left in place postoperatively. In addition, nasal packing that has been coated with antimicrobial ointment at the time of insertion at surgery reduces the growth of bacteria on the packing and decreased the severity of pain on removal of the pack. A study was done in 1995 which compared the subjective and objective signs of sinusitis in a group of patients who underwent FESS where half of the patients were treated with low dose erythromycin post surgery and half received no anti-microbial therapy. The patient who received erythromycin had less signs of residual sinusitis than the control patients. Current recommendations are to give anti-staph coverage in patients with nasal packing and to coat merocel packing with antibiotic ointment.

Thyroid, Parotid, and Submandibular surgery

Retrospective studies of thyroid, parotid, and submandibular gland surgery demonstrate no efficacy of giving prophylactic therapy in these cases assuming the surgical field is not contaminated with gross infection. Therefore antibiotic therapy is not routinely recommended.

Cranial Base Surgery

Patients who undergo cranial base procedures represent a high-risk group for post- operative infections with possible contamination of the intracranial contents with contents of the upper aerodigestive tract. Few studies have been done and they suggest that a single broad spectrum antibiotic for 48 hours is effective. Additional studies need to be done before final recommendations can be made.

Oncologic Head and Neck Surgery

Patients needing major oncologic head and neck surgery are at high risk for post operative infection when the surgical site is contaminated by secretions from the aerodigestive tract. In a retrospective study of clean contaminated cases of head and neck tumor resection, the overall wound complication rate was found to be 28 per cent. Other studies quote rates from 28%-87%. A major fistula was the most common complication with a rate of 9.2 per cent. This study showed a seven day course of Keflex and metronidazole is effective in prophylaxis of head and neck surgery. In a study by Johnson et al., a comparison was made between five perioperative doses of unasyn versus clindamycin. The incidence of wound infection in both groups was 14% with treatment. with no statistically significant difference when comparing one antibiotic with the other. Another study compared the length of treatment of prophylactic therapy with the rate of wound infection. In this study, there was not significant decrease in the rate of wound infection post surgery with 3 days of treatment versus only 1 day. Recently, there have also been studies comparing the efficacy of topical antibiotics(e.g. clindamycin mouthwash) versus parenteral antibiotics. In a study by Grandis et al., perioperative mouthwash reduced the number of anaerobic and aerobic bacteria intraoperatively cultured by greater than 90%. Antibiotics are currently recommended in major clean-contaminated H &N cases. The need for gram negative coverage in clean contaminated surgery remains a question. Studies by Gerard, et al suggested a reduction in infection rate from 36 to 10% with the addition of an aminoglycoside. A short course of antibiotics if efficacious in preventing wound infections in most H & N cases.

Contaminated head and neck cases should also receive prophylactic antibiotics. Most of these infections are polymicrobial. Studies have shown that maximal effectiveness of the treatment is achieved if the antibiotics are given prior to contamination. If they are given more that 3 hours after contamination, they are of minimal benefit. Clindamycin is a good choice for most surgeries however this should be based on the individual case.

SUMMARY

The decision of whether or not to give peri-operative antibiotics is usually based on the individual case. However, the following guidelines may be useful in arriving at a decision. A post-operative infection can be so devastating that preventing just one infection is worth it from a cost, medicolegal and patient outcome viewpoint. Studies show that the number of hospital days of patients who develop post-operative infection is two to three times that of those who do not. On the other hand, use of prophylactic antibiotics may encourage poor surgical technique. It is associated with toxic, allergic, and other side effects, may promote antibiotic resistance, contribute to superinfection, and it is costly.

BIBLIOGRAPHY

1. Lucente, F.E., and Sobol, S.M. Essentials in Otolaryngolgy, Third edition, 1993.

2. Mader, Jon. Antibiotics and Head and Neck Infectious Diseases, July 1997.

3. Strauss M., et al. Cephazolin and metronidazole prophylaxis in head and neck surgery. Journal of Laryngology and Otology. July 1997. 631-4.

4. Morton, R.G., et al., Antimicrobials in Otolaryngology, UTMB Dept. of Otolaryngology Grand Rounds, May, 1989.

5. Johnson, et al, Comparison of ampicillin/sulbactam versus clindamycin in the prevention of infection of patients undergoing head and neck surgery. Head and Neck, Aug 1997, 367-71.

6. Righi, M. et al., Short-term versus long-term antimicrobial prophylaxis in oncologic head and neck surgery. Head and Neck, Sept-Oct, 1996, 399-404.

7. Maier, W., et al., Concentration of cephalosporins in tissues of head and neck after parenteral infusion., Chemotherapy, Nov-Dec, 1995, 421-6.

8. Blair, E. A. et al., Cost analysis of antibiotic prophylaxis in clean head and neck surgery. Archives of Otolaryngology - Head and Neck Surgery, Mar., 1995, 269-71.

9. Grandis, J.R., et al., The efficacy of topical antibiotic prophylaxis for contaminated head and neck surgery., Laryngoscope., Jun. 1994, 719-24.

10. Dohar, J.E., et. al., In vitro susceptibility of aural isolates of Pseudomonas aeruginosa to commonly used ototopical antibiotics.

11. Sanford, et al., The Sanford guide to Antimicrobial Therapy, 1997.

12. Fulmer, R. P. Antibiotic Prophylaxis in Otolaryngologic Surgery, Dept. of Otolaryngology Grand Rounds, June 1991.

13. Choi, S., et al, Relative Incidence and Alternative Approached for Surgical Drainage of Different Types of Deep Neck Space Abscesses in Children, Arch. of Otolaryngolgy and Head and Neck Surgery, Dec, 1997, 1271-1273

14. Gyo,K. et al., Residual bacterial infection in the tympanic cavity following surgery for ears with chronic drainage., Auris, Nasus, Larynx 23:13-9, 1996.

15. Hester, T., et. al., Prophylactic antibiotic drops after tympanostomy tube placement., Archives of Otolaryngology-Head and Neck Surgery, 121, 445-8.

16. Mandel, et. al., Acute Otorrhea:bacteriology of a common complication of tympanostomy tubes., Annals of Otology, Rhinology, & Laryngology, Sept. 1994, 713-8.

17. Telian, S., et al., The effect of antibiotic therapy on recovery after tonsillectomy in children., Archives of Otolaryngology-HNS., June 1986, 610-5.

18. Shilani. A., Use of antibiotics for expansion of merocel packing following endoscopic sinus surgery., Ear, Nose and Throat Journal. Aug. 1996, 524-6.

19. Moriyama, H. et al., Evaluation of endoscopic sinus surgery for chronic sinusitis: post-operative erythromycin therapy., Rhinology, Sep 1995, 166-70.

20. Pou, A.M and Johnson, J. T., Use of Prophylactic Antibiotics in Otolaryngology, Complications of Head and Neck Surgery, Thieme Medical Publishers, 1995, 159-171.