ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Sept. 1992, p. 2014-2019 0066-4804/92/092014-06$02.00/0
Vol. 36, No. 9
Antimicrobial Prophylaxis for Major Head and Neck Surgery in Cancer Patients: Sulbactam-Ampicillin versus Clindamycin-Amikacin M. PHAN,1 P. VAN DER AUWERA,l* G. ANDRY,2 M. AOUN,1 G. CHANTRAIN,2 R. DERAEMAECKER,2 P. DOR,2 D. DANEAU,' P. EWALENKO,3 AND F. MEUNIER1t Infectious Diseases and Microbiology Laboratory, Service de Me6decine et Laboratoire d'Investigation Clinique H. J. Tagnon, 1 Department of Head and Neck Cancer Surgery,2 and Anesthesiology and Surgical Intensive Care Unit, 3 Institut Jules Bordet, Centre des Tumeurs de l'Universite6 Libre de Bru"elles, rue Heger-Bordet 1, B-1000 Brussels, Belgium Received 27 January 1992/Accepted 24 June 1992
A total of 99 patients with head and neck cancer who were to undergo surgery were randomized in a prospective comparative study of sulbactam-ampicillin (1:2 ratio; four doses of 3 g of ampicillin and 1.5 g of sulbactam intravenously [i.v.] every 6 h) versus clindamycin (four doses of 600 mg i.v. every 6 h)-amikacin (two doses of 500 mg i.v. every 12 h) as prophylaxis starting at the induction of anesthesia. The two groups of evaluable patients (43 in the clindamicin-amikacin treatment group and 42 in the sulbactam-ampicillin treatment group) were comparable as far as age (mean, 57 years; range, 21 to 84 years), sex ratio (71 males, 28 females), weight (mean, 66 kg; range, 40 to 69 kg), indication for surgery (first surgery, 48 patients; recurrence, 37 patients), previous anticancer treatment (surgery, radiation therapy, chemotherapy), type of surgery, and stage of cancer. The overall infection rate (wound, bacteremia, and bronchopneumonia) within 20 days after surgery was 20 patients in each group. Wound infections occurred in 14 (33%) sulbactamampicillin-treated patients and 9 (21%) clindamycin-amikacin-treated patients (P = 0.19; not significant). The rates of bacteremia were 2 and 4%, respectively. The rates of bronchopneumonia were 14.3 and 23.2%, respectively (P was not significant). Most infections were polymicrobial, but strict anaerobes were recovered only from patients who received sulbactam-ampicillin. Antimicrobial treatment was required within 20 days after surgery for 42% of the sulbactam-ampicillin-treated patients and 44% of the clindamycin-amikacintreated patients. By comparison with previous studies, we observed a decreased efficacy of antimicrobial prophylaxis in patients with head and neck cancer undergoing surgery because of the increased proportion of patients who were at very high risk for infection (extensive excision and plastic reconstruction in patients with recurrent stage III and IV cancers) and because of the longer durations of surgery.
It has been proven and widely accepted that patients with head and neck cancer undergoing surgery (clean contaminated procedures) benefit from preoperative antibiotic prophylaxis once the skin and oropharyngeal cavities are opened (5, 17, 18, 27, 30). Simple laryngectomy has been associated with a very low risk of infection (5 cm of erythema and induration). A mucocutaneous fistula also reflected a wound infection. This definition corresponds to grades 4 and 5 of Johnson and colleagues (5, 16-20). All wound specimens (swabs or syringe aspirates) were processed microbiologically both for aerobic and anaerobic culture, in addition to analysis of volatile fatty acids by gas-liquid chromatography to indicate the presence of strict anaerobes (26). Pulmonary infection was characterized by the production of purulent sputum, radiological signs of bronchopneumonia, and/or rales. The minimal criteria for the diagnosis of pneumonia were a new infiltrate on the chest X ray and purulent sputum in a febrile (>38°C) patient. Microorganisms isolated from the patients were considered significant pathogens if they were present on Gram staining and were isolated in pure culture or as the predominant microorganisms. A delay to the time of infection corresponded to the time between surgery and the first signs or symptoms of infection at each relevant site. In vitro susceptibility testing of aerobes and facultative bacteria was done by the disk diffusion method described by the National Committee for Clinical Laboratory Standards (25a). Anaerobes were tested by disk diffusion on blood agar by using the Rosco agar disk diffusion method (7a). The respective Neosensitab disks (Rosco) contained 25 ,ug of clindamycin and 30 ,ug each of ampicillin and sulbactam. Anaerobes were tested on Mueller-Hinton agar with 5%
2015
horse blood (Bio-Merieux, Marcy-l'Etoile, France). The corresponding breakpoints are diameters of .28 mm (susceptible) and c23 mm (resistant) for clindamycin and .32 mm (susceptible) and c24 mm (resistant) for the ampicillinsulbactam combination. Zone diameters were read after 48 h of incubation at 37°C under strictly anaerobic conditions. The strains used for quality control were Bacteroidesffragilis ATCC 25285 and Bacteroides thetaiotaomicron ATCC 29741; both strains are susceptible to ampicillin-sulbactam, B. fragilis is susceptible to clindamycin, and B. thetaiotaomicron is resistant to clindamycin. This method is similar to the method of Horn et al. (13), which has been validated by Barry et al. (2). The validity of a 1:1 ratio for the ampicillin-sulbactam test disk has recently been discussed extensively by Jenkins (15). Inclusion of 50 patients in each arm of the study had a power of 0.79 to detect a difference in cure rate of 0.20 (from 0.65 to 0.85) with an alpha error of 0.1 (single tailed). All statistical tests were done with Macintosh SE/30 hardware and Statview 512+ software (Version 1.1, 1986; Abacus Concepts). Comparisons of proportions were done by using a chi-square test with Yates continuity correction. Single-tailed tests were done to assess statistical significance. A result was considered statistically significant if the P value was c0.05. RESULTS The two groups of patients were very similar, as shown in Table 1. Most patients had a very poor prognosis, as exemplified by the large proportion of patients with stage III and IV cancers on the one hand and recurrent disease on the other. All patients had involvement of the oropharyngeal cavity. Similarly, most of them underwent very extensive surgery in addition to neoadjuvant chemotherapy and radiation therapy. Total tumor excision and bilateral radical neck dissection with plastic reconstruction, including free flap reconstruction, corresponds to a prolonged surgical procedure with a time range of 12 to 24 h. Figure 1 shows the time delay from the time of surgery to the appearance of infectious complications. Because of the small number of patients included in the study, we were not able to show a significant difference in the rate of postoperative wound infection, bacteremia, or bronchopneumonia (Table 2). However, strict anaerobes were not isolated from patients who developed infections after clindamycin-amikacin prophylaxis, whereas strict anaerobes were associated with the wound infections of six patients in the sulbactam-ampicillin group. A similar proportion (42 and 44%, respectively) of the patients required antibiotic treatment within 20 days of surgery for a proven or suspected infection. This proportion corresponds to the overall failure rate of the two prophylactic regimens. The pathogens isolated from wound infections are listed in Table 3. Staphylococci were the most prevalent bacteria among the gram-positive organisms. Most gram-negative bacilli were typically of nosocomial origin and included multiresistant members of the family Enterobactenaceae and Pseudomonas aeruginosa. Table 3 shows that most pathogens that caused wound infections after clindamycin-amikacin prophylaxis were still susceptible to both antibiotics, whereas more than half of the microorganisms isolated after sulbactam-ampicillin prophylaxis were resistant to the combination. As far as wound infections are considered, five patients had mixed infections with the following combinations of offending pathogens: for
ANTIMICROB. AGENTS CHEMOTHER.
PHAN ET AL.
2016
TABLE 1. Characteristics of the patients included in the study Characteristic
Sulbactamampicillin (group 1)
sulbactam
+
ampicillin
Clindamycinamikacin (group 2) 0
No. randomized
48
51
No. inevaluable Ineligible Lower gastrointestinal tract
6 0
8 1
3
0
0i
6)4
surgery
Other antibiotics (day 1) Surgery canceled Protocol violation
0
2 3 2
No. of evaluable patients
42
43
No. of males/no. of females
35/7
36/7
3 0
day after surgery ), bronchopneumoFIG. 1. Occurrence of wound infection ( nia (n), and bacteremia (E) after surgery in patients with head and neck cancer. Cl, no focus of infection.
Age (yr) Mean Range
56 42-80
58 21-86
Weight (kg) Mean Range
63 41-91
68 40-123
Cancer stage (no. II III IV Cancer
[%])
occurrence
2 (7) 11 (42) 13 (50)
4 (16) 11(45)
)
(no.)
Primary Recurrent Previous treatment (no.) Irradiation Chemotherapy Surgery Irradiation and chemotherapy Surgery and chemotherapy Surgery and irradiation No. irradiated/total no. tested Mean delay from irradiation (mo)
Type of present surgery (no. [%]) Total excision Subtotal excision Excision and radical neck dissection Excision and flap reconstruction Radical neck dissection
26 16
22 21
9 11 1
10 10 2 4 1 8 22/43 7
5
1 6 20/42 6
tam group, microbiological documentation of the infection
available for three of them, including one patient each with methicillin-susceptible S. aureus, P. aeruginosa, and Haemophilus influenzae. Among the 10 patients with bronchopneumonia from the clindamycin-amikacin group, microbiological documentation of the infection was available for 7 of them, including 1 with methicillin-resistant S. aureus, 1 with K pneumoniae, 1 with M. morganii combined with S. anginosus, 2 with E. coli, and 2 with M. morganii. Seven of 51 patients who had received clindamycin-amikacin developed early bronchopneumonia (12 h), (iii) potential for selective digestive decontamination to prevent bronchopneumonia, which has not been adequately prevented with the currently available regimens (1), (iv) use of topical antimicrobial agents to reduce the bacterial burden in heavily colonized patients (20, 22), and (v) reassessment of preventive measures in the operating room (gloves and masks are ineffective after several hours of use, and multiple surgical sites are difficult to manage aseptically). The two regimens tested in the study described here seemed to have similar efficacies in preventing postsurgical infections in patients undergoing surgery for head and neck cancer, although the small number of subjects in the study did not allow us to detect significant differences. It seems, however, that ampicillin-sulbactam was less effective than
2018
PHAN ET AL.
ANTIMICROB. AGENTS CHEMOTHER.
TABLE 4. Increased risk of infection at the Institut Jules Bordet from 1973 to the present and relation of infection to radical dissection as a marker for very major surgerys Year
1973 1976 1981
1982 1988 Present Study
Reference
9
10 25
27 11
No. of patients included
Antibiotic regimen
% of patients with: n Radical neck Infection dissection
pb
Placebo Ampicillin-cloxacillin
50 52
22 21
24 6
0.02
Ticarcillin (4 days) Carbenicillin
56 51
23 21
11 8
0.85
Carbenicillin, short (1 day) Carbenicillin, long (4 days)
72
14
14
68
15
10
0.52 0.58
Clindamycin (1 day) Clindamycin-netilmicin
37
22
43
19
16 9
Clindamycin-amikacin Ticarcillin-clavulanic acid
58 55
62 62
36
Clindamycin-amikacin Ampicillin-sulbactam
43 42
81 82
20
10
33
Vol. 36, No. 9
Antimicrobial Prophylaxis for Major Head and Neck Surgery in Cancer Patients: Sulbactam-Ampicillin versus Clindamycin-Amikacin M. PHAN,1 P. VAN DER AUWERA,l* G. ANDRY,2 M. AOUN,1 G. CHANTRAIN,2 R. DERAEMAECKER,2 P. DOR,2 D. DANEAU,' P. EWALENKO,3 AND F. MEUNIER1t Infectious Diseases and Microbiology Laboratory, Service de Me6decine et Laboratoire d'Investigation Clinique H. J. Tagnon, 1 Department of Head and Neck Cancer Surgery,2 and Anesthesiology and Surgical Intensive Care Unit, 3 Institut Jules Bordet, Centre des Tumeurs de l'Universite6 Libre de Bru"elles, rue Heger-Bordet 1, B-1000 Brussels, Belgium Received 27 January 1992/Accepted 24 June 1992
A total of 99 patients with head and neck cancer who were to undergo surgery were randomized in a prospective comparative study of sulbactam-ampicillin (1:2 ratio; four doses of 3 g of ampicillin and 1.5 g of sulbactam intravenously [i.v.] every 6 h) versus clindamycin (four doses of 600 mg i.v. every 6 h)-amikacin (two doses of 500 mg i.v. every 12 h) as prophylaxis starting at the induction of anesthesia. The two groups of evaluable patients (43 in the clindamicin-amikacin treatment group and 42 in the sulbactam-ampicillin treatment group) were comparable as far as age (mean, 57 years; range, 21 to 84 years), sex ratio (71 males, 28 females), weight (mean, 66 kg; range, 40 to 69 kg), indication for surgery (first surgery, 48 patients; recurrence, 37 patients), previous anticancer treatment (surgery, radiation therapy, chemotherapy), type of surgery, and stage of cancer. The overall infection rate (wound, bacteremia, and bronchopneumonia) within 20 days after surgery was 20 patients in each group. Wound infections occurred in 14 (33%) sulbactamampicillin-treated patients and 9 (21%) clindamycin-amikacin-treated patients (P = 0.19; not significant). The rates of bacteremia were 2 and 4%, respectively. The rates of bronchopneumonia were 14.3 and 23.2%, respectively (P was not significant). Most infections were polymicrobial, but strict anaerobes were recovered only from patients who received sulbactam-ampicillin. Antimicrobial treatment was required within 20 days after surgery for 42% of the sulbactam-ampicillin-treated patients and 44% of the clindamycin-amikacintreated patients. By comparison with previous studies, we observed a decreased efficacy of antimicrobial prophylaxis in patients with head and neck cancer undergoing surgery because of the increased proportion of patients who were at very high risk for infection (extensive excision and plastic reconstruction in patients with recurrent stage III and IV cancers) and because of the longer durations of surgery.
It has been proven and widely accepted that patients with head and neck cancer undergoing surgery (clean contaminated procedures) benefit from preoperative antibiotic prophylaxis once the skin and oropharyngeal cavities are opened (5, 17, 18, 27, 30). Simple laryngectomy has been associated with a very low risk of infection (5 cm of erythema and induration). A mucocutaneous fistula also reflected a wound infection. This definition corresponds to grades 4 and 5 of Johnson and colleagues (5, 16-20). All wound specimens (swabs or syringe aspirates) were processed microbiologically both for aerobic and anaerobic culture, in addition to analysis of volatile fatty acids by gas-liquid chromatography to indicate the presence of strict anaerobes (26). Pulmonary infection was characterized by the production of purulent sputum, radiological signs of bronchopneumonia, and/or rales. The minimal criteria for the diagnosis of pneumonia were a new infiltrate on the chest X ray and purulent sputum in a febrile (>38°C) patient. Microorganisms isolated from the patients were considered significant pathogens if they were present on Gram staining and were isolated in pure culture or as the predominant microorganisms. A delay to the time of infection corresponded to the time between surgery and the first signs or symptoms of infection at each relevant site. In vitro susceptibility testing of aerobes and facultative bacteria was done by the disk diffusion method described by the National Committee for Clinical Laboratory Standards (25a). Anaerobes were tested by disk diffusion on blood agar by using the Rosco agar disk diffusion method (7a). The respective Neosensitab disks (Rosco) contained 25 ,ug of clindamycin and 30 ,ug each of ampicillin and sulbactam. Anaerobes were tested on Mueller-Hinton agar with 5%
2015
horse blood (Bio-Merieux, Marcy-l'Etoile, France). The corresponding breakpoints are diameters of .28 mm (susceptible) and c23 mm (resistant) for clindamycin and .32 mm (susceptible) and c24 mm (resistant) for the ampicillinsulbactam combination. Zone diameters were read after 48 h of incubation at 37°C under strictly anaerobic conditions. The strains used for quality control were Bacteroidesffragilis ATCC 25285 and Bacteroides thetaiotaomicron ATCC 29741; both strains are susceptible to ampicillin-sulbactam, B. fragilis is susceptible to clindamycin, and B. thetaiotaomicron is resistant to clindamycin. This method is similar to the method of Horn et al. (13), which has been validated by Barry et al. (2). The validity of a 1:1 ratio for the ampicillin-sulbactam test disk has recently been discussed extensively by Jenkins (15). Inclusion of 50 patients in each arm of the study had a power of 0.79 to detect a difference in cure rate of 0.20 (from 0.65 to 0.85) with an alpha error of 0.1 (single tailed). All statistical tests were done with Macintosh SE/30 hardware and Statview 512+ software (Version 1.1, 1986; Abacus Concepts). Comparisons of proportions were done by using a chi-square test with Yates continuity correction. Single-tailed tests were done to assess statistical significance. A result was considered statistically significant if the P value was c0.05. RESULTS The two groups of patients were very similar, as shown in Table 1. Most patients had a very poor prognosis, as exemplified by the large proportion of patients with stage III and IV cancers on the one hand and recurrent disease on the other. All patients had involvement of the oropharyngeal cavity. Similarly, most of them underwent very extensive surgery in addition to neoadjuvant chemotherapy and radiation therapy. Total tumor excision and bilateral radical neck dissection with plastic reconstruction, including free flap reconstruction, corresponds to a prolonged surgical procedure with a time range of 12 to 24 h. Figure 1 shows the time delay from the time of surgery to the appearance of infectious complications. Because of the small number of patients included in the study, we were not able to show a significant difference in the rate of postoperative wound infection, bacteremia, or bronchopneumonia (Table 2). However, strict anaerobes were not isolated from patients who developed infections after clindamycin-amikacin prophylaxis, whereas strict anaerobes were associated with the wound infections of six patients in the sulbactam-ampicillin group. A similar proportion (42 and 44%, respectively) of the patients required antibiotic treatment within 20 days of surgery for a proven or suspected infection. This proportion corresponds to the overall failure rate of the two prophylactic regimens. The pathogens isolated from wound infections are listed in Table 3. Staphylococci were the most prevalent bacteria among the gram-positive organisms. Most gram-negative bacilli were typically of nosocomial origin and included multiresistant members of the family Enterobactenaceae and Pseudomonas aeruginosa. Table 3 shows that most pathogens that caused wound infections after clindamycin-amikacin prophylaxis were still susceptible to both antibiotics, whereas more than half of the microorganisms isolated after sulbactam-ampicillin prophylaxis were resistant to the combination. As far as wound infections are considered, five patients had mixed infections with the following combinations of offending pathogens: for
ANTIMICROB. AGENTS CHEMOTHER.
PHAN ET AL.
2016
TABLE 1. Characteristics of the patients included in the study Characteristic
Sulbactamampicillin (group 1)
sulbactam
+
ampicillin
Clindamycinamikacin (group 2) 0
No. randomized
48
51
No. inevaluable Ineligible Lower gastrointestinal tract
6 0
8 1
3
0
0i
6)4
surgery
Other antibiotics (day 1) Surgery canceled Protocol violation
0
2 3 2
No. of evaluable patients
42
43
No. of males/no. of females
35/7
36/7
3 0
day after surgery ), bronchopneumoFIG. 1. Occurrence of wound infection ( nia (n), and bacteremia (E) after surgery in patients with head and neck cancer. Cl, no focus of infection.
Age (yr) Mean Range
56 42-80
58 21-86
Weight (kg) Mean Range
63 41-91
68 40-123
Cancer stage (no. II III IV Cancer
[%])
occurrence
2 (7) 11 (42) 13 (50)
4 (16) 11(45)
)
(no.)
Primary Recurrent Previous treatment (no.) Irradiation Chemotherapy Surgery Irradiation and chemotherapy Surgery and chemotherapy Surgery and irradiation No. irradiated/total no. tested Mean delay from irradiation (mo)
Type of present surgery (no. [%]) Total excision Subtotal excision Excision and radical neck dissection Excision and flap reconstruction Radical neck dissection
26 16
22 21
9 11 1
10 10 2 4 1 8 22/43 7
5
1 6 20/42 6
tam group, microbiological documentation of the infection
available for three of them, including one patient each with methicillin-susceptible S. aureus, P. aeruginosa, and Haemophilus influenzae. Among the 10 patients with bronchopneumonia from the clindamycin-amikacin group, microbiological documentation of the infection was available for 7 of them, including 1 with methicillin-resistant S. aureus, 1 with K pneumoniae, 1 with M. morganii combined with S. anginosus, 2 with E. coli, and 2 with M. morganii. Seven of 51 patients who had received clindamycin-amikacin developed early bronchopneumonia (12 h), (iii) potential for selective digestive decontamination to prevent bronchopneumonia, which has not been adequately prevented with the currently available regimens (1), (iv) use of topical antimicrobial agents to reduce the bacterial burden in heavily colonized patients (20, 22), and (v) reassessment of preventive measures in the operating room (gloves and masks are ineffective after several hours of use, and multiple surgical sites are difficult to manage aseptically). The two regimens tested in the study described here seemed to have similar efficacies in preventing postsurgical infections in patients undergoing surgery for head and neck cancer, although the small number of subjects in the study did not allow us to detect significant differences. It seems, however, that ampicillin-sulbactam was less effective than
2018
PHAN ET AL.
ANTIMICROB. AGENTS CHEMOTHER.
TABLE 4. Increased risk of infection at the Institut Jules Bordet from 1973 to the present and relation of infection to radical dissection as a marker for very major surgerys Year
1973 1976 1981
1982 1988 Present Study
Reference
9
10 25
27 11
No. of patients included
Antibiotic regimen
% of patients with: n Radical neck Infection dissection
pb
Placebo Ampicillin-cloxacillin
50 52
22 21
24 6
0.02
Ticarcillin (4 days) Carbenicillin
56 51
23 21
11 8
0.85
Carbenicillin, short (1 day) Carbenicillin, long (4 days)
72
14
14
68
15
10
0.52 0.58
Clindamycin (1 day) Clindamycin-netilmicin
37
22
43
19
16 9
Clindamycin-amikacin Ticarcillin-clavulanic acid
58 55
62 62
36
Clindamycin-amikacin Ampicillin-sulbactam
43 42
81 82
20
10
33
