CEFAMANDOLE LEVELS IN PRIMARY AQUEOUS HUMOR IN MAN JUDITH L. AXELROD, M.D., AND RICHARD S. KOCHMAN, M.D. New York, New York
Cefamandole nafate is a new parenteral semisynthetic cephalosporin with a broad spectrum of antibacterial acitivity.1 In comparison to other available cephalosporins, cefamandole is more active against most strains of Hemophilus influenzae2 and most Enterobactereaceae, 1-3 including indole-positive Proteus strains. Cefamandole is not active against Pseudomonas species and Serratia.1'3 Cefamandole has also been shown to dif fuse well into cerebrospinal fluid,4 soft tissue interstitial fluid, and bile. 5 The purpose of this study was to evaluate the penetration of cefamandole into human aqueous humor. SUBJECTS AND METHODS
Patients were selected for study who were about to undergo elective cataract extraction and who had not received any antibiotic for one month before surgery. Patients were excluded if they stated that they were allergic to penicillins or to cephalosporins. Informed written con sent was obtained in all cases. Patients were divided into three groups on the basis of the dose and route of administration of cefamandole. Group 1 received 1 g intramuscularly; Group 2 received 1 g intravenously; and Group 3 received 2 g intravenously. An additional group, Group 4, included patients with From the Departments of Medicine (Infectious Diseases) (Dr. Axelrod) and Ophthalmology (Dr. Kochman), St. Luke's Hospital Center, New York, New York. This study was supported by a grant from Eli Lilly and Co., Indianapolis, Indiana. This study was presented in part at the 10th International Congress of Chemotherapy, Zurich, Switzerland, Sept. 21, 1977. Reprint requests to Judith L. Axelrod, M.D., Sec tion of Infectious Diseases, St. Luke's Hospital Center, Amsterdam Avenue at 114th Street, New York, NY 10025. 342
varying degrees of renal failure. All pa tients were scheduled to receive cefaman dole from 30 minutes to six hours before surgery. For intramuscular injection, 1 g of cefamandole was dissolved into 3 ml of sterile water and injected deep into the gluteus maximus muscle. For intravenous injection, each gram of cefamandole was dissolved into 10 ml of sterile water and infused over a five-minute period. Patients were prepared for surgery with retrobulbar injections of 2% lidocaine (Xylocaine) and topical application of 0.5% pontocaine with 1 drop of Argyrol. The eye was then washed with hexachlorophene (pHisoHex) and the cul-de-sacs were irrigated with normal saline. The residual Argyrol was wiped out with a saline moistened cotton swab. Just before cataract extraction, a 2-mm, nonpenetrating incision was made in the corneoscleral limbus and the anterior chamber was entered with a 27-gauge needle attached to a 2.5-ml plastic sy ringe. The aqueous humor was aspirated, placed in a sterile vial, and immediately frozen at -20°C until assayed. From 0.1 to 0.2 ml of aqueous humor were obtained with this method. Simultaneous venous samples of blood were also obtained, spun, and the serum frozen at -20°C until the time of assay. Antibiotic assays on serum and aque ous humor were performed with the cupplate method using Bacillus subtilis as the test organism. Penassay Seed Agar Difco B-263 was inoculated with B. subti lis spore suspension in a concentration of 0.2 ml/100 ml of agar. Four milliliters of inoculated seed agar was then poured over 10 ml of streptomycin agar in a 100-mm petri dish and six sterile penicylinders were placed on each dish. Alter nate cylinders were filled with control or
AMERICAN JOURNAL OF OPHTHALMOLOGY 85:342-348, 1978
CEFAMANDOLE IN AQUEOUS HUMOR
VOL. 85, NO. 3 TABLE 1
CEFAMANDOLE NAFATE LEVELS IN SERUM AND AQUEOUS HUMOR IN GROUP 1 AFTER 1 G INTRAMUSCULARLY
Level (n-g/ml) Serum Aqueous Humor
Case No.
Time After Injection
1 2 3 4 5 6 7
1 hr 9 min 1 hr 20 min 1 hr 27 min 2 hrs 15 min 3 hrs 8 min 4 hrs 10 min 4 hrs 28 min
33.6 34.4 20.0 12.9 12.0 4.7 7.0
0 0 0 0 0 0 0
343
of cefamandole would be within this curve. Controls for the aqueous humor samples were prepared similarly to those for serum, but pH6 phosphate buffer was used as the diluent. Concentrations of cefamandole for the aqueous humor con trol curve varied from 0.8 u.g/ml to 5 fig/ml. All aqueous humor samples were assayed undiluted. RESULTS
specimen samples. Controls for serum were prepared by dissolving known amounts of cefamandole in pooled human serum. Concentrations for the standard serum control curve varied from 0.3 to 5 ng/ml and specimens of serum were diluted with pooled human serum such that the expected final concentration
After a 1-g dose intramuscularly, no assayable concentrations of cefamandole were detected in the primary aqueous humor (Table 1). The serum and aqueous humor levels obtained with the 1-g intra venous dose are presented (Table 2). Serum levels are consistent with previ ously reported data.6 At approximately 30 minutes after injection, the average aque ous humor level was 0.33 u.g/ml with a range from 0 to 0.68 u.g/ml. At one, two,
TABLE 2 CEFAMANDOLE NAFATE LEVELS IN SERUM AND AQUEOUS HUMOR IN GROUP 2 AFTER 1 G INTRAVENOUSLY
Case No.
Time After Injection
Level ((JLg/ml) Serum Aqueous Humor
Average levels (u.g/ml) (time after injection) Serum Aqueous Humor
1 2 3 4
28 31 32 34
min min min min
51.2 115 51.8 78
0.68 0.44 0.20 0
(Approximately 30 min) 74.0 0.33
5 6 7 8 9 10
48 min 52 min 1 hr 10 min 1 hr 20 min 1 hr 20 min 1 hr 28 min
64.0 38.4 33.6 36 31.5 32.2
0 0.8 0.7 1.1 0.62 0.32
(Approximately 1 hr) 39.3 0.59
11 12 13 14 15
1 hr 42 min 2 hrs 5 min 2 hrs 25 min 2 hrs 30 min 2 hrs 40 min
12.5 16 7.9 4.2 5.7
0 0.5 0 0.31 0.26
(Approximately 2 hr) 9.3 0.21
16 17 18 19 20
3 hrs 33 min 3 hrs 36 min 4 hrs 4 hrs 30 min 4 hrs 35 min
0.22 0.22 0.28 0 0
(Approximately 4 hr) 3.3 0.14
6.8 2.4 3.0 2.9 1.25
344
AMERICAN JOURNAL OF OPHTHALMOLOGY
MARCH, 1978
TABLE 3 CEFAMANDOLE NAFATE LEVELS IN SERUM AND AQUEOUS HUMOR IN GROUP 3 AFTER 2 G INTRAVENOUSLY
Case No.
Time After Injection
Level ((ig/ml) Serum Aqueous Humor
1 2 3 4 5 6 7 8
28min 28min 30 min 30min 31 min 32 min 35 min 45 min
120 156 123 112 50 68 80 92.8
0.5 0.7 0.26 1.48 3.3 0.62 0.34 2.9
9 10 11 12 13 14 15 16
47 min 49 min 54 min 55 min 1 hr 4 min 1 hr 9 min 1 hr 12 min 1 hr 18 min
116 100.5 62.4 112.5 97 38 55 69
1.56 0.37 1.1 0.76 1.39 0.76 1.2 0.88
17 18 19 20 21
2 hrs 5 min 2 hrs 8 min 2 hrs 9 min 2 hrs 26 min 2 hrs 31 min
20 32 15 36 34.2
1.4 2.1 0.66 2.6 1.1
22 23 24 25 26 27 28 29
3 hrs 42 min 3 hrs 59 min 4 hrs 4 hrs 5 min 4 hrs 10 min 4 hrs 25 min 4 hrs 35 min 4 hrs 45 min
10.9 10.8 0.414 8.9 16 4.5 6.6 8.5
0.7 0.5 0.12 0.4 1.05 1.8 0.34 0.96
30 31 32 33 34 35 36
5 hrs 39 min 6 hrs 6 hrs 9 min 6 hrs 10 min 6 hrs 15 min 6 hrs 15 min 6 hrs 40 min
9.0 4.78 2.3 0.89 10.6 6.2 1.0
0.55 0.92 0 0 0.5 0.4 0
37
7 hrs 30 min
0.515
and four hours after injection the average aqueous humor levels were 0.59, 0.21, and 0.14 u.k/ml, respectively. Serum and aqueous humor concentrations of cefa mandole after 2 g intravenously are listed (Table 3). Again serum levels were similar to those published previously.6 In con trast to the levels after the 1-g dose, aque
Average Levels (|ig/ml) (time after injection) Serum Aqueous Humor
(Approximately 30 min) 100.2 1.26
(Approximately 1 hr) 81.3 1.00
(Approximately 2 hrs) 27.4 1.57
(Approximately 4 hrs) 8.3 0.73
(Approximately 6 hrs) 5.0 0.34
0
ous humor levels after the 2-g dose were higher and more prolonged. The highest levels, 2.9 and 3.3 |xg/ml, were achieved in two patients at 30 minutes after injection. Average aqueous humor levels at one, two, four, and six hours were 1.00, 1.57, 0.73, and 0.34 u.g/ml, respectively. Of note is that assayable
VOL. 85, NO. .3
CEFAMANDOLE IN AQUEOUS HUMOR
345
TABLE 4 CEFAMANDOLE NAFATE LEVELS IN SERUM AND AQUEOUS HUMOR IN GROUP 4 PATIENTS WITH RENAL FAILURE
Case No. 1 2 3 4 5
Creatinine (mg/100 ml) 13.0 9.9 9.3 3.1 7.6
Dose (g) 2 2 2 2 1
Time After Injection 1 hr 1 hr 2 hrs 2 hrs 4 hrs
16 min 19 min 9 min 38 min 48 min
Level (fig/ml) Serum
Aqueous Humor
72.0 73.5 38.7 103.5 53.25
1.25 1.15 2.1 0.78 2.2
levels of cefamandole in primary aqueous of cataract operations,7 and in from 1 to humor were found in all 29 patients up to 18% of filtering bleb procedures for glau coma.8 The organism responsible most four hours after injection. 1 9 We measured the serum and aqueous commonly is Staphylococcus aureus. - A humor levels achieved in five patients variety of gram-negative organisms, spe with varying degrees of renal failure (Ta cifically, P. aeruginosa, indole-positive ble 4). With the exception of Case 4, the and negative Proteus strains, Escherichia other four patients were on chronic hemo- coli, H. influenzae, and Klebsiella species 9 dialysis. Patients underwent hemodialy- account for about one third of cases. sis one day before surgery, and the creati Once endophthalmitis occurs, the results nine values listed reflect the predialysis can be devastating with most patients 7 value on the presurgery day. In four pa losing the use of the eye. To avert this tients (Cases 1-4), all of whom received adverse outcome, recommendations have 7 2 g intravenously one to two hours before been made for prophylactic antibiotics, surgery, serum and aqueous humor levels for early anterior chamber taps to estab 9 were within the ranges of those in pa lish a bacteriologic diagnosis, and for tients with normal renal function, al administration of antibiotics either perithough the serum level in Case 4 and the ocularly or by the intravitreal route, as 10 aqueous humor level in Case 3 were well as systemically. Antibiotic penetra above the averages. In one patient (Case tion into aqueous humor after systemic 5), who received 1 g of cefamandole ap administration is, in general, poor; but proximately four hours before surgery, periocular injection often produces ex both serum and aqueous humor levels treme pain and chemosis, and intravitreal were well above the averages of patients injection must be performed in the ope rating room. Hence, the search continues in group 2. for antibiotics that penetrate into aqueous No adverse reactions occurred in any humor after systemic administration. patient after injection of cefamandole. Those patients who received the drug We reviewed the mean and range of intramuscularly complained of transient minimum inhibitory concentrations of pain at the injection site. There were no cefamandole against those pathogens postoperative infections in any of the 69 most commonly responsible for bacterial patients studied. endophthalmitis (Table 5). Concentra tions of cefamandole equivalent to the DISCUSSION mean concentration required to inhibit S. Bacterial endophthalmitis occurs after aureus were achieved in six of 15 patients severe trauma to the eye, in less than 1% from 30 minutes to two hours after the 1-g
346
AMERICAN JOURNAL OF OPHTHALMOLOGY
MARCH, 1978
TABLE 5 SUSCEPTIBILITY O F COMMON PATHOGENS TO CEFAMANDOLE IN VARIOUS STUDIES
Minimum Inhibitory Concentration, ng/ml Mean (range) Shemonsky, Carrizosa, and Levison3
Organism Gram-positive Staphylococcus aureus S. epidermidis Streptococcus pneumoniae St. pyogenes, Group A Gram-negative Enterobacter species E. coli H. influenzae Klebsiella species Proteus, indole-positive P. mirabilis Pseudomonas
0.4 (0.2-1.6)
Meyers and associates11
Bodey and Weaver12
0.46(0.16-1.25) 0.25(0.1-0.8) 0.18(0.06-1.2) 0.04 (0.02-0.12)
3.3 (0.8-5.0) 1.2 (0.8-50)
19.5(0.9-55) 4.43 (0.35-25) 1.43 (0.25-5) 2.4 (0.35-25) 3.35 (0.7-15) 2.09 (0.75-3.0) >50 (>50)
1.0 (0.8-12.5) 2.0 (0.1-6.3) 3.2 (0.8-6.3)
intravenous dose, and in 18 of 21 patients from 30 minutes to two hours after the 2-g dose (Table 6). Therapeutic levels against Streptococcus pneumoniae and St. pyoge nes were achieved in 11 of 15 patients within two hours after the 1-g dose, and in all 29 patients within five hours after the 2-g dose. The mean concentrations of cefaman dole required to inhibit gram-negative pathogens were variable, although eight of 22 mean minimum inhibitory concen trations of cefamandole against Enterobactereaceae were ^-1 (xg/ml, and an addi tional five were ^ 2 ng/ml (Table 5). Aqueous humor concentrations of 1 fig/ml were achieved only once with the
Eickhoff and Ehret13 0.7 (0.2-3.1) 0.5 (0.1-6.2) 0.04 (0.03-0.125) 0.05 (0.03-0.5)
100 (0.78->100) 1.3(0.2-100) 0.4 (0.025-100) 1.0 (0.2-100) 0.18 (0.06-0.5) 2.0 (0.1-100) 1.0 (0.2-100) 18 (0.012-100) 0.4 (0.2-50) 0.3 (0.05-100) 1.0 (0.4-3.2)
1-g dose, but in 11 of 21 patients within two hours after the 2-g dose. Levels of 2 Hg/ml were achieved in no patients with the 1-g dose and in only four patients with the 2-g dose. Thus, concentrations of cefamandole effective against most Enterobactereaceae were not consistently achieved. Since aqueous humor antibiotic levels are increased in secondary aqueous humor13 and since secondary aqueous humor levels are thought to approximate more closely those levels achieved in the inflamed eye,13 it is possible that levels of cefamandole effective against more Enterobactereaceae might be achieved in the infected eye. We reviewed concentrations of other
TABLE 6 THERAPEUTIC IMPLICATIONS O F CEFAMANDOLE LEVELS IN PRIMARY AQUEOUS HUMOR
Time (hrs)
No. with Level s> 0.5
1/2 1 2 4 6
1/4 4/6 1/5 0/5
1JL Intravenously No. with Level s> 1.0 0 1/6 0/5 0/5
No. wiith Level ^ 2.0
No. with Level ^ 0.5
0 0 0 0
6/8 7/8 5/5 5/8 3/7
2 g Intravenously No. with Level s> 1.0 3/8 4/8 4/5 2/8 0/7
No. with Level ^ 2.0 2/8 0/8 2/5 0/8 0/7
VOL. 85, NO. 3
347
CEFAMANDOLE IN AQUEOUS HUMOR TABLE 7
COMPARISON O F ANTIBIOTIC PENETRATION O F PARENTERAL CEPHALOSPORINS INTO PRIMARY AQUEOUS HUMOR IN MAN
Investigators Macllwaine, Sande, and Mandell14
Drug Cephalothin
Riley, Boyle, Cephaloridine and Leopold15
Macllwaine, Sande, and Mandell14
No. of Subjects Dose and Route Studied of Administration8 2g I.V.
19
Cefazolin
I.M.
Average Concentration (u,g/ml) Time After Aqueous Injection Serum Humor 30min 40 min 45 min 50 min 1 hr. Approximately 2 hrs Approximately 4 hrs Approximately 6 hrs
61 58 41 32
3.3 2.1 1.5 1.6
31.5 32.7 26.5 5.7
0.8 1.3 3.0 1.2
0.5 g I.V.
Approximately 40 min
35
Cefamandole nafate is a new parenteral semisynthetic cephalosporin with a broad spectrum of antibacterial acitivity.1 In comparison to other available cephalosporins, cefamandole is more active against most strains of Hemophilus influenzae2 and most Enterobactereaceae, 1-3 including indole-positive Proteus strains. Cefamandole is not active against Pseudomonas species and Serratia.1'3 Cefamandole has also been shown to dif fuse well into cerebrospinal fluid,4 soft tissue interstitial fluid, and bile. 5 The purpose of this study was to evaluate the penetration of cefamandole into human aqueous humor. SUBJECTS AND METHODS
Patients were selected for study who were about to undergo elective cataract extraction and who had not received any antibiotic for one month before surgery. Patients were excluded if they stated that they were allergic to penicillins or to cephalosporins. Informed written con sent was obtained in all cases. Patients were divided into three groups on the basis of the dose and route of administration of cefamandole. Group 1 received 1 g intramuscularly; Group 2 received 1 g intravenously; and Group 3 received 2 g intravenously. An additional group, Group 4, included patients with From the Departments of Medicine (Infectious Diseases) (Dr. Axelrod) and Ophthalmology (Dr. Kochman), St. Luke's Hospital Center, New York, New York. This study was supported by a grant from Eli Lilly and Co., Indianapolis, Indiana. This study was presented in part at the 10th International Congress of Chemotherapy, Zurich, Switzerland, Sept. 21, 1977. Reprint requests to Judith L. Axelrod, M.D., Sec tion of Infectious Diseases, St. Luke's Hospital Center, Amsterdam Avenue at 114th Street, New York, NY 10025. 342
varying degrees of renal failure. All pa tients were scheduled to receive cefaman dole from 30 minutes to six hours before surgery. For intramuscular injection, 1 g of cefamandole was dissolved into 3 ml of sterile water and injected deep into the gluteus maximus muscle. For intravenous injection, each gram of cefamandole was dissolved into 10 ml of sterile water and infused over a five-minute period. Patients were prepared for surgery with retrobulbar injections of 2% lidocaine (Xylocaine) and topical application of 0.5% pontocaine with 1 drop of Argyrol. The eye was then washed with hexachlorophene (pHisoHex) and the cul-de-sacs were irrigated with normal saline. The residual Argyrol was wiped out with a saline moistened cotton swab. Just before cataract extraction, a 2-mm, nonpenetrating incision was made in the corneoscleral limbus and the anterior chamber was entered with a 27-gauge needle attached to a 2.5-ml plastic sy ringe. The aqueous humor was aspirated, placed in a sterile vial, and immediately frozen at -20°C until assayed. From 0.1 to 0.2 ml of aqueous humor were obtained with this method. Simultaneous venous samples of blood were also obtained, spun, and the serum frozen at -20°C until the time of assay. Antibiotic assays on serum and aque ous humor were performed with the cupplate method using Bacillus subtilis as the test organism. Penassay Seed Agar Difco B-263 was inoculated with B. subti lis spore suspension in a concentration of 0.2 ml/100 ml of agar. Four milliliters of inoculated seed agar was then poured over 10 ml of streptomycin agar in a 100-mm petri dish and six sterile penicylinders were placed on each dish. Alter nate cylinders were filled with control or
AMERICAN JOURNAL OF OPHTHALMOLOGY 85:342-348, 1978
CEFAMANDOLE IN AQUEOUS HUMOR
VOL. 85, NO. 3 TABLE 1
CEFAMANDOLE NAFATE LEVELS IN SERUM AND AQUEOUS HUMOR IN GROUP 1 AFTER 1 G INTRAMUSCULARLY
Level (n-g/ml) Serum Aqueous Humor
Case No.
Time After Injection
1 2 3 4 5 6 7
1 hr 9 min 1 hr 20 min 1 hr 27 min 2 hrs 15 min 3 hrs 8 min 4 hrs 10 min 4 hrs 28 min
33.6 34.4 20.0 12.9 12.0 4.7 7.0
0 0 0 0 0 0 0
343
of cefamandole would be within this curve. Controls for the aqueous humor samples were prepared similarly to those for serum, but pH6 phosphate buffer was used as the diluent. Concentrations of cefamandole for the aqueous humor con trol curve varied from 0.8 u.g/ml to 5 fig/ml. All aqueous humor samples were assayed undiluted. RESULTS
specimen samples. Controls for serum were prepared by dissolving known amounts of cefamandole in pooled human serum. Concentrations for the standard serum control curve varied from 0.3 to 5 ng/ml and specimens of serum were diluted with pooled human serum such that the expected final concentration
After a 1-g dose intramuscularly, no assayable concentrations of cefamandole were detected in the primary aqueous humor (Table 1). The serum and aqueous humor levels obtained with the 1-g intra venous dose are presented (Table 2). Serum levels are consistent with previ ously reported data.6 At approximately 30 minutes after injection, the average aque ous humor level was 0.33 u.g/ml with a range from 0 to 0.68 u.g/ml. At one, two,
TABLE 2 CEFAMANDOLE NAFATE LEVELS IN SERUM AND AQUEOUS HUMOR IN GROUP 2 AFTER 1 G INTRAVENOUSLY
Case No.
Time After Injection
Level ((JLg/ml) Serum Aqueous Humor
Average levels (u.g/ml) (time after injection) Serum Aqueous Humor
1 2 3 4
28 31 32 34
min min min min
51.2 115 51.8 78
0.68 0.44 0.20 0
(Approximately 30 min) 74.0 0.33
5 6 7 8 9 10
48 min 52 min 1 hr 10 min 1 hr 20 min 1 hr 20 min 1 hr 28 min
64.0 38.4 33.6 36 31.5 32.2
0 0.8 0.7 1.1 0.62 0.32
(Approximately 1 hr) 39.3 0.59
11 12 13 14 15
1 hr 42 min 2 hrs 5 min 2 hrs 25 min 2 hrs 30 min 2 hrs 40 min
12.5 16 7.9 4.2 5.7
0 0.5 0 0.31 0.26
(Approximately 2 hr) 9.3 0.21
16 17 18 19 20
3 hrs 33 min 3 hrs 36 min 4 hrs 4 hrs 30 min 4 hrs 35 min
0.22 0.22 0.28 0 0
(Approximately 4 hr) 3.3 0.14
6.8 2.4 3.0 2.9 1.25
344
AMERICAN JOURNAL OF OPHTHALMOLOGY
MARCH, 1978
TABLE 3 CEFAMANDOLE NAFATE LEVELS IN SERUM AND AQUEOUS HUMOR IN GROUP 3 AFTER 2 G INTRAVENOUSLY
Case No.
Time After Injection
Level ((ig/ml) Serum Aqueous Humor
1 2 3 4 5 6 7 8
28min 28min 30 min 30min 31 min 32 min 35 min 45 min
120 156 123 112 50 68 80 92.8
0.5 0.7 0.26 1.48 3.3 0.62 0.34 2.9
9 10 11 12 13 14 15 16
47 min 49 min 54 min 55 min 1 hr 4 min 1 hr 9 min 1 hr 12 min 1 hr 18 min
116 100.5 62.4 112.5 97 38 55 69
1.56 0.37 1.1 0.76 1.39 0.76 1.2 0.88
17 18 19 20 21
2 hrs 5 min 2 hrs 8 min 2 hrs 9 min 2 hrs 26 min 2 hrs 31 min
20 32 15 36 34.2
1.4 2.1 0.66 2.6 1.1
22 23 24 25 26 27 28 29
3 hrs 42 min 3 hrs 59 min 4 hrs 4 hrs 5 min 4 hrs 10 min 4 hrs 25 min 4 hrs 35 min 4 hrs 45 min
10.9 10.8 0.414 8.9 16 4.5 6.6 8.5
0.7 0.5 0.12 0.4 1.05 1.8 0.34 0.96
30 31 32 33 34 35 36
5 hrs 39 min 6 hrs 6 hrs 9 min 6 hrs 10 min 6 hrs 15 min 6 hrs 15 min 6 hrs 40 min
9.0 4.78 2.3 0.89 10.6 6.2 1.0
0.55 0.92 0 0 0.5 0.4 0
37
7 hrs 30 min
0.515
and four hours after injection the average aqueous humor levels were 0.59, 0.21, and 0.14 u.k/ml, respectively. Serum and aqueous humor concentrations of cefa mandole after 2 g intravenously are listed (Table 3). Again serum levels were similar to those published previously.6 In con trast to the levels after the 1-g dose, aque
Average Levels (|ig/ml) (time after injection) Serum Aqueous Humor
(Approximately 30 min) 100.2 1.26
(Approximately 1 hr) 81.3 1.00
(Approximately 2 hrs) 27.4 1.57
(Approximately 4 hrs) 8.3 0.73
(Approximately 6 hrs) 5.0 0.34
0
ous humor levels after the 2-g dose were higher and more prolonged. The highest levels, 2.9 and 3.3 |xg/ml, were achieved in two patients at 30 minutes after injection. Average aqueous humor levels at one, two, four, and six hours were 1.00, 1.57, 0.73, and 0.34 u.g/ml, respectively. Of note is that assayable
VOL. 85, NO. .3
CEFAMANDOLE IN AQUEOUS HUMOR
345
TABLE 4 CEFAMANDOLE NAFATE LEVELS IN SERUM AND AQUEOUS HUMOR IN GROUP 4 PATIENTS WITH RENAL FAILURE
Case No. 1 2 3 4 5
Creatinine (mg/100 ml) 13.0 9.9 9.3 3.1 7.6
Dose (g) 2 2 2 2 1
Time After Injection 1 hr 1 hr 2 hrs 2 hrs 4 hrs
16 min 19 min 9 min 38 min 48 min
Level (fig/ml) Serum
Aqueous Humor
72.0 73.5 38.7 103.5 53.25
1.25 1.15 2.1 0.78 2.2
levels of cefamandole in primary aqueous of cataract operations,7 and in from 1 to humor were found in all 29 patients up to 18% of filtering bleb procedures for glau coma.8 The organism responsible most four hours after injection. 1 9 We measured the serum and aqueous commonly is Staphylococcus aureus. - A humor levels achieved in five patients variety of gram-negative organisms, spe with varying degrees of renal failure (Ta cifically, P. aeruginosa, indole-positive ble 4). With the exception of Case 4, the and negative Proteus strains, Escherichia other four patients were on chronic hemo- coli, H. influenzae, and Klebsiella species 9 dialysis. Patients underwent hemodialy- account for about one third of cases. sis one day before surgery, and the creati Once endophthalmitis occurs, the results nine values listed reflect the predialysis can be devastating with most patients 7 value on the presurgery day. In four pa losing the use of the eye. To avert this tients (Cases 1-4), all of whom received adverse outcome, recommendations have 7 2 g intravenously one to two hours before been made for prophylactic antibiotics, surgery, serum and aqueous humor levels for early anterior chamber taps to estab 9 were within the ranges of those in pa lish a bacteriologic diagnosis, and for tients with normal renal function, al administration of antibiotics either perithough the serum level in Case 4 and the ocularly or by the intravitreal route, as 10 aqueous humor level in Case 3 were well as systemically. Antibiotic penetra above the averages. In one patient (Case tion into aqueous humor after systemic 5), who received 1 g of cefamandole ap administration is, in general, poor; but proximately four hours before surgery, periocular injection often produces ex both serum and aqueous humor levels treme pain and chemosis, and intravitreal were well above the averages of patients injection must be performed in the ope rating room. Hence, the search continues in group 2. for antibiotics that penetrate into aqueous No adverse reactions occurred in any humor after systemic administration. patient after injection of cefamandole. Those patients who received the drug We reviewed the mean and range of intramuscularly complained of transient minimum inhibitory concentrations of pain at the injection site. There were no cefamandole against those pathogens postoperative infections in any of the 69 most commonly responsible for bacterial patients studied. endophthalmitis (Table 5). Concentra tions of cefamandole equivalent to the DISCUSSION mean concentration required to inhibit S. Bacterial endophthalmitis occurs after aureus were achieved in six of 15 patients severe trauma to the eye, in less than 1% from 30 minutes to two hours after the 1-g
346
AMERICAN JOURNAL OF OPHTHALMOLOGY
MARCH, 1978
TABLE 5 SUSCEPTIBILITY O F COMMON PATHOGENS TO CEFAMANDOLE IN VARIOUS STUDIES
Minimum Inhibitory Concentration, ng/ml Mean (range) Shemonsky, Carrizosa, and Levison3
Organism Gram-positive Staphylococcus aureus S. epidermidis Streptococcus pneumoniae St. pyogenes, Group A Gram-negative Enterobacter species E. coli H. influenzae Klebsiella species Proteus, indole-positive P. mirabilis Pseudomonas
0.4 (0.2-1.6)
Meyers and associates11
Bodey and Weaver12
0.46(0.16-1.25) 0.25(0.1-0.8) 0.18(0.06-1.2) 0.04 (0.02-0.12)
3.3 (0.8-5.0) 1.2 (0.8-50)
19.5(0.9-55) 4.43 (0.35-25) 1.43 (0.25-5) 2.4 (0.35-25) 3.35 (0.7-15) 2.09 (0.75-3.0) >50 (>50)
1.0 (0.8-12.5) 2.0 (0.1-6.3) 3.2 (0.8-6.3)
intravenous dose, and in 18 of 21 patients from 30 minutes to two hours after the 2-g dose (Table 6). Therapeutic levels against Streptococcus pneumoniae and St. pyoge nes were achieved in 11 of 15 patients within two hours after the 1-g dose, and in all 29 patients within five hours after the 2-g dose. The mean concentrations of cefaman dole required to inhibit gram-negative pathogens were variable, although eight of 22 mean minimum inhibitory concen trations of cefamandole against Enterobactereaceae were ^-1 (xg/ml, and an addi tional five were ^ 2 ng/ml (Table 5). Aqueous humor concentrations of 1 fig/ml were achieved only once with the
Eickhoff and Ehret13 0.7 (0.2-3.1) 0.5 (0.1-6.2) 0.04 (0.03-0.125) 0.05 (0.03-0.5)
100 (0.78->100) 1.3(0.2-100) 0.4 (0.025-100) 1.0 (0.2-100) 0.18 (0.06-0.5) 2.0 (0.1-100) 1.0 (0.2-100) 18 (0.012-100) 0.4 (0.2-50) 0.3 (0.05-100) 1.0 (0.4-3.2)
1-g dose, but in 11 of 21 patients within two hours after the 2-g dose. Levels of 2 Hg/ml were achieved in no patients with the 1-g dose and in only four patients with the 2-g dose. Thus, concentrations of cefamandole effective against most Enterobactereaceae were not consistently achieved. Since aqueous humor antibiotic levels are increased in secondary aqueous humor13 and since secondary aqueous humor levels are thought to approximate more closely those levels achieved in the inflamed eye,13 it is possible that levels of cefamandole effective against more Enterobactereaceae might be achieved in the infected eye. We reviewed concentrations of other
TABLE 6 THERAPEUTIC IMPLICATIONS O F CEFAMANDOLE LEVELS IN PRIMARY AQUEOUS HUMOR
Time (hrs)
No. with Level s> 0.5
1/2 1 2 4 6
1/4 4/6 1/5 0/5
1JL Intravenously No. with Level s> 1.0 0 1/6 0/5 0/5
No. wiith Level ^ 2.0
No. with Level ^ 0.5
0 0 0 0
6/8 7/8 5/5 5/8 3/7
2 g Intravenously No. with Level s> 1.0 3/8 4/8 4/5 2/8 0/7
No. with Level ^ 2.0 2/8 0/8 2/5 0/8 0/7
VOL. 85, NO. 3
347
CEFAMANDOLE IN AQUEOUS HUMOR TABLE 7
COMPARISON O F ANTIBIOTIC PENETRATION O F PARENTERAL CEPHALOSPORINS INTO PRIMARY AQUEOUS HUMOR IN MAN
Investigators Macllwaine, Sande, and Mandell14
Drug Cephalothin
Riley, Boyle, Cephaloridine and Leopold15
Macllwaine, Sande, and Mandell14
No. of Subjects Dose and Route Studied of Administration8 2g I.V.
19
Cefazolin
I.M.
Average Concentration (u,g/ml) Time After Aqueous Injection Serum Humor 30min 40 min 45 min 50 min 1 hr. Approximately 2 hrs Approximately 4 hrs Approximately 6 hrs
61 58 41 32
3.3 2.1 1.5 1.6
31.5 32.7 26.5 5.7
0.8 1.3 3.0 1.2
0.5 g I.V.
Approximately 40 min
35
