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Am .. J. Obstct. Gvnewl.

hydronephrosis, and oligohydramnios. The urinarY tract was successfully decompressed and the pregnancv proceeded without complications. The child was born at 35 weeks but died soon after birth because of lung hypoplasia. At autopsy the urethra was completely occluded by posterior urethral valves. The kidneys showed Potter type IV cystic dysplasia. Apparently, at the time of the fetal surgical procedure (21 weeks), the renal damage was already too advanced. Harrison and associates believe that the development of oligoh\·dramnios is a reliable indicator of severe renal impairment. The sequence of events described in our patient could support the suggestion of Harrison and associates. At 185 /7 weeks sudden oligohydramnios occurred, and from that moment on the bladder distention and hydronephrosis were remarkably moderate, reflecting, in our opinion, progressing renal damage. It appears that in this case intrauterine intervention might have been useful before the occurrence of oligohydramnios, at 18 weeks at the latest. It is obvious that intrauterine surgery at such an early gestational stage will raise many still unresolved technical and ethical questions. We wish to thank the Institute of Pathology of the State Cniversitv of Utrecht.

Fig. 2. Autopsy specimen of tVOgenital tract.

lation, the infant died after 20 hours of life. Catheterization of the urethra revealed a complete obstruction at 3 em from the meatus. Autopsy was performed. The lungs showed moderate hyaline membrane disease and interstitial emphysema but no hypoplasia at routine microscopic examination. The urethra was completely obstructed by prostatic urethral valves; the bladder was hypertrophic, and the ureters were dilated. The kidneys showed severe medullary dysplasia. and the cortex was extremely hypoplastic (Fig. 2). Subcapsular cysts were clearly present. Osathanondh and Potter' classified this cystic dysplasia, which is caused by urethral obstruction, as type IV. Beck 2 has shown in fetal lambs that urethral obstruction produced by ligation in the last half of gestation produces only simple hydronephrotic kidneys. However, ligation in the first half of gestation resulted in dysplasia and failure of formation of the nephron. Elevated pressure in the developing nephron system apparently interferes with normal cellular proliferation and differentiation. Harrison and associatesa performed a bilateral ureterostomy in a 21-week-old fetus with urethral stenosis,

REFERENCES I. Osathanondh. V.. and Potter. E.: Pathogenesis of polycvstic kidneys. Type 4 due to urethral obstruction, Arch. Pathol. 77:502, 1964. 2. Beck, A. D.: The effect of intrauterine urinary obstruction upon the development of the fetal kidnev, J. Urol. 105:784, 1971. :>. Harrison, M. R., Golbus, M. S.. Fillv, R. A.. Callen, P. W.. Katz. M.. De Lorimer. A. A., Rozen: M., and Jones, A. R.: Fetal surgery for congenital hydronephrosis. N. Engl. .J. Med. 306:591. 1982.

Serum tobramycin levels in puerperal women Jorge D. Blanco, M.D., Ronald S. Gibbs, M.D., Patrick Duff, M.D., and Yolanda S. Castaneda, R.N. Department of Obstetrics and G.vnecology, The Univenity of Texas Health Science Center at San Antonio, San Antonio. Texas

Because of the excellent activity of aminoglycosides against gram-negative aerobic bacilli. they are often used, in conjunction with penicillin or dindamycin, to treat postpartum infections. 1 Use of aminoglycosides, This study was approved by the Institutional Review Board of The University of Texas Health Science Center at San Antonio. Reprint requests: Jorge D. Blanco, M.D., Department of Obstetrics and Gynecology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio. Texas 78284.

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Table I. Various characteristics for all patients and for patients in the "therapeutic" and "subtherapeutic" groups Total group (N = 29)

Age (yr) Weight (kg) Height (inches) Serum creatinine (mg/dl) Postoperative hematocrit (%) Day of sampling Tobramycin dose (mg/8 hours) Postinfusion tobramycin level (tJ.g/ml)

23.3 73.0 61.7 0.75 29.6 2.7 108.9 5.4

± ± ± ±

± ± ±

±

5.1 13.1 2.4 O.ll 3.6 0.6 18.8 2.1

"Subtherapeutic" (N = 12)

23.4 ± 67.6 ± 61.5 ± 0.76 ± 30.5 :!: 2.8:!: 101.2 :!: 3.6:!:

5.1 10.7 2.9 0.14 3.7 0.6 16.2 0.8

"Therapeutic" (N = 17)

NS 0.05

NS NS NS NS 0.06 0.001

23.3 :!: 76.9 :!: 62.0:!: 0.74 :!: 29.0:!: 2.6:!: ll4.3:!: 6. 7 :!:

5.2 13.6 2.2 0.09 3.6 0.6 19.1 I. 7

Data are expressed as mean :!: SD.

however, may be fraught with problems. Inappropriate serum levels may lead to nephrotoxicity or ototoxicity, especially in patients with compromised renal function, and low serum levels may not eradicate the focus of infection.~· " Since clinical measures, such as weight, height, serum creatinine level, creatinine clearance, and hematocrit, do not provide precise estimates of dosage requirements, aminoglycoside serum levels are often necessary to assure optimal doses. Further, because of more rapid elimination, obstetric patients may have increased aminoglycoside requirements. In a study of gentamicin levels in postpartum women, Duff and associates~ showed that a 3 mg/kg/day dosage regimen results in "therapeutic" serum levels in only 65.8~t. The present studv describes the serum levels of tobramvcin in women with endometritis after cesarean section receiving a 4.5 mg/kg/day regimen. The pharmacokinetics of tobramvcin are very similar to those of gentamicin. This imestigation was conducted from April to October, 1982, at the ::vledical Center Hospital. All patients were receiving clindamycin plus tobramycin for post -cesarean section endometritis. Tobramycin was administered in a dose of 1.5 mg/kg of actual body weight e\Try 8 hours intravenously with no correction for obesity. The dose in I 00 ml of diluent was infused over a 30-minute period. Each patient also received clindamycin, 600 mg intravenously, every 8 hours. The usual length of therapy was 5 days when the response was good. On the second or third day of therapy, blood specimens \\-ere drawn for determination of tobramycin concentration. The first sample, considered the trough level, was drawn 30 minutes prior to the administration of the next dose. Thirty minutes after completion of the administration, a second sample was drawn and considered the postinfusion level. The blood samples were centrifuged, and the serum was frozen at -20° C until the antibiotic assay was performed. Within 4 days of collection, an agar diffusion bioassay was performed to obtain the tobramycin level. 4 The test organism was Klebsiella pneumoniae (A TCC 27799). The lower level of sensitivity of the assay was I JJ..g/ mi. Each patient had a complete blood count performed and a serum creatinine level measured before, during, and after antibiotic treatment. Prior to the onset of

therapy, all patients had an intrauterine transcervical lavage culture, as well as blood cultures. The clinical results of antibiotic therapy were noted for each patient. None of the patients had audiometric testing. A serum level between 5 and 10 JJ..g/ml of tobramycin in the postinfusion sample was considered "therapeutic." Levels below 5 JJ..g/ml were considered "subtherapeutic."2 Susceptibility testing of gram-negative aerobic bacilli was performed by the Kirby-Bauer technique with a 10 JJ..g tobramycin disk. A zone diameter ~ 14 mm indicated susceptibility. Statistical analysis was by x2 for discrete data and unpaired Student's t test for continuous data. Twenty-nine patients participated in the study. Table I lists various characteristics of the entire group. The trough level in all patients was :5:1 JJ..g/ml of tobramycin. The mean (±SD) postinfusion level was 5.4 ± 2.1 JJ..g/ml. Twelve patients (41.4%) had "subtherapeutic" levels, and 17 (58.6%) patients had "therapeutic" levels. One of these patients had a postinfusion level above 10 JJ..g/ml (11.5 JJ..g/ml). She weighed 65.8 kg and received 99.0 mg of tobramycin every 8 hours. None of the patients in either the "therapeutic" group or the "subtherapeutic" group showed a rise in serum creatinine level ~0.3 mg/dl during therapy. Ten of the 29 (34.5%) patients had aerobic gramnegative bacilli in the intrauterine culture. These isolates were Escherichia coli, 9; Klebsiella pneumoniae, 4; and Proteus mirabilis, 3. These isolates were susceptible to tobramycin in vitro. One patient had a bacteremia with a sensitive E. coli. Three of the 10 patients with gram-negative bacilli in the intrauterine culture failed to respond to therapy (including the one with the E. coli bacteremia). The intrauterine isolates in these patients were E. coli and P. mirabilis. For these cases, the serum tobramycin levels were 7.2, 5.5, and 2.3 JJ..g/ml. Reculture demonstrated persistence of susceptible E. coli in the patients with levels of 7.2 and 5.5 JJ..g/ml, while the third had no isolates recovered in the repeat culture. Even though the serum tobramycin levels in the first two patients were "therapeutic," the E. coli persisted with no other evident cause of failure. It is interesting to note the persistence of these microorganisms despite "therapeutic" serum levels. Also, three of the seven patients with aerobic gram-negative bacilli and a good response had "subtherapeutic" serum tobramycin levels.

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Aminoglycosides, in combination with other antibiotics, are commonly administered for treating postpartum infections. 1 Proper dosage of these antibiotics is important to achieve optimal serum levels. While too low a serum level may result in "breakthrough" bacteremia or lack of response, excessive levels may lead to nephrotoxicity or ototoxicity. With such a narrow therapeutic range, measurement of serum levels is recommended, especially in severely ill patients and some obstetric patients. 2 · " Correct dosing is complicated further in obstetric patients because of the normal renal and volume changes of pregnancy. In pregnancy, there is an expanded extracellular fluid space and increased fat deposition. These changes begin to regress in the puerperium and alter the handling of aminoglycosides by postpartum patients. Aminoglycosides are distributed throughout the extracellular fluid space, and the volume of distribution varies widely in obstetric patients.'1 Zaske and co-workers'1 showed that the gentamicin half-life in obstetric patients was 1.4 hours compared to nonpregnant values of 2.5 to 4.0 hours. In their study of 67 obstetric patients, the mean gentamicin dose required to achieve therapeutic levels was 5.2 mg/kg/day. This dose is higher than the manufacturer's recommendation of 3 to 5 mg/kg/day and much higher than the regimens of 3 mg/kg/day or 80 mg every 8 hours often used in clinical practice. 1• 2 With a 3 mg/kg/dav, Duff and associates 2 reported that 34.2% of puerperal patients with endometritis had "subtherapeutic" serum levels of gentamicin. Few patients in that study had gram-negative bacilli isolated from the uterus, and the low gentamicin level did not result in any clinical failures. With very similar patients but a dose increase to 4.5 mg of tobramycin/kg/day. 41.3% of the patients in this study had "subtherapeutic" levels. Although the mean dose of aminoglycoside in the study by Duff and colleagues was significantly lower than the present values (74.8 ± 17.0 versus 108.9 ± 18.8 p,g/ml, p <0.001). the mean serum level and number of patients with "subtherapeutic" levels were comparable (NS). Since the pharmacokinetics of tobramycin and gentamicin are similar and the patient population was similar, the reason for comparable serum levels despite a higher dose is unclear.


Shorter dosing intervals or higher doses mav be needed to obtain adequate levels. Antibiotic activity is related not just to the postinfusion level but also to the length of time that antibiotic levels remain above the level of sensitivity of the infecting organism. Since all patients (in both studies) had trough levels ~I p,g/ml. more frequent dosing is probably safe and may be useful to assure adequate antibiotic levels. To prevent extended periods of subinhibitory concentrations, Zaske and associates'1 shortened the dosing interval to 6 hours or less in 59 of 67 patients with good results.' 1 While theoretical concern exists because of the large number of patients with "subtherapeutic" levels, the clinical significance of"subtherapeutic" levels is unclear because of the small number of studies 1vhich report serum aminoglycoside levels for puerperal patients. Further clinical studies with shorter intervals, serum levels, and varying doses are required to develop recommendations for aminoglycoside use in puerperal patients. Serum aminoglycoside levels should be determined in severely ill patients, particularly individuals with compromised renal function. Also, determinations of serum levels may be clinically useful in puerperal patients receiving high doses of aminoglycosides. Further, this study shows that even a 4.5 mg/kg/day dose may result in "subtherapeutic" aminoglycoside serum leYels in many puerperal patients.

REFERENCES I. di Zerega. G., Yonekura. L.. Roy, S., Nakamura, R. M., and

Ledger, W. J.: A comparison of dindamycin-gentamicin and penicillin-gentamicin in the treatment of post-cesarean section endomyometritis, AM. J. 0BSTET. GYNE-

COL. 134:238, 1979. 2. Duff. P., Jorgensen, J. H., Gibbs, R. S., Blanco, ]. D., Alexander, G., and Castaneda, Y. S.: Serum gentamicin

levels in patients with post-cesarean endomyometritis. Obstet. Gynecol. 61:723, 1983. 3. Zaske, D. E., Cipolle, R. J., Strate, R. G., Malo, J. W., and Koszalka, M. F.: Rapid gentamicin elimination in obstetrics patients, Obstet. Gynecol. 56:559, 1980. 4. Sabath, L. D., and Anhalf, J. R.: Assay of antimicrobics, in Lennette, E. H., Balows, A., Hausler, W. J., and Truant, ]. P., editors: Manual of Clinical Microbiology, ed. 3, Washington, D. C., 1980. American Society for Microbiology, pp. 485-490.