Antibiotic prophylaxis in clean-contaminated head and neck oncological surgery

Antibiotic prophylaxis in clean-contaminated head and neck oncological surgery

ARTICLE IN PRESS Journal of Cranio-Maxillofacial Surgery (2007) 35, 15–20 r 2007 European Association for Cranio-Maxillofacial Surgery doi:10.1016/j.j...

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ARTICLE IN PRESS Journal of Cranio-Maxillofacial Surgery (2007) 35, 15–20 r 2007 European Association for Cranio-Maxillofacial Surgery doi:10.1016/j.jcms.2006.10.006, available online at

Antibiotic prophylaxis in clean-contaminated head and neck oncological surgery Neven SKITARELIC´1, Miro MOROVIC´2, Darko MANESTAR3 1

Department of Otolaryngology Head and Neck Surgery, (Chair: M. Kovacic, MD), Zadar General Hospital, Croatia; 2Department of Infectious Disease, (Chair: B. Ozelalija MD, PED), Zadar General Hospital; 3 Department of Otolaryngology, (Chair: D. Manestar, MD, PhD), Clinical Hospital Rijeka, Croatia

Background: Perioperative antibiotic prophylaxis has significantly reduced wound infection rates in clean-contaminated head and neck surgical procedures but controversy still remains regarding the optimal antibiotic regime. Objective: To examine the efficacy of different antibiotics in head and neck oncological surgery prophylaxis. Patients and methods: In this prospective, double-blind clinical trial, 189 patients with carcinoma of the upper aerodigestive tract were randomized to receive amoxicillin-clavulanate or cefazolin intravenously up to 1 h before surgery and at 8-h intervals for an additional three doses. Results: An overall wound infection rate of 22% was observed. The infection rate in patients receiving cefazolin was 24% (22/92) vs. 21% (20/97) in those receiving amoxicillin-clavulanate; the difference was not statistically significant. Postoperative overall non-wound infection developed in 12% (22/189) patients; the rate of infection was 9.8% (9/92) in patients receiving cefazolin vs. 13.4% (13/97) in those receiving amoxicillin-clavulanate, without a statistically significant difference between the two groups. Gram-negative bacteria were more often isolated with Pseudomonas aeruginosa as the dominant species. The risk of postoperative infection was more influenced by the type of surgical procedure than by disease stage. Conclusion: In clean-contaminated head and neck oncologic surgery amoxicillin-clavulanate prophylaxis was at least as efficient as cefazolin. However, when taking into account the fact that beta-lactamase containing strains have recently been spreading, amoxicillin-clavulanate should be the logical first choice. r 2007 European Association for Cranio-Maxillofacial Surgery


Keywords: clean-contaminated-surgery; oncology; antibiotics

for postoperative infections in patients who had undergone head and neck tumour surgery.

INTRODUCTION Cancer of the upper aerodigestive tract constitutes approximately 4% of all malignancies (Muir and Weiland, 1995) and the main treatment in the management of these patients remains surgical. Significant morbidity in the immediate postoperative period is caused by wound, and by non-wound infections. There is general agreement that perioperative antibiotic prophylaxis for 24-h reduces the risk of colonization/super-infection (Kaiser, 1990). Cephalosporins have emerged as the drug of choice for perioperative prophylaxis because of their (wide) antibacterial spectrum and low incidence of allergy and side effects (Kaiser, 1990). The Antimicrobial Agents Committee of the Surgical Infection Society of the United States of America recommends cefazolin for prophylaxis in clean-contaminated head and neck surgery, although it has Gram-positive aerobic coverage only (Rodrigo et al., 1997). To date, it remains the mainstay for prophylaxis in cleancontaminated head and neck surgery (Shinagawa et al., 2003; Rodrigo et al., 2004). The purpose of the present study was to compare the efficacy of amoxicillin plus clavulanic acid with the cefazolin regime, and to identify the risk factors

PATIENTS AND METHODS A prospective, randomized, double-blind clinical trial of patients was conducted at the Department of Otolaryngology and Head and Neck Surgery, Zadar General Hospital, Croatia, from January 2000 to December 2003. The protocol had been reviewed and approved by the local Ethics Committee. Patients eligible to be included in this trial were those scheduled to undergo oncological surgery involving a clean-contaminated wound. Clean-contaminated wounds were defined as sterile initially, but the mucosal barrier was crossed or a potentially infected anatomical cavity was entered during the operation. Patients with histologically confirmed squamous cell carcinoma of the upper aerodigestive tract without preoperative irradiation were included in this study. In all cases, surgical treatment was the first choice. Patients having recurrences or another primary tumour, and those who underwent reconstruction with a microvascular free-tissue transplantation were excluded from the study, because they had been 15

ARTICLE IN PRESS 16 Journal of Cranio-Maxillofacial Surgery

submitted to prolonged antibiotic administration. Also cases with transoral resections and isolated tracheotomies, or tumour types other than squamous cell carcinoma were excluded from the study. In addition, the following exclusion criteria were taken into account: pregnancy, hypersensitivity to penicillins or cephalosporins, patients who received a systemic antibiotic drug within 72 h prior to the planned procedure, those who had clinical or laboratory evidence of a preexisting infection or had serious systemic renal disease. On the basis of the examination data, patients were divided into four clinical disease stages according to the American Joint Committee on Cancer (AJCC) criteria from 1998 (Fleming et al., 1998). Out of 193 patients studied, 189 fulfilled the inclusion criteria. Tumour characteristics at clinical examination were grouped according to the TNM classification (Table 1). Patient characteristics included age at diagnosis (range 33–78 years, median 56.8 years) in 168 (89%) males and 21 (11%) females. Based on a computer-generated randomization code, patients were assigned into groups A and B. Group A patients received cefazolin 1.0 g and group B patients received amoxicillin/clavulanic acid 1.2 g 1 h preoperatively. The hospital pharmacist maintained the randomization code and dispensed all study drug supplies. The clinical investigators and coordinators were blinded to drug assignment. After surgery, patients continued to receive their assigned study drug at 8-h intervals for the total of three doses. Patients were examined daily for signs and symptoms of infection during their hospital stay. Any wound graded 4+ or above (0 ¼ no erythema, 1+ ¼ less than 1 cm of erythema, 2+ ¼ less than 5 cm of erythema and induration, 3+ ¼ geater than 5 cm of erythema and induration, 4+ ¼ purulent drainage, and 5+ ¼ wound breakdown with mucocutaneous fistula) were considered infected. An attempt was made to document all postoperative wound and non-wound infections by appropriate culture.

Specimens for aerobic and anaerobic cultures were obtained from open wound drainage, aspirated seromas and suction drainage as well. Non-wound infections were defined as infections of the tracheobronchial tree, urinary tract or blood as proven by the isolation of pathogenic organisms from the appropriate sources in the clinical settings of fever, leukocytosis, purulent sputum, pyuria or sepsis (Garner et al., 1988). In all cases antibiotic sensitivity tests were done. All patients signed their informed consent prior to participation in the study. Statistical analysis of the data was performed using w2 test with Yates correction on an IBM compatible PC system. Significance was defined at the po0.05 level for all comparisons.

Table 1 – Tumour characteristics in 189 patients




Tumour location

Oral cavity Oropharynx Hypopharynx Larynx Paranasal sinuses

RESULTS The study comprises data from 189 patients who were enrolled into the study and received drug therapy: 92 received cefazolin, and 97 received amoxicillin/ clavulanic acid. No antibiotic toxicity was identified. In total, only 22% (42/189) patients developed postoperative wound infections. The infection rate was 24% (22/92) in patients receiving cefazolin and 21% (20/97) in the other group. There was no statistically significant difference between the two (p40.05). Postoperative non-wound infections developed in 12% (22/189) patients. The infection rate was 10% (9/92) in patients receiving cefazolin vs. 13% (13/97) Table 2 – Infection rate by primary site of tumour Site

Oral cavity Oropharynx Hypopharynx Larynx Paranasal sinuses

Number of patients 50 28 32 75 4 189

Patients with wound infection (%)

Patients with non-wound infection (%)

10 5 9 18 —

5 4 4 9 —

(20%) (18%) (28%) (24%)

42 (22%)

(10%) (14%) (12.5%) (12%)

22 (12%)

Number of patients Table 3 – Infection rate by surgical procedures 50 28 32 75 4

Clinical stage


108 81

Size of primary tumour

T1–T2 T3–T4

70 119

Involvement of lymph nodes

N0 N+

79 110

Distant metastasis

M0 M1

189 —


Composite resection Maxillectomy Mandibulectomy Glossectomy Pharyngectomy Partial laryngectomy Total laryngectomy Total

Number of patients

37 6 22 8 9 46 61 189

Patients with wound infection (%)

Patients with nonwound infection (%)

6 — 6 — 3 10 17

3 — 2 1 1 7 8

(15%) (27%) (33%) (22%) (28%)

42 (22%)

(8%) (9%) (12.5%) (11%) (15%) (13%)

22 (12%)

ARTICLE IN PRESS Antibiotic prophylaxis in clean-contaminated head and neck oncological surgery 17

of those receiving amoxicillin/clavulanic acid. There was also no statistically significant difference between the two groups (p40.05). The patient distribution and overall infection rates by tumour site and surgical procedure are listed in Tables 2 and 3. The highest rates of wound infection were in those patients with a hypopharyngeal primary site (28%), whereas in those with a non-wound infection the oropharynx was the most commonly affected (14%) followed by hypopharynx (12.5%) and larynx (12%). The surgical procedure with the highest overall infection rate was pharyngectomy (33%) followed by total laryngectomy (28%; Table 3). According to the AJCC criteria (Fleming et al., 1998) patients were grouped into I–III stage (108 patients) and IV stage (81 patients; Table 4). Neither tumour (T) size nor involvement of lymph node (N) was correlated with an increased wound infection rate, although there was a tendency toward increasing wound infections with increasing disease stage (Table 4). This did not reach statistical significance (p40.05). Fifty-two bacterial isolates were obtained in 29 of the 42 patients (69%) with a wound infection (Table 5). In 18 patients, just one organism was identified while in the remaining 11 patients two or three bacterial organisms were isolated from the infected wounds. The most frequently encountered bacteria were Gram-negative aerobes (33/52 or 63%) followed by Gram-positive aerobes (12/52 or 23%) and anaerobes (4/52 or 8%). The most prevalent single bacterium among the Gram-negative aerobes was Pseudomonas aeruginosa. In non-wound infections (Table 6), the most frequently encountered bacteria were again Gramnegative aerobes (9/16 or 56%) with P. aeruginosa as a dominant species isolated; seven out of the total number of isolates (44%) were classified as resistant organisms. Pulmonary infections predominated with 17 infections (11 pneumonia and 8 tracheobronchitis), while enterocolitis and urinary tract infections

were noted rarely. In 11 infections, no microorganism could be isolated. DISCUSSION The so-called clean-contaminated head and neck surgical procedure has long been recognized as having a risk of postoperative wound infections. The incidence of these without administration of perioperative antibiotics ranges from 24% to 87% Table 5 – Bacteria isolated in two groups of patients with wound infections (per patient) Microorganism


Amoxicillin/ clavulanic acid


2 3 3 —

1 — 1 1



1 1 1 2 4 2 1 —

— 3 4 4 7 — 2 1



1 1 1

— — 1

Subtotal anaerobes



Candida albicans





Gram-positive aerobes Streptococcus viridans Methicillin-resistant Staphylococcus aureus Staphylococcus aureus Streptococcus species Enterococcus species Subtotal Gram-positive Gram-negative aerobes Enterobacter species Proteus mirabilis Escherichia coli Serratia species Pseudomonas aeruginosa Morganella morgagni Klebsiella species Serratia marcescens Subtotal Gram-negative Anaerobes Bacteroides species Bacteroides melaninogenicus Peptostreptococcus

Overall total

Table 4 – Characteristics of 189 squamous cell carcinomas and infection rate Number of patients

Patients with wound infection (%)


Patients with nonwound infections (%)


Size of primary tumour T1–T2 T3–T4

70 119

10 (14%) 32 (27%)


9 (13%) 13 (11%)


Involvement of lymph nodes N0 N+

79 110

20 (25%) 22 (20%)


11 (14%) 11 (10%)


Distant metastasis M0 M1

189 —

42 (22%) —


22 (12%) —


Clinical stage I–III IV

108 81

18 (17%) 24 (30%)


11 (10%) 11 (14%)


Disease characteristics

There were no statistical differences between each pair.

ARTICLE IN PRESS 18 Journal of Cranio-Maxillofacial Surgery Table 6 – Bacteria isolated in patients with non-wound infections Prophylactic antibiotic

Site of infection



Amoxicillin/clavulanic acid

Urinary tract Pneumonia Pneumonia

Escherichia coli Escherichia coli Streptococcus viridans Pseudomonas aeruginosa — — Pseudomonas aeruginosa Serratia marcescens Staphylococcus aureus Pseudomonas aeruginosa — — — —

S S S R — — R R S R — — — —

Staphylococcus aureus Pseudomonas aeruginosa Streptococcus pneumoniae Escherichia coli — — Staphylococcus aureus — — Methicillin-resistant Staphylococcus aureus Serratia marcescens Streptococcus species —

S R S S — — S — —

Pneumonia Pneumonia Pneumonia Pneumonia Tracheobronchitis Tracheobronchitis Tracheobronchitis Tracheobronchitis Enterocolitis Cefazolin

Pneumonia Pneumonia Pneumonia Pneumonia Pneumonia Tracheobronchitis Tracheobronchitis Tracheobronchitis Tracheobronchitis Enterocolitis

R R S —

S-sensitive, R-resistant, — none isolated.

(Weber and Callender, 1992). This stems primarily from the gross and often extensive and prolonged contamination of the neck wound with oropharyngeal secretions. Recently, the use of perioperative antibiotics has been shown to significantly reduce postoperative wound infections. Prospective studies report wound infection rates in the range of 14–40% (Cole et al., 1987; Girod et al., 1995; Johnson et al., 1997; Penel et al., 2001, 2004; Rodrigo et al., 1997; Sabirana et al., 2001). However, even the best operative techniques and appropriate antibiotics have not completely eliminated this problem. In this study only patients were included with procedures that involved a neck wound in communication with the oral cavity or pharynx. Twenty two percent of these patients who received perioperative antibiotic prophylaxis developed a wound infection. The highest overall infection rate was noted following pharyngectomy (33%) followed by total laryngectomy (28%). Wound infections are typically polymicrobial and differentiation between pathogenic and colonizing organisms is problematic. The principal organisms in saliva that must be targeted are Gram-positive aerobes and anaerobes. Gram–negative aerobic organisms (Klebsiella, Pseudomonas and Proteus) are not usually present in the saliva of healthy individuals but they may be readily obtained from preoperative necrotic tumour cultures (Weber et al., 1992) while Gram-negative aerobic bacilli were also frequently isolated in wound

infections (Johnson et al., 1987 and 1997; Rodrigo et al., 1997; Callender, 1999; Penel et al., 2004). From the tumour bed alone S. aureus and multiple streptococcal species were also isolated (Sweeney et al., 1984). The most frequently encountered bacteria in this study were Gram-negatives, especially P. aeruginosa which is generally the sole organism frequently found in cancer patients (Bodey, 2001; Rodrigo et al., 2004). In this study, anaerobic organisms were rarely found in the infected wounds in contrast with some reports by Robbins et al. (1988), Weber et al. (1992), Clayman et al. (1993). This may be explained by the small number of infected patients in this series (3.2%) who underwent concomitant intraoperative mandibulectomy and dental extractions, a well-recognized factor associated with anaerobic wound infections (Clayman et al., 1993). Technical difficulty in isolating anaerobes is also well known (Clayman et al., 1993). The incidence of non-wound infections in the patients of this study was 12% with the majority being pulmonary; 11 out of 22 patients had pneumonia and 8 tracheobronchitis. Other investigators have reported similar findings in number and location of non-wound infections (McGuirt et al., 1979; Weber et al., 1993; Khuri et al., 1997; Barie, 2000) with mortality rates of 10–18% (Fabian, 2000). No patient in this study died. An increased risk of pulmonary infections was not influenced by the primary tumour site; however,

ARTICLE IN PRESS Antibiotic prophylaxis in clean-contaminated head and neck oncological surgery 19

resection of the tongue, pharynx, larynx or denervation of these structures may promote postoperative aspiration due to loss of effective swallowing and airway protective mechanisms. This allows secretions to enter the lower respiratory tract. In contrast to tumour size, node involvement and clinical stage did not show any significant influence to the frequency of any kind of infection in this study (Girod et al., 1995; Rodrigo et al., 1997). Mortimore and Thorp (1998) reported two patients who developed a necrotizing fasciitis after ablation of a tumour from the upper aerodigestive tract. Despite the fact that there was a patient with a necrotizing fasciitis in this hospital before (Skitarelic´ et al., 2003), there was no such case included in this study. Previous publications have demonstrated similar effects of a variety of antibiotics when used to prevent postoperative infections following major clean-contaminated head and neck surgical procedures. All antibiotic regimes have in common an activity against bacteriological flora normally found on the mucosa of the upper aerodigestive tract. There was a higher rate of wound infections in the patients who received cefazolin vs. those who received amoxicillin/clavulanic acid while the nonwound infection rate was somewhat higher in patients who received the latter drug combination; however, these differences were not statistically significant. These results must be interpreted with care because of the small number of patients in the groups. Since many oral Gram-negative anaerobic bacteria produce beta-lactamases, antibiotics resistant to betalactamases are preferred for prophylactic use in head and neck surgery (Bradford, 2001; Schwaber et al., 2005). Besides, the majority of infecting organisms found in this study were Gram-negative in both types of infections, with P. aeruginosa being the predominant species isolated. Frequent resistance of this organism to the perioperatively administered antibiotics indicates the need for a more careful assessment of the appropriate therapeutic antibiotic selected to treat postoperative infections. This is of particular significance most recently when different species including Enterobacteriaceae and P. aeruginosa were shown to produce an extended spectrum of beta lactamases (Bradford, 2001; Schwaber et al., 2005). Therefore, when empirical therapy must be initiated, the clinician’s knowledge of the most frequently isolated organisms by site of infection and their antibiotic sensitivity is important.

CONCLUSION Amoxicillin/clavulanic acid is at least as safe and effective as cefazolin in preventing infections in oncologic head and neck surgery. If it were to demonstrate a statistically significant difference, more than 1000 patients would have been necessary for a study of this type and meta-analyses should be

performed to give the most scientifically accurate answer to this problem (Rosenfield, 2004).

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Neven SKITARELIC´, MD, PhD Put Murvice 33 23000 Zadar Croatia Tel.: +385 23 314157 E-mail: [email protected] Paper received 13 January 2006 Accepted 25 October 2006