Gentamicin dosing in postpartum women with endometritis

Gentamicin dosing in postpartum women with endometritis Gerald G. Briggs, BPharm,·,b Peter Ambrose, PharmD,·,b and Michael P. Nageotte, MD" Long Beach and San Francisco, California Postpartum women receiving gentamicin for endometritis were studied to determine if selective determination of gentamicin serum levels was cost-effective in terms of safety and efficacy. The women were randomized into two groups of 30 patients each. In the control group gentamicin serum levels were determined after the third dose. In the study group, levels were determined only if renal dysfunction was evident or if the patient failed to respond to therapy. Determination of serum levels did not assure a better therapeutic outcome in either group, as measured by hospital stay, duration of treatment, total cost of antibiotics, and hospital readmissions. Although pharmacokinetic dosing equations were used, the use of 1.75 mg/kg every 8 hours based on actual body weight in patients with average heights and weights would have produced acceptable results. We conclude that routine monitoring of gentamicin serum levels is not required in otherwise healthy postpartum women with endometritis. (AM J OSSTET GVNECOL 1989;160:309-13.)

Key words: Endometritis, gentamicin, dosing regimens, serum levels Gentamicin, an aminoglycoside antibiotic, is often used in combination with other antibiotics for the treatment of postpartum endometritis. This agent has proved effective and is one of the least expensive parenteral antibiotics available. Although both nephrotoxicity and ototoxicity may occur with excessive serum gentamicin concentrations, this is rarely a problem during the usual short-term therapy required for postpartum endometritis. To the contrary, after dosing with the usual regimens, low gentamicin levels occur due to the increased glomerular filtration rate and volume of distribution that are physiologic consequences of pregnancy. Because of these factors, determination of at least one set of peak and trough gentamicin levels is recommended for all postpartum women to assure therapeutic drug concentrations. \·4 However, the cost of these determinations is relatively high, thereby offsetting much of the savings realized from the use of this antibiotic. Therefore we have routinely determined gentamicin serum levels only in selected patients: those who fail to respond to therapy within 24 hours and those with any degree of renal dysfunction. The objectives of this study were twofold: (1) to determine if selective sampling was comparable in safety and efficacy to sampling all women treated with gentamicin for postpartum endometritis, and (2) to determine if the apparent savings realized by selective sampling was offset by longer hospital stay. From the Women's Hospxtal Memorial Medical Center,' Long Beach, and University of Califomxa, San Francisco. b Received for publication April 29, 1988; revised July 7, 1988; accepted July 29, 1988. Reprint requests: Gerald G. Briggs, BPharm, Women's HOSpital Memonal Medical Center of Long Beach, 2801 Atlantxc Ave., Long Beach, CA 90801-1428.

Material and methods The study protocol was approved in accordance with the ethical standards of the hospital's committees on human experimentation. A total of 60 women in the immediate postpartum period (within 5 days of delivery) were prospectively enrolled in the study (30 in each group) between April 1987 and September 1987, provided their physician agreed and the following criteria were met: (1) they were diagnosed as having endometritis, (2) intravenous gentamicin therapy has been ordered, (3) they were not receiving other potentially renal-toxic drugs, and (4) informed consent was obtained. All gentamicin doses and serum level determinations were ordered by the pharmacy staff in Women's Hospital. Antibiotic therapy in addition to gentamicin was not controlled but its use was tabulated. Patients were randomized to one of two groups. Loading gentamicin doses were calculated to obtain an estimated peak concentration of 8 jLg/ml, followed by maintenance doses at 8-hour intervals to produce peak levels of 7 to 8 jLg/ml and trough levels less than 1.5 jLg/ml. All doses were mixed with 30 to 60 ml dextrose 5% in water (volume dependent on concentration of gentamicin) and infused intravenously over 30 minutes. Serum samples were drawn both 30 to 60 minutes after infusion of a dose and 4 hours thereafter. Because of the rapid half-life in this patient population, the time of the second gentamicin level was set at 4 hours so that a measurable concentration was obtained and pharmacokinetic parameters could be determined accurately. Samples obtained at the time of the actual trough invariably contain concentrations below the sensitivity of the assay and cannot be used for pharmacokinetic calculations. All samples were placed immediately on ice and frozen until analysis. Levels were

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February 1989 Am J Obstet Gynecol

Table I. Demographic data Charactenstic

Age (yr) Height (em) Actual body weight (kg) Ideal body weight (kg) Gravidity Parity Race White Black Latin Asian Clinic patients

Control group (n = 28)

Study group (n = 28)

P Value

26.1 ± 4.9 159.5 ± 9.6 78.9 ± 17.5

27.6 ± 6.6* 162.0 ± 6.3* 82.8 ± 26.1*

0.17 0.13 0.26

52.4 ± 7.4 3.0 ± 1.8 2.0 ± 1.6

54.3 ± 5.7* 2.7 ± 1.7* 1.8 ± 1.1*

0.14 0.26 0.29

20 (71%) 4 (14%) 2 (7%) 2 (7%) 1 (4%)

16 (57%)t 7 (25%)* 3 (11 %)* 2 (7%)* 0*

0.40

0.50

Data are the mean ± SD.

determined by the laboratory once daily by a radioimmunoassay (Diagnostics Products, Los Angeles, Calif.) with a coefficient of variation of 16% at a concentration of 1.0 ILg/ml and of 8% at a concentration of 6.5 ILg/ml. In the control group, gentamicin levels were measured after the third dose. Subsequent doses and dosing intervals were adjusted, if necessary, to maintain peak concentrations in the 7 to 8 ILg/ml range and trough concentrations less than 1.5 ILg/ml. For patients in the study group, gentamicin levels were measured only if at least one of three conditions was present: (1) the patient had renal impairment as evidenced by two successively measured serum creatinine values above 1.0 mgldl drawn 24 hours apart, (2) the patient had only one functioning kidney, or (3) the patient still had febrile morbidity 24 hours or more after the first dose of gentamicin. When gentamicin levels were measured in the study group, subsequent doses of the antibiotic were adjusted as in the control group. Endometritis was diagnosed on the basis of febrile morbidity, foul-smelling lochia, unusual uterine and parametrial tenderness, and no laboratory or physical evidence of infection at another source.' Febrile morbidity was defined as an oral temperature of 100.40 F (38.0 0 C) or greater measured twice, at least 4 hours apart, excluding the first 24 hours. 6 Wound infection was defined as drainage, purulence, or cellulitis in the wound of a febrile patient. 6 A diagnosis of urinary tract infection was made if more than 100,000 organisms per milliliter were present in a clean-catch urine specimen or one obtained by catheterization. Serum creatinine levels were determined in all patients before the first dose of gentamicin and then repeated at 3-day intervals as long as the patient was receiving gentamicin. Initial serum creatinine values greater than 1.0 mgldl were repeated in 24 hours. Other laboratory tests, ordered at the discretion of the

attending physician, included complete blood counts, urinalysis, and appropriate bacterial cultures. Standard equations were used to calculate the initial and maintenance doses of gentamicin and the various pharmacokinetic parameters. 7 Statistical analysis of the study data was by X2 analysis with Yates' correction, the Fisher exact test, the Student t test, or a paired t test. Significance was determined by p < 0.05.

Results Four patients, two in each group, were excluded from analysis. One patient was excluded based on age (14 years), because the procedures for estimating pharmacokinetic parameters were not designed for patients less than 16 years old. The other three patients were excluded because the diagnosis of endometritis was changed by the attending physician after the start of therapy. There were no statistical differences between the groups in demographic characteristics (Table I) or cesarean section rate, risk factors for infection, and site(s) of infection (Table II). Thirty-three (18 controls and 15 in the study group) of 48 (68%) patients delivered by cesarean section were given cephalosporins for prophylaxis immediately after surgery. Two patients (1 control and 1 study patient) received prophylactic ampicillin. Although their use was not controlled, the antibiotics used with gentamicin (Table III) were similar for the two groups. Of the 28 patients not receiving an initial antibiotic to cover enterococcus infection (i.e., ampicillin), six had ampicillin added within 24 to 48 hours because of continuing fever. Each of the six patients had received cephalosporin prophylaxis. Bacterial culture materials were obtained for 22 (79%) of the controls and for 21 (75%) of the study patients. No endometrial culture materials were obtained after surgery. Aerobic gram-negative bacilli were cultured from

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Table II. Cesarean section rate: Obstetric complications, and site(s) of infection Study group

Control group (n = 28)

Cesarean section Complication Morbid obesity (>91 kg) Preterm labor Premature rupture of membranes Rupture of membranes> 12 hr Pregnancy-induced hypertension Diabetes mellitus (insulin-requiring) Chronic hypertension Site(s) of infection Amnionitis Endometritis Urinary tract Wound

four patients (Escherichia coli [n = 2] and Morganella morgani [n = 1] from urine specimens, and Enterobacter cloacae [n = 1] from a placenta), and all were sensitive to gentamicin (minimum inhibitory concentration <0.5 JLg/ml). Gentamicin therapy was begun in both groups a mean 1.5 days post partum. Serum levels were measured on (mean) postpartum day 2.5 for controls and 2.9 for study patients (difference NS). Mean serum creatinine values were identical (0.8 mg/dl) for the two groups. No statistical differences were found between the groups for estimated pharmacokinetic parameters. Because only five patients in the study group had gentamicin levels determined, the pharmacokinetic data for gentamicin for all patients with levels (28 control and 5 in the study group) were pooled and compared (Table IV). Statistically significant differences were found for each comparison. Peak and trough gentamicin levels did not exceed 7.9 JLg/ml and 1.0 JLg/ml, respectively, in any patient. In those patients who had levels determined, gentamicin doses were increased for 13 patients (10 control and 3 study patients) to maintain peak levels in the desired range of 7 to 8 JLg/ml. The mean peak concentration in these patients before dose adjustment was 5.8 JLg/ml. In every case, however, the patients were afebrile «100.4° F/38.0° C) before the dose was increased. In seven cases (6 control and 1 study patient), initial peak levels (mean 7.4 JLg/ml) were within the targeted range of 7 to 8 JLg/ml. In the remaining 13 women (12 control and 1 study patient), gentamicin concentrations were less than the desired range (mean 5.8 JLg/ml), but the patients were afebrile and the intravenous antibiotics had been discontinued by the attending physician shortly after the blood samples were drawn. The duration of gentamicin therapy, days hospitalized after the start of gentamicin therapy, and the total antibiotic cost per patient were nearly identical for the

(n

= 28)

P Value

23 (82%)

25 (89%)

0.65

4 10 13 10 5 2 2

8 8 14 12 6 0 2

0.19 0.78 1.00 0.79 1.00 0.79 1.00

6 (21%) 28 (100%) 2 (7%) 0

8 (29%) 28 (100%) 1(4%) 1(4%)

0.78 1.00 0.79 0.50

Table III. Intravenous antibiotic regimens Antibiotic regimen* Gentamicin + ampicillin Gentamicin + clindamycin Gentamicin + metronidazole Gentamicin + cefazolin Gentamicin + clindamycin + ampicillin Gentamicin + metronidazole + ampicillin

Control group (n = 28)

initial!fi nalt 8/6 13111

III

III

Study group (n = 28)

initial!finalt 9/8

10/6 2/2

III

5/8

5/9

011

112

*Dosages used: Ampicillin, 2 gm every 4 hr; cefazolin, I gm every 8 hr; clindamycin, 900 mg every 8 hr; and metronidazole, 1000 mg load, then 500 mg every 6 hr. tChange from initial to final antibiotic regimen occurred within 24 to 48 hours in each case.

two groups of patients (Table V). The power of this study to detect a difference between the groups of 25%, 35%, and 50% in days of hospital stay was 75%, 95%, and 99%, respectively. None of the patients were readmitted to the hospital for an infection within 30 days of discharge.

Comment Various strategies have been proposed for the dosing of aminoglycosides in pregnant or postpartum women. Most have attempted to allow for the increased renal clearance and volume of distribution that normally occur in these patients. These strategies usually involve some type of pharmacokinetic dosing equations, followed by routine determination of serum levels. l-4 Other methods involve dosing based on actual body weight (e.g., 1.0 to 1.5 mg/kg every 8 hours) either with"' 9 or without'° determination of serum levels. To our knowledge, none have attempted to administer therapy based on pharmacokinetic principles combined with selective determination of serum concentrations.

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Table IV. Pooled actual versus estimated gentamicin pharmacokinetic data Parameter

Volume of distribution (L) Volume of distribution (Llkg IBW) Gentamicin clearance (ml/min) Serum half-life (hr) Gentamicin concentration (fLg/ml) Peak Trough

EstImated (n = 33)

15.9 0.31 92 2.1

± ± ± ±

Actual (n = 33)

2.7 0.03 18 0.4

19.7 0.38 129 1.8

7.6 ± 0.2 0.6 ± 0.3

p Value*

± 5.2

<0.001 <0.001 <0.001 <0.05

6.1 ± 1.1 0.4 ± 0.3

<0.001 <0.001

± 0.09 ± 29 ± 0.5

Data are the mean ± SD. Ideal body weight.

IBW,

Table V. Antibiotic cost, duration of gentamicin therapy, and hospital stay

Duration of gentamicin therapy (days) Days hospitalized after start of gentamicin Total antibiotic cost per patient ($)

Control group (n = 28)

Study group (n = 28)

P value

2.7 ± 1.2

2.7 ± 1.1

0.50

3.5 ± 1.2

3.5 ± 1.1

0.90

339 ± 189

332 ± 199

0.45

Data are the mean ± SD.

Some authors have suggested that the newer broadspectrum 13-lactam antibiotics should be used because it is difficult to determine the aminoglycoside dose required to reach therapeutic levels. 9 However, this approach does not consider the higher cost that occurs from using these agents. At Memorial Medical Center, the acquisition cost of a typical gentamicin dose is $0.20 to $0.30. Changing to more expensive drugs seems counterproductive in light of tight budgetary controls. The published medical literature supports gentamicin peak and trough concentrations of 6 to 10 f.Lg/ml and 0.5 to 1.5 f.Lg/ml, respectively, as being effective. 1I The midrange of 7 to 8 f.Lg/ml was chosen for calculations because prior experience at Memorial Medical Center indicated this would produce therapeutic, but not potentially toxic, levels in this patient population. As predicted, true mean peak and trough levels were within the therapeutic ranges cited above. Although subgroups of patients had mean gentamicin concentrations less than 6.0 f.Lg/ml, there was no detectable adverse effect of these subtherapeutic levels on patient outcome. In a previous study, similar patients responded to low gentamicin levels. s The authors of that study speculated that the response may have been due to lack of infection with gram-negative bacilli or organisms very sensitive to gentamicin. Thus there was no demonstrable benefit from monitoring gentamicin concentrations in this study. The use of gentamicin, 1.5 mg/kg actual body weight every 8 hours, has been reported. 10 The use of this

method in the present study would have resulted in mean doses of 120 mg every 8 hours with peak and trough levels of 6.0 and 0.4 f.Lg/ml, respectively. These values are identical to the results obtained from pharmacokinetic calculations. Using 1. 75 mg/kg actual body weight would have resulted in doses and levels of 140 mg every 8 hours, 7.0 and 0.4 f.Lg/ml, respectively. With this higher dose, the only potentially toxic levels (peak 11.5 f.Lg/ml and trough 1.6 f.Lg/ml) would have occurred in a patient substantially below (129.5 cm) the average (160.8 cm) height in this study. Two patients, both with average heights, would have had very low peak levels (4.1 and 3.5 f.Lg/ml, respectively). Thus if gentamicin dosing based on pharmacokinetic parameters is not available, a dose of 1.75 mg/kg actual body weight every 8 hours is recommended. Determinations of gentamicin serum levels are probably not needed unless the patient's height or weight is much different from normal or if renal function is abnormal. Determining one set of peak and trough gentamicin levels at Memorial Medical Center costs approximately $150. During the 12-month period immediately preceeding this study, 209 patients with endometritis were treated with gentamicin. Measuring levels in all patients would have cost $31,350. By selective sampling, only 46 (22%) of these patients had levels determined, with a cost of $6,900, a savings of $24,450. None of the 46 patients had levels in the toxic range. Similar results have been produced annually since 1980. We conclude that, when gentamicin doses are deter-

Gentamicin dosing in endometritis

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mined by methods described herein, routine monitoring of gentamicin levels in women with endometritis and normal renal function does not assure a better therapeutic outcome as measured by hospital stay, duration of treatment, total cost of antibiotics, and hospital readmissions. Large cost savings can be realized by monitoring levels only in selected patients as described in this study. Moreover, greater savings can result by waiting at least 48 hours after the start of therapy to determine levels in women with persistent febrile morbidity; additional studies are required to determine if even this interval is beneficial. Calculation of gentamicin dosage by pharmacokinetic principles lessens the risk that potentially toxic levels will occur in these patients. In normal healthy patients, the use of 1.75 mg/kg actual body weight every 8 hours can be used. Patients with body heights or weights much different from average should have serum levels determined. Any patient with abnormal renal function, regardless of the dosing method used, should also have serum gentamicin levels determined. We thank Wendy Dorchester, MS, for the statistical calculations.

REFERENCES 1. Weinstein AJ, Gibbs RS, Gallagher M. Placental transfer of clindamycin and gentamicin in term pregnancy. AM J OBSTET GVNECOL 1976;124:688-91. 2. Zaske DE, Cipolle RJ, Strate RG, et al. Rapid gentamicin elimination in obstetric patients. Obstet Gynecol 1980; 56:559-64. 3. Gardner DK, Schneider PJ. Gentamicin dosage requirements in postpartum patients. Clin Pharm 1984;3:416-8. 4. Lazebnik N, Noy S, Lazebnik R, et al. Gentamicin serum half-life: a comparison between pregnant and nonpregnant women. Postgrad MedJ 1985;61:979-81. 5. Rudd EG, Cobey EA, Long WH, et al. Prevention of endomyometritis using antibiotic irrigations during cesarean section. Obstet Gynecol 1982;60:413-6. 6. Swartz WH, Grolle K. The use of prophylactic antibiotics in cesarean section. A review of the literature. J Reprod Med 1981 ;26:595-609. 7. Winter ME. Basic clinical pharmacokinetics. 2nd ed. San Francisco: Applied Therapeutics, 1988. 8. Duff P, Jorgensen JH, Gibbs RS, et al. Serum gentamicin levels in patients with post-cesarean endomyometritis. Obstet Gynecol 1983;61:723-7. 9. PastorekJG II, Ragan FAJr, Phelan M. Tobramycin dosing in the puerperal patient. J Reprod Med 1987;32: 343-6. 10. Walmer D, Walmer KR, Gibbs RS. Enterococci in postcesarean endometritis. Obstet GynecoI1988;71:159-61. II. Anonymous. Drug concentration monitoring. Perspect Clin Pharmacol 1984;2:84-5.

Format of an obstetrics and gynecology journal club and four years' experience Gary R. Thurnau, MD, and John I. Fishburne, Jr., MD

OklahorTUl City, OklahorTUl Departmental journal clubs have experienced varied degrees of success and longevity. Although a high degree of enthusiasm is difficult to maintain, clear objectives are key factors that encourage active participation. In this report we present a journal club format that has demonstrated popularity and 4 years of longevity. On the basis of this experience, we believe a journal club forum offers medical students and residents the optimal opportunity to learn an approach to critical reading of medical reports. In addition, they gain understanding of experimental design and research protocols and ultimately acquire knowledge of the current medical literature. (AM J OSSTET GVNECOL 1989;160:313-6.)

Key words: Journal club, critical reading, experimental design, medical literature Historically, departmental journal clubs have experienced varied degrees of success and longevity. Although a high degree of enthusiasm for a journal club From the Department of Obstetrics and Gynecology, University of Oklahoma College of Medicine. Received for publication Feb. 23, 1988; revised June 12, 1988; accepted July 29, 1988. Reprint requests: Gary R. Thurnau, MD, Associate Professor of Obstetrics and Gynecology, University of Oklahoma College of Medicine, P.O. Box 26901, Oklahoma City, OK 73190.

is difficult to maintain irrespective of the format (faculty led or resident led), I clear objectives are key factors that encourage active participation. 2 These objectives include (1) the use of a checklist system3 and format that enable one to select and read medical reports critically, (2) provision of an opportunity for each resident to gain experience in evaluating journal articles, and (3) elucidation of criteria on how to detect and prevent errors in the medical literature. I The purposes of this report are (1) to describe a 313