Use of Aminoglycosides in Surgical Infections H. HARLAN STONE, M.D., LAURA D. KOLB, B.S., CAROL E. GEHEBER, B.S., E. JANELLE DAWKINS, B.S.
Most infections on the surgical ward are due to one or more gram-negative rods, acting either as the sole pathogens or as principal components in a polymicrobial flora. To date, parenteral aminoglycosides have proven to be the most effective antibiotics for control or treatment of such sepsis. Unfortunately, however, serious complications as well as therapeutic failures do occur. During a 40-month period, 405 surgical patients receiving aminoglycosides (Gentamicin, Tobramycin, Sisomicin, or Amikacin) were prospectively studied with respect to: indications for the antibiotic; patient population; serum concentrations of antibiotic according to route of administration, dose in mg/kg/day, and renal function; rapidity of antibiotic excretion in the urine; causative bacteria and their sensitivities to each aminoglycoside as determined by both disc and tube dilution methods; severity and frequency of drug complications; and clinical efficacy of each study antibiotic. Results supported the contention of a superior effectiveness from aminoglycosides for established abdominal and unspecified surgical infections, more rapid development of therapeutic blood levels by intravenous administration, need to alter drug dose according to frequent serum creatinine determinations, increased drug toxicity in dehydrated and shocked patients, preventability of complicating Candida sepsis, and the importance of early as well as adequate surgical debridement and drainage.
THE MAJORITY of infections on any surgical ward are usually due to one or more of the gram-negative bacilli.7 Such pathogens either act singly, as is the case with most hospital acquired infections, or instead participate in the creation of a bacterial synergism by combining with various other aerobic species and, perhaps even more commonly, with a multitude of heretofore seldom recognized anaerobes.6 Although surgical therapy in the form of abscess drainage, debridement of necrotic tissue, or other procedure is unquestionably important, antibiotics nevertheless play a significant role Supported by grants from Eli Lilly and Company, the Corporation, and Bristol Laboratories.
From the Department of Surgery,
Emory University School of Medicine 69 Butler Street, Atlanta, Georgia 30303
in the overall control of sepsis. Of the different groups of antimicrobials that have been used to treat these infections, aminoglycosides have proven to be the most reliably effective of all such agents.7 During the 40-month period ending 30 April 1975, 405 patients on the Trauma, Burn, and Pediatric Surgical Services at Grady Memorial Hospital received one or more courses of therapy with a parenteral aminoglycoside. During the first 4-month period, Tobramycin was the antibiotic almost routinely selected. Thereafter, in three equal 12-month intervals, the antibiotics administered were, respectively: a randomization (according to odd and even hospital numbers) between Tobramycin and Gentamicin; Sisomicin alone; and similar randomization between Amikacin and Gentamicin. Criteria demanded for case inclusion in the study were: 1) a presumed or already proven gram-negative infection which could at least potentially be cultured; and 2) a drug permission form sighed by either the informed patient himself or an appropriate family member or guardian. Procedures
The usual dose of Gentamicin, Sisomicin and Tobramycin was 1 mg per kilogram of body weight, administered intramuscularly or intravenously every 8 hours.7 That for Amikacin, an antibiotic closely akin to Kanamycin, was 5 mg per kg of body weight, given similarly and according to the same time schedule. Any impairment Schering in renal function dictated a longer interval between times of antibiotic administration, with the serum creatinine 660
Vol. 183 . NO. 6
AMINOGLYCOSIDES
661
TABLE 1. Response of Infections to Aminoglycoside Therapy Number of Patients
Apparent Cure
Controlled, Then Recurred
No Response
Candida Sepsis
201 96 17 30 23 15 23 405
185 84 14 14 18 8 12 335
9 5
6 3 2 3 3 4 1 22
1 4
Generalized peritonitis Intra-abdominal abscess
Cholecystitis/cholangitis Burn Wound Sepsis* Other Wound Infections* Pneumonia/empyema* Miscellaneous Totals *
5 1 2 2 24
Indeterminate Cases
1
8 1 1 8 10
14
Significantly poorer response to therapy than other categories (P = 0.05)
being used as the multiplying factor. For example, a serum creatinine of 3 mg% indicated that the aminoglycoside should be given only every 24 hours, that is, 8 hours multiplied by the serum creatinine of three. Whenever possible, cultures of the foci responsible for sepsis were processed by anaerobic as well as aerobic techniques. Even though speciation was accomplished for both, antibiotic sensitivities generally were run only on the aerobic isolates. Both disc1 and tube dilution4 methods for antibiotic susceptibility were employed. Patients were monitored for effectiveness of antibiotic in controlling or eliminating the infection, pharmacology of each drug with respect to blood levels and urinary excretion,8 and potential for aminoglycoside toxicity.2,3'7 The latter included routine blood counts, basic liver function tests, evaluation of renal function (urine analysis, blood urea nitrogen, serum creatinine, and clearances of both urea and creatinine), and tests for function of the eighth cranial nerve (audiograms and electronystagmograms).2 An attempt was made to obtain such studies prior to, during, and after therapy in each case; yet this was not always possible. The clinical course of the patient and benefits of specific surgical procedures were also recorded. After completion of therapy, analyses were made in order to determine antibiotic efficacy and safety. Other factors, such as ideal dosage of the several aminoglycosides, importance of host resistance, and proper role of surgery, were likewise considered.
Results The average age for the 405 patients was 34 years, with a range of 10 months to 89 years. There were 309 Negroes, 95 Caucasians, and one American Indian. The sex ratio was 258 males to 147 females. No significant differences were noted between the individual antibiotic categories. The majority of patients had peritoneal infections, with 201 cases of generalized peritonitis and 96 with intra-abdominal abscesses (Table 1). Sepsis arising from a burn or other woiund accounted for an additional 53 patients. Infections of the biliary tract, lung, and various other areas made up the remaining 55 cases. The distribution of forms of sepsis among the several study antibiotics did not vary significantly, that is with the single exception that Amikacin was administered only half as frequently as were the other antimicrobials
(Table 2). Pharmacology Antibiotic therapy was given for an average of 10 days, with a range varying from three to 29 days. In general, previously stated goals of antibiotic dosage and frequency of administration were routinely met. Blood levels achieved with Gentamicin, Sisomicin, and Tobramycin were quite similar (Fig. 1). Following an intramuscular injection of 1 mg/kg of body weight, serum concentrations averaged 2.2 mcg/ml at 2 hours,
TABLE 2. Response of Sepsis to Aminoglycoside Therapy
Tobramycin Gentamicin Sisomicin Amikacin Totals
Number of Patients
Apparent
Controlled,
No
Candida
Cure
Then Recurred
Response
Sepsis
Indeterminate Cases
129 107 114 55 405
103 91 100 41 335
8 6 6 4 24
6 5 5 6* 22
8t 3 1 2 14
4 2 2 2 10
* Significantly lower response rate with Amikacin (P = 0.05). t Significantly greater incidence of complicating Candida sepsis (P = 0.05).
662
STONE AND OTHERS
4F
Ann. Surg. a June 1976
6
Sisomicin 0-a Gentamicin 0---_ Tobramycin Range Dose: lmg/Kg (intramuscular)
31
2[
o---o IV. in 5 min. I.V. in 30 min.
DOSE: I mg/kg
E
N
E
E
IIM.
4
2
l1 2
4
t
2
4-
Injection
05
6
8
HOURS
Injection
FIG. 3. Serum levels of sisomicin after various routes of parenteral administration.
HOURS
reaffirmed in all cases. An average of 67% of administered antibiotic could be recovered in the urine at 6 hours; 86%, by 12 hours (Fig. 4). This dependence on normal 0.9 mcg/ml at 6 hours, and 0.2 mcg/ml at 12 hours. renal function was well exemplified by the inverse relaValues obtained for Amikacin were approximately four tionship of serum creatinine to rapidity of antibiotic times these. As expected, the greater the dose given as excretion (Fig. 5). In patients whose serum creatinine expressed in mg/kg of body weight, the higher the peak was 4 mgo or higher, the serum level of aminoglycoside serum level became and the longer the antibiotic could noted at 6 hours was consistently greater than the peak be detected in circulating blood (Fig. 2). The intravenous route gave much higher and more immediate blood con100r centrations, although serum levels at 6 and 8 hours were not significantly different regardless of the mode of ,87% administration (Fig. 3). 80The renal mechanism for aminoglycoside excretion was FIG. 1. Average serum concentrations of aminoglycoside following intramuscular injection at a dose of lmg/kg body weight.
an
0
a*
/o
..-
601
t
c._ 48
40 It
E
Range
- ^ Sisomicin °-o Gentomicin
20
0-6 Tobromycin
Dose: a
i
1
a
2
3
4
5
6
HOURS
FIG. 2. Serum levels of aminoglycoside following graded doses of sisomicin given intramuscularly.
t
2
4
6
Img/ Kg 1L M. I
8
I
10
.I
12
Injection
HOURS FIG. 4. Per cent of aminoglycoside recoverable from the urine after intramuscular injections at a dose of lmg/kg body weight.
Vol. 183 No. 6
AMINOGLYCOSIDES
663 blood concentration achieved at 1 and 2 hours with a similarly administered dose of the antibiotic in individuals with relatively normal renal function.
Bacteriology
E%
Almost 75% of the 530 aerobic bacterial isolates were gram-negative rods (Tables 3 and 4). E. coli represented approximately half of these. Nevertheless, one or more anaerobic species could be grown from the principle site of infection in almost 88% of the cases. Indeed, a polymicrobial flora was generally the rule rather than the exception. Sensitivity testing demonstrated no significant difference between any of the new study antibiotics, i.e., Tobramycin, Sisomicin, and Amikacin (Tables 3 and 4). This was true for both disc and tube dilution methods. Somewhat lower minimal inhibitory concentrations for those agents with less exposure to hospital pathogens was generally noted on comparing their action to that of gentamicin. Kanamycin and Cephalophin were definitely inferior antibiotics in regard to most gram-negative rods, although the cephalosporin was essentially equivalent to the study aminoglycosides on testing against Staphylo-
4-
2
Injection I mg/ kg
4
coccus aureus.
HOURS
FIG. 5. Serum levels of sisomicin noted after an intramuscular injection (at 1 mg/kg body weight) in patients with varying renal functions as exhibited by individual serum creatinine concentrations.
Outcome Survival of the patient was considerably dependent upon the seriousness of the infection. As categorized
TABLE 3. Disc Sensitivities of Bacterial Isolates Per cent of Isolates Sensitive
E.coli
Kleb-Enterobacter Ps. aeruginosa Proteus sp. Misc. gram-negative rods Enterococcus Staph. aureus Streptococcus
Number of Isolates
Tobramycin (10 mcg)
Gentamicin (10 mcg)
Sisomicin (10 mcg)
Amikacin (10 mcg)
Kanamycin
Cephalothin
(30 mcg)
(30 mcg)
206 73 61 52 33 67 32 6
99 99 97 92 97 16 97 17
99 100 95 92 97 85 100 17
100 100 99 92 97 25 100 17
96 93 84 87 94 6 94 17
87 91 0 87 88 -
63 38 0 58 64 16 100 100
TABLE 4. Tube Dilution Sensitivities of Bacterial Isolates
E. coli Kleb-Enterobacter Ps. aeruginosa Proteus sp. Misc. gram-negative rods
Enterococcus
Staph. aureus Streptococcus
Average Minimal Inhibitory Concentration (mcg/ml)
Number of Isolates
Tobramycin
Gentamicin
Sisomicin
Amikacin
Kanamycin
Cephalothin
206 73 61 52 33 67 32 6
3.94 3.01 .77 8.22 8.25 34.28 1.06 22.50
3.61 2.37 2.87 6.36 5.56 17.01 .06 31.25
2.73 1.37 .43 4.29 5.58 26.50
11.27 9.05 3.87 17.94 9.69 31.81 1.96 12.05
13.48 9.75 42.54 18.76 17.82
17.72 17.95 48.33 15.42 35.48 20.88 1.09 .10
.06 16.25
-
664
Ann. Surg. * June 1976
STONE AND OTHERS
TABLE 5. Response According to Identified Pathogens Number of Patients E. coli Kleb-Enterobacter Ps. aeruginosa Proteus sp. Mixed gram-negatives Staph. aureus Streptococcus Enterococcus Anaerobes Mixed (aerobes & anaerobes) No growth No culture Indeterminate Totals
37 13 26 15 62 12 3 5 17 176 21 8 10 405
Bacterial Sepsis
Died of Bacterial Sepsis
Complicating Candida Sepsis
1 2 1 1 4
9
1 13
2 11
3
24
22
14
Cured
Recurred
35 11 14 12 51 2 3 5 14 149 21 8
1 2 2 5 -
335
by temperature., magnitude of leukocytosis, and presence of shock, septic patients considered to be critical had a mortality of 25%, while those judged to have only mild or moderately serious infections had fatality rates of 2%. The overall mortality rate for the entire series was 10. 1%.Cnlun 10.1%. . . Significantly poorer results to antibiotic therapy were noted in patients with extra-abdominal sepsis, that is, in cases of burn and other wound infections and in patients with gram-negative pneumonia (Table 1). In addition, failure to respond to treatment with antibiotics was more likely in those patients given amikacin than when therapy was based upon one of the other study aminoglycosides (Table 2). Refractory infections were more commonly those caused by a mixture of gram-negative rods, especially when such pathogens were acting in symbiosis with anaerobic species (Table 5). Complicating the analysis of these results was the apparently increased incidence of Candida sepsis5'7 in cases of burn wound infection, intra-abdominal abscess, fungemia following treatment with Tobramycin, and when the infecting bacterium was Pseudomonas aeruginosa (Tables 1, 2, and 5). Such conclusions were spurious, however, as they were drawn from data obtained from patients
2
treated earlier in the study and thus before the routine administration of oral nystatin prophylaxis. Cause of Death
Continuing or recurrent bacterial sepsis accounted for rrcretbcellspl cone o 21 of the 41 deaths. Nine other fatalities were unrelated to the initial infection. Ten deaths, however, were due directly to a complicating candidiasis. As noted abov'e, appropriate prophylaxis with oral nystatin essentially
eliminated the occurrence of this one problem in the later
caseS.5 . .
Forty-three instances of antibiotic related complications developed in 30 of the 405 patients (Table 6). Varying degrees of nephrotoxicity were the most common of these complications. Such was noted in 22 or 5% of the total series, although pre-existing shock and/or severe dehydration appeared to be the primary cause for the renal failure in 16 of the cases. A pure drug-induced effect could be incriminated in only 6 of the patients. Ototoxicity developed in 6 patients, an overall incidence of just over 1%. In 3 of the patients, it affected
TABLE 6. Complications of Parenteral Aminoglycosides
Tobramycin Renal Toxicity drug alone with shock/dehydration
Gentamicin
2 6
2 5
1 2
2 1
8
3 2 96 107
Sisomicin 1 3
Amikacin
Total
1 2
6 16
1
4 3
2 2 49 55
14 10 365 405
Ototoxicity cochlear vestibular New Pathogen Candida Sepsis Indeterminate No Complication Total Patients
4
111 129
1 2 109 114
Vol. 183
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6
AMINOGLYCOSIDES
665
TABLE 7. Response of Sepsis to Drainage (Drainage inclusive of debridement, as warranted)
Already draining Spontaneous drain Operative drainage Never drained** Indeterminate Totals
49 92 136 118 10 405
Complicating Candida Sepsis*
Cured
Recurred
Died of Bacterial Sepsis
35 83 122 93
2 2 3 17
2 2 4 14
8 1 5
335
24
22
14
Bacterial Sepsis
Number of Patients
* Candida sepsis developed almost solely in patients with extensive thermal burns or intestinal fistulas. ** Significantly increased rates in mortality and recurrence of bacterial sepsis (P = 0.01) for both).
charging pus prior to the initiation of antibiotic therapy or subsequently drained through either spontaneous rupture of the abscess or purposeful surgical incision (Table 7). The establishment of such drainage favorably influenced the likelihood of permanent cure, decreased the risk of death from the primary infection, and lessened chances of recurrence of sepsis as well. Susceptibility of responsible pathogens to the individual antibiotic administered was also important (Table 8). For example, if the bacterial flora was universally resistant to the antimicrobial given, the mortality for such cases was 9%; and the rate for recurrence of sepsis, 11%. If, however, all species of identifiable pathogens were susceptible to the administered antibiotic, comparable rates were 5% for the mortality and 4% for infection recrudescence. Just as critical to eventual survival, if not even more so, was the presence of a disease state that caused an impairment in host resistance. Comparison of the outcome for those 149 patients with an altered immune response to the results obtained in the 246 individuals presumed to have a relatively normal resistance mechanism reflected a striking difference, that is, mortalities of 19 and 2% respectively, due to sepsis. Even after exclusion of patients dying from Candida sepsis., the difference was still highly significant (P = 0.01). When the relative importance of these three aspects of Determinants of Response to Therapy surgical infections were compared-drainage of the Drainage of the surgical infection was exceedingly septic process, pathogen susceptibility to the adminisimportant, irrespective as to whether the area was dis- tered antibiotic, and competence of the host defense
the cochlear division; a vestibular injury occurred in two; while both components of the eighth cranial nerve showed damage in the sixth patient. In each instance, some additional factor seemed to play a major role in causing the inner ear derangement. Specifically, a significant reduction in renal function and thus antibiotic excretion was noted in 5 patients; neomycin had been applied topically and thereby absorbed in four; and prolonged aminoglycoside therapy had been given to two. There was recovery from the renal injury in all patients who survived, yet kidney failure significantly contributed toward death in the remainder. By contrast, no measureable improvement could be detected in eighth nerve function in any of the patients who demonstrated ototoxicity. No instances of myoneural blockade causing respiratory arrest were noted. Candida sepsis was an extremely serious complication and was itself the basic cause for death in 10 of the 14 patients who acquired this superinfection. The majority of these cases were noted earlier in the study and led to a frightening 8% incidence of Candida sepsis. Following appropriate prophylaxis, once it was realized that intestinal persorption was the usual portal for entry of such fungi,5 the frequency of this one complication was reduced dramatically-to less than 1%.
TABLE 8. Importance of Bacterial Susceptibility to Aminoglycoside Number of Patients All isolated pathogens resistant Only one isolated pathogen sensitive All isolated pathogens sensitive No growth/no culture Indetenninate Totals
47 197 122 29 10 405
Complicating
Cured
Recurred
Died of Bacterial Sepsis
36 166 104 29
5 14 5
4 12 6
2 5 7
335
24
22
14
Bacterial Sepsis
Candida Sepsis
666
STONE AND OTHERS
Ann. Surg. * June 1976
mechanism-the value of antibiotic therapy was the least impressive of all. The chances for altering the course of a surgical infection by treatment with an antimicrobial was significant at a probability of only P = 0.10, while the significance for benefit by drainage and an effective host defense mechanism was at the 0.01 level.
supported by the other. Although aerobic gram-negative rods can survive alone, the anaerobes are totally dependent upon the immediate proximity of necrotic tissue or locally available aerobic species.6 Accordingly, elimination or a significant reduction in the population of the aerobic component will lead to death of most of the anaerobes provided that the volume of necrotic tissue Comment is not great. This may well be the true explanation for an Infections due solely to aerobic gram-negative rods apparent benefit gained from antibiotics lacking activity consistently respond to parenteral aminoglycoside against anaerobic bacteria. therapy whenever the area of sepsis has a good blood References supply, all species of pathogenic bacteria are sensitive M: to the administered antibiotic, host defense mechanisms 1. Bauer, A. W., Kirby, W. M. M., Sherris, J. D. and Tuck Antibiotic Susceptibility Testing by a Standardized Single are routinely normal, and the amount of necrotic tissue Disk Method. Am. J. Clin. Pathol., 45:493, 1966. is negligible.7 Drainage of the infection can usually over- 2. Cox, R. H. and Spongberg, A. K.: Electronystagmography: One Year's Experience at Ochsner Clinic. South. Med. J., 65: come any significant deficiencies in the above, that is, 38, 1972. necrotic of accumulation antibiotic-resistant bacteria, 3. Davia, J. E., Siemsen, A. W. and Anderson R. W.: Uremia, debris, and an altered immune response. Thus, the major Deafness, and Paralysis Due to Irrigating Antibiotic Solutions. Arch. Intern. Med., 125:135, 1970. role of antibiotic therapy often becomes the mere control 4. Gavan, T. L. and Town, M. A.: A Microdilution Method for of sepsis until drainage and/or surgical debridement can Antibiotic Susceptibility Testing: An Evaluation. Am. J. Clin. be achieved. Pathol., 53:880, 1970. H. H., Kolb, L. D., Currie, C. A., et al.: Candida Why patients with infections due to a mixed bacterial 5. Stone, Sepsis; Pathogenesis and Principles of Treatment. Ann. Surg., flora-including aminoglycoside-resistant anaerobes179:697, 1974. respond to such antibiotic therapy has been poorly 6. Stone, H. H., Kolb, L. D. and Geheber, C. E.: Incidence and Significance of Intraperitoneal Anaerobic Bacteria. Ann. Surg., understood. However, these symbiotic bacterial re181:705, 1975. lationships are based upon the anaerobe providing en- 7. Stone, H. H., Kolb, L. D., Geheber, C. E. and Currie, C. A.: Treatment of Surgical Infections with Tobramycin. Am. zymes for tissue digestion and thus nutrient assimilation Surg., 41:301, 1975. for all participating species, while the aerobes maintain a 8. Winters, R. E., Litwack, K. D. and Hewitt, W. L.: Relation lowered oxidation-reduction potential through use of all Between Dose and Levels of Gentamicin in Blood. J. Infect. Dis., 124:590, 1971 available oxygen. Each set of partners is thereby
DISCUSSION DR. BOYD W. HAYNES, JR. (Richmond, Virginia): The Bard Parker is still the best treatment for abdominal sepsis, where pus is present; that pus is thoroughly drained is still laudable. However, he was a little surprising to me when he stated that the antibiotic sensitivity of the given organisms doesn't seem to be as important as many of us think. In our experience, the treatment of gram negative infections, particularly on the burn wound, is often difficult to manage, because, although there is a relatively high sensitivity to gentamicin, and it certainly is the best agent available now to treat that particular spectrum of gram negative organisms, there appears to be a group of
pseudomonads now appearing on our wounds which don't seem to be sensitive as they were previously. This is of some concern to me, and I would like Dr. Stone's comment about this, and also if he as
thinks that the addition of carbenicillin adds a significant method of control to gram negative sepsis of this type. DR. H. HARLAN STONE (Closing discussion): The greater importance of host resistance and drainage over antibiotic susceptibility was somewhat amazing to us. If the infection was already draining, antibiotics were effective in determining and controlling which bacteria colonized the wound and thereby would subsequently invade. However, if drainage was accomplished by operation or developed spontaneously, the correlation of antibiotic sensitivities and clinical effectiveness was poor. I agree with Dr. Haynes' comment that, should there be established drainage, and yet sepsis is still a problem, then antibiotics become quite useful in controlling bacteremia until local wound care can reverse the process. Nevertheless, it is crucial that the antibiotic reach the primary site of infection. For example, parenteral agents for burn wound sepsis fail to work anywhere near as well as do the various topical antimicrobials.
Most infections on the surgical ward are due to one or more gram-negative rods, acting either as the sole pathogens or as principal components in a polymicrobial flora. To date, parenteral aminoglycosides have proven to be the most effective antibiotics for control or treatment of such sepsis. Unfortunately, however, serious complications as well as therapeutic failures do occur. During a 40-month period, 405 surgical patients receiving aminoglycosides (Gentamicin, Tobramycin, Sisomicin, or Amikacin) were prospectively studied with respect to: indications for the antibiotic; patient population; serum concentrations of antibiotic according to route of administration, dose in mg/kg/day, and renal function; rapidity of antibiotic excretion in the urine; causative bacteria and their sensitivities to each aminoglycoside as determined by both disc and tube dilution methods; severity and frequency of drug complications; and clinical efficacy of each study antibiotic. Results supported the contention of a superior effectiveness from aminoglycosides for established abdominal and unspecified surgical infections, more rapid development of therapeutic blood levels by intravenous administration, need to alter drug dose according to frequent serum creatinine determinations, increased drug toxicity in dehydrated and shocked patients, preventability of complicating Candida sepsis, and the importance of early as well as adequate surgical debridement and drainage.
THE MAJORITY of infections on any surgical ward are usually due to one or more of the gram-negative bacilli.7 Such pathogens either act singly, as is the case with most hospital acquired infections, or instead participate in the creation of a bacterial synergism by combining with various other aerobic species and, perhaps even more commonly, with a multitude of heretofore seldom recognized anaerobes.6 Although surgical therapy in the form of abscess drainage, debridement of necrotic tissue, or other procedure is unquestionably important, antibiotics nevertheless play a significant role Supported by grants from Eli Lilly and Company, the Corporation, and Bristol Laboratories.
From the Department of Surgery,
Emory University School of Medicine 69 Butler Street, Atlanta, Georgia 30303
in the overall control of sepsis. Of the different groups of antimicrobials that have been used to treat these infections, aminoglycosides have proven to be the most reliably effective of all such agents.7 During the 40-month period ending 30 April 1975, 405 patients on the Trauma, Burn, and Pediatric Surgical Services at Grady Memorial Hospital received one or more courses of therapy with a parenteral aminoglycoside. During the first 4-month period, Tobramycin was the antibiotic almost routinely selected. Thereafter, in three equal 12-month intervals, the antibiotics administered were, respectively: a randomization (according to odd and even hospital numbers) between Tobramycin and Gentamicin; Sisomicin alone; and similar randomization between Amikacin and Gentamicin. Criteria demanded for case inclusion in the study were: 1) a presumed or already proven gram-negative infection which could at least potentially be cultured; and 2) a drug permission form sighed by either the informed patient himself or an appropriate family member or guardian. Procedures
The usual dose of Gentamicin, Sisomicin and Tobramycin was 1 mg per kilogram of body weight, administered intramuscularly or intravenously every 8 hours.7 That for Amikacin, an antibiotic closely akin to Kanamycin, was 5 mg per kg of body weight, given similarly and according to the same time schedule. Any impairment Schering in renal function dictated a longer interval between times of antibiotic administration, with the serum creatinine 660
Vol. 183 . NO. 6
AMINOGLYCOSIDES
661
TABLE 1. Response of Infections to Aminoglycoside Therapy Number of Patients
Apparent Cure
Controlled, Then Recurred
No Response
Candida Sepsis
201 96 17 30 23 15 23 405
185 84 14 14 18 8 12 335
9 5
6 3 2 3 3 4 1 22
1 4
Generalized peritonitis Intra-abdominal abscess
Cholecystitis/cholangitis Burn Wound Sepsis* Other Wound Infections* Pneumonia/empyema* Miscellaneous Totals *
5 1 2 2 24
Indeterminate Cases
1
8 1 1 8 10
14
Significantly poorer response to therapy than other categories (P = 0.05)
being used as the multiplying factor. For example, a serum creatinine of 3 mg% indicated that the aminoglycoside should be given only every 24 hours, that is, 8 hours multiplied by the serum creatinine of three. Whenever possible, cultures of the foci responsible for sepsis were processed by anaerobic as well as aerobic techniques. Even though speciation was accomplished for both, antibiotic sensitivities generally were run only on the aerobic isolates. Both disc1 and tube dilution4 methods for antibiotic susceptibility were employed. Patients were monitored for effectiveness of antibiotic in controlling or eliminating the infection, pharmacology of each drug with respect to blood levels and urinary excretion,8 and potential for aminoglycoside toxicity.2,3'7 The latter included routine blood counts, basic liver function tests, evaluation of renal function (urine analysis, blood urea nitrogen, serum creatinine, and clearances of both urea and creatinine), and tests for function of the eighth cranial nerve (audiograms and electronystagmograms).2 An attempt was made to obtain such studies prior to, during, and after therapy in each case; yet this was not always possible. The clinical course of the patient and benefits of specific surgical procedures were also recorded. After completion of therapy, analyses were made in order to determine antibiotic efficacy and safety. Other factors, such as ideal dosage of the several aminoglycosides, importance of host resistance, and proper role of surgery, were likewise considered.
Results The average age for the 405 patients was 34 years, with a range of 10 months to 89 years. There were 309 Negroes, 95 Caucasians, and one American Indian. The sex ratio was 258 males to 147 females. No significant differences were noted between the individual antibiotic categories. The majority of patients had peritoneal infections, with 201 cases of generalized peritonitis and 96 with intra-abdominal abscesses (Table 1). Sepsis arising from a burn or other woiund accounted for an additional 53 patients. Infections of the biliary tract, lung, and various other areas made up the remaining 55 cases. The distribution of forms of sepsis among the several study antibiotics did not vary significantly, that is with the single exception that Amikacin was administered only half as frequently as were the other antimicrobials
(Table 2). Pharmacology Antibiotic therapy was given for an average of 10 days, with a range varying from three to 29 days. In general, previously stated goals of antibiotic dosage and frequency of administration were routinely met. Blood levels achieved with Gentamicin, Sisomicin, and Tobramycin were quite similar (Fig. 1). Following an intramuscular injection of 1 mg/kg of body weight, serum concentrations averaged 2.2 mcg/ml at 2 hours,
TABLE 2. Response of Sepsis to Aminoglycoside Therapy
Tobramycin Gentamicin Sisomicin Amikacin Totals
Number of Patients
Apparent
Controlled,
No
Candida
Cure
Then Recurred
Response
Sepsis
Indeterminate Cases
129 107 114 55 405
103 91 100 41 335
8 6 6 4 24
6 5 5 6* 22
8t 3 1 2 14
4 2 2 2 10
* Significantly lower response rate with Amikacin (P = 0.05). t Significantly greater incidence of complicating Candida sepsis (P = 0.05).
662
STONE AND OTHERS
4F
Ann. Surg. a June 1976
6
Sisomicin 0-a Gentamicin 0---_ Tobramycin Range Dose: lmg/Kg (intramuscular)
31
2[
o---o IV. in 5 min. I.V. in 30 min.
DOSE: I mg/kg
E
N
E
E
IIM.
4
2
l1 2
4
t
2
4-
Injection
05
6
8
HOURS
Injection
FIG. 3. Serum levels of sisomicin after various routes of parenteral administration.
HOURS
reaffirmed in all cases. An average of 67% of administered antibiotic could be recovered in the urine at 6 hours; 86%, by 12 hours (Fig. 4). This dependence on normal 0.9 mcg/ml at 6 hours, and 0.2 mcg/ml at 12 hours. renal function was well exemplified by the inverse relaValues obtained for Amikacin were approximately four tionship of serum creatinine to rapidity of antibiotic times these. As expected, the greater the dose given as excretion (Fig. 5). In patients whose serum creatinine expressed in mg/kg of body weight, the higher the peak was 4 mgo or higher, the serum level of aminoglycoside serum level became and the longer the antibiotic could noted at 6 hours was consistently greater than the peak be detected in circulating blood (Fig. 2). The intravenous route gave much higher and more immediate blood con100r centrations, although serum levels at 6 and 8 hours were not significantly different regardless of the mode of ,87% administration (Fig. 3). 80The renal mechanism for aminoglycoside excretion was FIG. 1. Average serum concentrations of aminoglycoside following intramuscular injection at a dose of lmg/kg body weight.
an
0
a*
/o
..-
601
t
c._ 48
40 It
E
Range
- ^ Sisomicin °-o Gentomicin
20
0-6 Tobromycin
Dose: a
i
1
a
2
3
4
5
6
HOURS
FIG. 2. Serum levels of aminoglycoside following graded doses of sisomicin given intramuscularly.
t
2
4
6
Img/ Kg 1L M. I
8
I
10
.I
12
Injection
HOURS FIG. 4. Per cent of aminoglycoside recoverable from the urine after intramuscular injections at a dose of lmg/kg body weight.
Vol. 183 No. 6
AMINOGLYCOSIDES
663 blood concentration achieved at 1 and 2 hours with a similarly administered dose of the antibiotic in individuals with relatively normal renal function.
Bacteriology
E%
Almost 75% of the 530 aerobic bacterial isolates were gram-negative rods (Tables 3 and 4). E. coli represented approximately half of these. Nevertheless, one or more anaerobic species could be grown from the principle site of infection in almost 88% of the cases. Indeed, a polymicrobial flora was generally the rule rather than the exception. Sensitivity testing demonstrated no significant difference between any of the new study antibiotics, i.e., Tobramycin, Sisomicin, and Amikacin (Tables 3 and 4). This was true for both disc and tube dilution methods. Somewhat lower minimal inhibitory concentrations for those agents with less exposure to hospital pathogens was generally noted on comparing their action to that of gentamicin. Kanamycin and Cephalophin were definitely inferior antibiotics in regard to most gram-negative rods, although the cephalosporin was essentially equivalent to the study aminoglycosides on testing against Staphylo-
4-
2
Injection I mg/ kg
4
coccus aureus.
HOURS
FIG. 5. Serum levels of sisomicin noted after an intramuscular injection (at 1 mg/kg body weight) in patients with varying renal functions as exhibited by individual serum creatinine concentrations.
Outcome Survival of the patient was considerably dependent upon the seriousness of the infection. As categorized
TABLE 3. Disc Sensitivities of Bacterial Isolates Per cent of Isolates Sensitive
E.coli
Kleb-Enterobacter Ps. aeruginosa Proteus sp. Misc. gram-negative rods Enterococcus Staph. aureus Streptococcus
Number of Isolates
Tobramycin (10 mcg)
Gentamicin (10 mcg)
Sisomicin (10 mcg)
Amikacin (10 mcg)
Kanamycin
Cephalothin
(30 mcg)
(30 mcg)
206 73 61 52 33 67 32 6
99 99 97 92 97 16 97 17
99 100 95 92 97 85 100 17
100 100 99 92 97 25 100 17
96 93 84 87 94 6 94 17
87 91 0 87 88 -
63 38 0 58 64 16 100 100
TABLE 4. Tube Dilution Sensitivities of Bacterial Isolates
E. coli Kleb-Enterobacter Ps. aeruginosa Proteus sp. Misc. gram-negative rods
Enterococcus
Staph. aureus Streptococcus
Average Minimal Inhibitory Concentration (mcg/ml)
Number of Isolates
Tobramycin
Gentamicin
Sisomicin
Amikacin
Kanamycin
Cephalothin
206 73 61 52 33 67 32 6
3.94 3.01 .77 8.22 8.25 34.28 1.06 22.50
3.61 2.37 2.87 6.36 5.56 17.01 .06 31.25
2.73 1.37 .43 4.29 5.58 26.50
11.27 9.05 3.87 17.94 9.69 31.81 1.96 12.05
13.48 9.75 42.54 18.76 17.82
17.72 17.95 48.33 15.42 35.48 20.88 1.09 .10
.06 16.25
-
664
Ann. Surg. * June 1976
STONE AND OTHERS
TABLE 5. Response According to Identified Pathogens Number of Patients E. coli Kleb-Enterobacter Ps. aeruginosa Proteus sp. Mixed gram-negatives Staph. aureus Streptococcus Enterococcus Anaerobes Mixed (aerobes & anaerobes) No growth No culture Indeterminate Totals
37 13 26 15 62 12 3 5 17 176 21 8 10 405
Bacterial Sepsis
Died of Bacterial Sepsis
Complicating Candida Sepsis
1 2 1 1 4
9
1 13
2 11
3
24
22
14
Cured
Recurred
35 11 14 12 51 2 3 5 14 149 21 8
1 2 2 5 -
335
by temperature., magnitude of leukocytosis, and presence of shock, septic patients considered to be critical had a mortality of 25%, while those judged to have only mild or moderately serious infections had fatality rates of 2%. The overall mortality rate for the entire series was 10. 1%.Cnlun 10.1%. . . Significantly poorer results to antibiotic therapy were noted in patients with extra-abdominal sepsis, that is, in cases of burn and other wound infections and in patients with gram-negative pneumonia (Table 1). In addition, failure to respond to treatment with antibiotics was more likely in those patients given amikacin than when therapy was based upon one of the other study aminoglycosides (Table 2). Refractory infections were more commonly those caused by a mixture of gram-negative rods, especially when such pathogens were acting in symbiosis with anaerobic species (Table 5). Complicating the analysis of these results was the apparently increased incidence of Candida sepsis5'7 in cases of burn wound infection, intra-abdominal abscess, fungemia following treatment with Tobramycin, and when the infecting bacterium was Pseudomonas aeruginosa (Tables 1, 2, and 5). Such conclusions were spurious, however, as they were drawn from data obtained from patients
2
treated earlier in the study and thus before the routine administration of oral nystatin prophylaxis. Cause of Death
Continuing or recurrent bacterial sepsis accounted for rrcretbcellspl cone o 21 of the 41 deaths. Nine other fatalities were unrelated to the initial infection. Ten deaths, however, were due directly to a complicating candidiasis. As noted abov'e, appropriate prophylaxis with oral nystatin essentially
eliminated the occurrence of this one problem in the later
caseS.5 . .
Forty-three instances of antibiotic related complications developed in 30 of the 405 patients (Table 6). Varying degrees of nephrotoxicity were the most common of these complications. Such was noted in 22 or 5% of the total series, although pre-existing shock and/or severe dehydration appeared to be the primary cause for the renal failure in 16 of the cases. A pure drug-induced effect could be incriminated in only 6 of the patients. Ototoxicity developed in 6 patients, an overall incidence of just over 1%. In 3 of the patients, it affected
TABLE 6. Complications of Parenteral Aminoglycosides
Tobramycin Renal Toxicity drug alone with shock/dehydration
Gentamicin
2 6
2 5
1 2
2 1
8
3 2 96 107
Sisomicin 1 3
Amikacin
Total
1 2
6 16
1
4 3
2 2 49 55
14 10 365 405
Ototoxicity cochlear vestibular New Pathogen Candida Sepsis Indeterminate No Complication Total Patients
4
111 129
1 2 109 114
Vol. 183
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6
AMINOGLYCOSIDES
665
TABLE 7. Response of Sepsis to Drainage (Drainage inclusive of debridement, as warranted)
Already draining Spontaneous drain Operative drainage Never drained** Indeterminate Totals
49 92 136 118 10 405
Complicating Candida Sepsis*
Cured
Recurred
Died of Bacterial Sepsis
35 83 122 93
2 2 3 17
2 2 4 14
8 1 5
335
24
22
14
Bacterial Sepsis
Number of Patients
* Candida sepsis developed almost solely in patients with extensive thermal burns or intestinal fistulas. ** Significantly increased rates in mortality and recurrence of bacterial sepsis (P = 0.01) for both).
charging pus prior to the initiation of antibiotic therapy or subsequently drained through either spontaneous rupture of the abscess or purposeful surgical incision (Table 7). The establishment of such drainage favorably influenced the likelihood of permanent cure, decreased the risk of death from the primary infection, and lessened chances of recurrence of sepsis as well. Susceptibility of responsible pathogens to the individual antibiotic administered was also important (Table 8). For example, if the bacterial flora was universally resistant to the antimicrobial given, the mortality for such cases was 9%; and the rate for recurrence of sepsis, 11%. If, however, all species of identifiable pathogens were susceptible to the administered antibiotic, comparable rates were 5% for the mortality and 4% for infection recrudescence. Just as critical to eventual survival, if not even more so, was the presence of a disease state that caused an impairment in host resistance. Comparison of the outcome for those 149 patients with an altered immune response to the results obtained in the 246 individuals presumed to have a relatively normal resistance mechanism reflected a striking difference, that is, mortalities of 19 and 2% respectively, due to sepsis. Even after exclusion of patients dying from Candida sepsis., the difference was still highly significant (P = 0.01). When the relative importance of these three aspects of Determinants of Response to Therapy surgical infections were compared-drainage of the Drainage of the surgical infection was exceedingly septic process, pathogen susceptibility to the adminisimportant, irrespective as to whether the area was dis- tered antibiotic, and competence of the host defense
the cochlear division; a vestibular injury occurred in two; while both components of the eighth cranial nerve showed damage in the sixth patient. In each instance, some additional factor seemed to play a major role in causing the inner ear derangement. Specifically, a significant reduction in renal function and thus antibiotic excretion was noted in 5 patients; neomycin had been applied topically and thereby absorbed in four; and prolonged aminoglycoside therapy had been given to two. There was recovery from the renal injury in all patients who survived, yet kidney failure significantly contributed toward death in the remainder. By contrast, no measureable improvement could be detected in eighth nerve function in any of the patients who demonstrated ototoxicity. No instances of myoneural blockade causing respiratory arrest were noted. Candida sepsis was an extremely serious complication and was itself the basic cause for death in 10 of the 14 patients who acquired this superinfection. The majority of these cases were noted earlier in the study and led to a frightening 8% incidence of Candida sepsis. Following appropriate prophylaxis, once it was realized that intestinal persorption was the usual portal for entry of such fungi,5 the frequency of this one complication was reduced dramatically-to less than 1%.
TABLE 8. Importance of Bacterial Susceptibility to Aminoglycoside Number of Patients All isolated pathogens resistant Only one isolated pathogen sensitive All isolated pathogens sensitive No growth/no culture Indetenninate Totals
47 197 122 29 10 405
Complicating
Cured
Recurred
Died of Bacterial Sepsis
36 166 104 29
5 14 5
4 12 6
2 5 7
335
24
22
14
Bacterial Sepsis
Candida Sepsis
666
STONE AND OTHERS
Ann. Surg. * June 1976
mechanism-the value of antibiotic therapy was the least impressive of all. The chances for altering the course of a surgical infection by treatment with an antimicrobial was significant at a probability of only P = 0.10, while the significance for benefit by drainage and an effective host defense mechanism was at the 0.01 level.
supported by the other. Although aerobic gram-negative rods can survive alone, the anaerobes are totally dependent upon the immediate proximity of necrotic tissue or locally available aerobic species.6 Accordingly, elimination or a significant reduction in the population of the aerobic component will lead to death of most of the anaerobes provided that the volume of necrotic tissue Comment is not great. This may well be the true explanation for an Infections due solely to aerobic gram-negative rods apparent benefit gained from antibiotics lacking activity consistently respond to parenteral aminoglycoside against anaerobic bacteria. therapy whenever the area of sepsis has a good blood References supply, all species of pathogenic bacteria are sensitive M: to the administered antibiotic, host defense mechanisms 1. Bauer, A. W., Kirby, W. M. M., Sherris, J. D. and Tuck Antibiotic Susceptibility Testing by a Standardized Single are routinely normal, and the amount of necrotic tissue Disk Method. Am. J. Clin. Pathol., 45:493, 1966. is negligible.7 Drainage of the infection can usually over- 2. Cox, R. H. and Spongberg, A. K.: Electronystagmography: One Year's Experience at Ochsner Clinic. South. Med. J., 65: come any significant deficiencies in the above, that is, 38, 1972. necrotic of accumulation antibiotic-resistant bacteria, 3. Davia, J. E., Siemsen, A. W. and Anderson R. W.: Uremia, debris, and an altered immune response. Thus, the major Deafness, and Paralysis Due to Irrigating Antibiotic Solutions. Arch. Intern. Med., 125:135, 1970. role of antibiotic therapy often becomes the mere control 4. Gavan, T. L. and Town, M. A.: A Microdilution Method for of sepsis until drainage and/or surgical debridement can Antibiotic Susceptibility Testing: An Evaluation. Am. J. Clin. be achieved. Pathol., 53:880, 1970. H. H., Kolb, L. D., Currie, C. A., et al.: Candida Why patients with infections due to a mixed bacterial 5. Stone, Sepsis; Pathogenesis and Principles of Treatment. Ann. Surg., flora-including aminoglycoside-resistant anaerobes179:697, 1974. respond to such antibiotic therapy has been poorly 6. Stone, H. H., Kolb, L. D. and Geheber, C. E.: Incidence and Significance of Intraperitoneal Anaerobic Bacteria. Ann. Surg., understood. However, these symbiotic bacterial re181:705, 1975. lationships are based upon the anaerobe providing en- 7. Stone, H. H., Kolb, L. D., Geheber, C. E. and Currie, C. A.: Treatment of Surgical Infections with Tobramycin. Am. zymes for tissue digestion and thus nutrient assimilation Surg., 41:301, 1975. for all participating species, while the aerobes maintain a 8. Winters, R. E., Litwack, K. D. and Hewitt, W. L.: Relation lowered oxidation-reduction potential through use of all Between Dose and Levels of Gentamicin in Blood. J. Infect. Dis., 124:590, 1971 available oxygen. Each set of partners is thereby
DISCUSSION DR. BOYD W. HAYNES, JR. (Richmond, Virginia): The Bard Parker is still the best treatment for abdominal sepsis, where pus is present; that pus is thoroughly drained is still laudable. However, he was a little surprising to me when he stated that the antibiotic sensitivity of the given organisms doesn't seem to be as important as many of us think. In our experience, the treatment of gram negative infections, particularly on the burn wound, is often difficult to manage, because, although there is a relatively high sensitivity to gentamicin, and it certainly is the best agent available now to treat that particular spectrum of gram negative organisms, there appears to be a group of
pseudomonads now appearing on our wounds which don't seem to be sensitive as they were previously. This is of some concern to me, and I would like Dr. Stone's comment about this, and also if he as
thinks that the addition of carbenicillin adds a significant method of control to gram negative sepsis of this type. DR. H. HARLAN STONE (Closing discussion): The greater importance of host resistance and drainage over antibiotic susceptibility was somewhat amazing to us. If the infection was already draining, antibiotics were effective in determining and controlling which bacteria colonized the wound and thereby would subsequently invade. However, if drainage was accomplished by operation or developed spontaneously, the correlation of antibiotic sensitivities and clinical effectiveness was poor. I agree with Dr. Haynes' comment that, should there be established drainage, and yet sepsis is still a problem, then antibiotics become quite useful in controlling bacteremia until local wound care can reverse the process. Nevertheless, it is crucial that the antibiotic reach the primary site of infection. For example, parenteral agents for burn wound sepsis fail to work anywhere near as well as do the various topical antimicrobials.
