Vancomycin elimination in patients with burn injury.

Patients with burns clinically appear to require considerably larger doses of vancomycin than normal to attain therapeutic serum concentrations. It has been presumed that this phenomenon is a result of increased renal elimination of this drug consequent to increased glomerular filtration rates in such patients, as has been documented with aminoglycoside antibiotics. We measured the serum clearance of vancomycin in 10 patients with burns and found this parameter to correlate closely with creatinine clearance (serum clearance = 12.5 + 0.695 creatinine clearance; r = 0.932; P less than 0.001). The slope of this relationship was similar to that reported by other investigators in patients not suffering from thermal injury. We conclude that at all levels of renal function, patients with burns clear vancomycin in a manner similar to that of other patients. Consequently, renal function can be used to select a dosing regimen for vancomycin in such patients.

Antibiotic concentration in maternal blood, cord blood, and placental membranes in chorioamnionitis.

Levels of five antibiotics used in treating chorioamnionitis were measured in maternal and cord blood and placenta. Ampicillin provided the highest ratio of cord to maternal blood (0.71). Gentamicin was also relatively high in this respect and also had the highest placenta to maternal blood ratio (3.97). Based on these findings, the commonly used combination of ampicillin and gentamicin seems appropriate, although additional anaerobic coverage may be needed.

Alterations in lower reproductive tract flora after single-dose piperacillin and triple-dose cefoxitin at vaginal and abdominal hysterectomy.

There are no current data regarding the effect of a newer, broad-spectrum penicillin on lower reproductive flora at hysterectomy. To identify any existing differential effect on species and their susceptibilities, we obtained pre- and postoperative lower reproductive tract culture material from 209 women who were given single-dose piperacillin, then placebo or triple-dose cefoxitin, intravenously for prophylaxis at vaginal and abdominal hysterectomy in a prospective, randomized, blinded clinical trial. Significantly more preoperative endocervical bacteria were susceptible to piperacillin. Piperacillin caused less alteration in the numbers of lower reproductive tract flora when preoperative species were compared with postoperative species. More resistance to cefoxitin was identified postoperatively in bacteria recovered from the vaginal cuff of women who remained uninfected.

Transfer of ceftizoxime surpasses that of cefoperazone by the isolated human placenta perfused in vitro.

The transfer of cefoperazone and ceftizoxime across the human placenta was compared using the in vitro, bidirectionally perfused human placental lobule. The mean (+/- SEM) clearance indices for ceftizoxime and cefoperazone were 0.124 +/- 0.02 and 0.037 +/- 0.01, respectively (P = .0013). Cefoperazone concentration plateaued at a fetal concentration of 4-5 micrograms/mL in a recirculating perfusion system. No evidence of a decreasing slope of ceftizoxime transfer to the fetal compartment was noted after 60 minutes of perfusion. In a closed-closed perfusion system with equal concentrations of ceftizoxime in each compartment, a 1.1:1 fetal gradient was noted. These data indicate that ceftizoxime crosses the placenta significantly better than does cefoperazone and support our in vivo study documenting preferential concentration of ceftizoxime in the fetal compartment.

Concomitant infection with Neisseria gonorrhoeae and Chlamydia trachomatis in pregnancy.

Gonorrhea is an important marker for endocervical chlamydial infections in nonpregnant women. Concomitant infection rates as high as 50% have been reported. There are few data on concomitant infection rates in pregnant patients. The purpose of this study was to examine the prevalence of endocervical chlamydial infections in pregnant women with gonorrhea. Patients with cervical cultures positive for Neisseria gonorrhoeae at their initial prenatal visit had endocervical specimens for Chlamydia trachomatis culture obtained before anti-gonorrheal therapy. Control patients were selected at random from the same prenatal population. The prevalence of C trachomatis in patients with gonorrhea was significantly greater than that in the control population (46 versus 5%; P less than .001). Patients with gonorrhea were younger, less often married, and more often black than the control population, but these demographic differences did not account for the large difference in the chlamydial prevalence. Erythromycin 500 mg four times daily provided an excellent cure rate without intolerable side effects. Pregnant patients being evaluated or treated for gonorrhea should also be considered at high risk for concomitant cervical chlamydial infection.

Penicillin levels following the administration of benzathine penicillin G in pregnancy.

OBJECTIVE: To investigate the distribution of penicillin in the maternal-placental-fetal unit at term gestation. METHODS: Twenty-five healthy gravidas at 38-39 weeks' gestation scheduled for elective repeat cesarean delivery under spinal anesthesia received benzathine penicillin G, 2.4 million units intramuscularly (IM) preoperatively. Ten women delivered 1 day after injection, five delivered 2-3 days after, and ten delivered 7 days after. We collected maternal serum and cerebrospinal fluid, amniotic fluid (AF), and cord serum at delivery. Penicillin levels were measured using a validated agar disc diffusion method (sensitivity 0.006 micrograms/mL) with Micrococcus lutea as the test organism. RESULTS: There was no significant difference in mean penicillin levels at day 1, day 2-3, or day 7 for maternal serum, maternal cerebrospinal fluid, cord serum, or AF. The mean (+/- standard error) penicillin concentration (range 0.005-0.59 micrograms/mL) in maternal serum declined from 0.14 +/- 0.04 micrograms/mL 1 day after injection to 0.08 +/- 0.06 micrograms/mL 7 days after injection. The proportion of patients with a penicillin concentration at or above 0.018 micrograms/mL in the maternal serum declined significantly from day 1 to day 7 (P = .03). Overall, nine of 25 women (36%) had serum penicillin levels that were less than 0.018 micrograms/mL. CONCLUSION: A wide range of penicillin levels were observed in gravidas at term in the maternal serum, cerebrospinal fluid, umbilical cord serum, and AF within 1 week after 2.4 million units of benzathine penicillin G IM. We speculate that altered pharmacokinetics may affect the efficacy of this drug for prevention of congenital syphilis in the near-term gestation.

Cefoperazone and cefoxitin prophylaxis for abdominal hysterectomy.

One hundred one women undergoing elective abdominal hysterectomy were given perioperative cefoperazone or cefoxitin in a prospective randomized blinded study. Both regimens were well tolerated and no significant toxic or allergic manifestations were observed. Interrelationships between antimicrobial concentration in serum and pelvic tissues, intraoperative cardinal ligament cultures, febrile morbidity, and major postoperative infection were determined. At uterine removal, mean cefoperazone concentrations in serum (56.1 micrograms/mL) and pelvic tissues (18.6 micrograms/g) were significantly higher than mean concentrations of cefoxitin, ie, 16.1 micrograms/mL and 8.1 micrograms/g, respectively (P less than .001). The incidence of major postoperative infection was 6% or less with both regimens. Perioperative prophylaxis significantly reduced the incidence of this infection. When it did develop, however, it continued to cause significant morbidity, prolonging hospital stay a mean of more than four days (P less than .001) and increasing the hospital bill a mean of almost $1500 (P less than .001).

Cefotaxime metabolism by hemolyzed blood: quantitation and inhibition of the deacetylation reaction.

The metabolism of cefotaxime (CTX) by hemolyzed blood at different concentrations, time intervals, and temperatures was studied. Cefotaxime and desacetylcefotaxime (DES) levels were quantitated by reverse phase high pressure liquid chromatography. When CTX was added to tubes with 10% hemolysis, CTX/DES levels (micrograms per milliliter) were 123/134, 161/114, and 202/60 at 37 degrees C, room temperature, and 4 degrees C, respectively, after a 1 hr incubation. No reduction in CTX was observed in control experiments (10% blood, no hemolysis) at these temperatures after 1 hr; 200 +/- 23 micrograms/ml CTX; 5 +/- 2 micrograms/ml DES. The disappearance half-life of CTX in 10% hemolyzed blood at 37 degrees C was 45.7 min and at room temperature 84.3 min (p less than 0.001). The addition of the enzyme inhibitors ethylenediaminetetraacetic acid and p-hydroxymercuibenzoate reduced the metabolism of CTX in the presence of 10% hemolysis after 1 hr at 37 degrees C from 41% to 19% with ethylenediaminetetraacetic acid (0.45 mM) and to 0% with p-hydroxymercuibenzoate (10 mM). Our results suggest that for accurate determinations of CTX serum levels, which often have some degree of hemolysis, such specimens should be collected in tubes with ethylenediaminetetraacetic acid or p-hydroxymercuibenzoate and transported at 4 degrees C.

Collagen shield delivery of amphotericin B.

By using a high-pressure liquid chromatography assay, we investigated the ability of collagen shield therapeutic contact lenses to release amphotericin B and deliver it to the anterior segment of rabbit eyes. In vitro studies showed that presoaked collagen shields released most of the amphotericin B within the first hour of elution. We compared the corneal and aqueous humor amphotericin B levels produced by collagen shields soaked in amphotericin B and frequent-drop therapy at four time points over a six-hour period. The collagen shields soaked in amphotericin B produced corneal levels that were higher than those produced by frequent-drop therapy at one hour, equivalent to drop therapy at two and three hours, and lower than drop therapy at six hours. There were no differences in amphotericin B levels in aqueous humor at any time point between rabbits treated with collagen shield delivery and rabbits treated with frequent-drop delivery. The results of this study suggest that amphotericin B delivery to the cornea by collagen shields is comparable to frequent-drop delivery but has the potential benefit of added convenience and compliance.

Studies on the placental transfer of cell-free human immunodeficiency virus and p24 antigen in an ex vivo human placental model.

OBJECTIVE: We studied whether the human placenta has the structural integrity to impede transplacental passage of cell-free human immunodeficiency virus (HIV)-1 or p24 antigen from the maternal to the fetal circulation. METHODS: Nine term human placentas from uncomplicated vaginal or cesarean section deliveries were studied ex vivo with a placental perfusion apparatus to determine whether cell-free HIV-1 at 200-2000 tissue culture infectious dose (TCID50/mL) would pass to the fetal circulation. Passage of virus or p24 was assessed by infectivity titration and/or p24 antigen capture enzyme immunoassay. RESULTS: Infectious HIV-1 was not detected in any of the fetal perfusate samples taken periodically during experiments. Low concentrations of HIV-1 p24 antigen, however, were detected in fetal perfusate samples from three placentas. CONCLUSIONS: The term human placenta effectively impedes passage of cell-free HIV-1 from the maternal to the fetal circulation. However, it may be permeable to passage of p24 antigen.

Possible pseudoresistance of Streptococcus pneumoniae to penicillin G in a patient with a mixed pneumococcus-Staphylococcus aureus pneumonia.

We report the case of a 53-year-old woman with a mixed pneumococcus-staphylococcus pneumonia, in which both organisms were recovered from both sputum and blood. Streptococcus pneumoniae persisted in sputum 48 hours after initiation of high-dose intravenous penicillin G. When nafcillin was substituted for penicillin G, both pneumococci and staphylococci were eradicated from blood and sputum. This strain of Streptococcus pneumoniae was highly susceptible to penicillin G, but the associated strain of Staphylococcus aureus was not. The staphylococcus produced large amounts of a penicillin -degrading betalactamase . We reviewed the records of ten cases of pneumococcus pneumonia from the Wayne State University-Detroit Medical Center admitted from March 1978 to April 1981, in which sputum cultures were repeated within one to ten days after penicillin G had been initiated. At second cultures of sputum, Streptococcus pneumoniae was recovered in none of these latter cases. We further showed that on a blood agar culture plate in the presence of penicillin G, a beta-lactamase positive strain of Staphylococcus aureus allowed growth of Streptococcus pneumoniae. Therefore, despite penicillin therapy, Staphylococcus aureus in sputum may facilitate the persistence of Streptococcus pneumoniae.

Single-agent therapy for acute pelvic inflammatory disease: sulbactam/ampicillin versus cefoxitin.

A total of 54 women with acute salpingitis were treated intravenously with ampicillin/sulbactam or cefoxitin in a prospective, randomized, ongoing study. Of the organisms isolated, Gram-negative species (excluding Neisseria gonorrhoeae) were considerably more likely to produce beta-lactamase than were Gram-positive species. Clinical efficacy was 94% for 2 g ampicillin plus 1 g sulbactam and 89% for 2 g cefoxitin, all given intravenously every 6 h. The addition of sulbactam, an irreversible beta-lactamase inhibitor, to ampicillin restored both the microbiological and clinical activities of ampicillin. Both regimens were equally safe and demonstrated good efficacy in the treatment of the acute, symptomatic phase of infection.

The ex vivo human placental transfer of the anti-HIV nucleoside inhibitor abacavir and the protease inhibitor amprenavir.

OBJECTIVE: The transfer of abacavir, a new nucleoside inhibitor, and amprenavir, a new protease inhibitor, used for the treatment of human immunodeficiency virus, has been studied in the ex vivo human placental model. METHODS: The ex vivo human placental model used C14 antipyrine to determine the transport fraction and clearance index of these compounds at both the peak and trough serum concentrations. The clearance index accumulation and tissue concentrations were determined for each drug by high pressure liquid chromatography. RESULTS: The clearance index of abacavir was 0.47 +/- 0.19 and 0.50 +/- 0.07 at peak and trough concentrations, respectively. The clearance index of amprenavir was 0.38 +/- 0.09 and 0.14 +/- 0.08 at peak and trough concentrations, respectively. There was no unusual accumulation of either drug in the media or tissue when the perfusion system was closed. CONCLUSION: Abacavir is the first nucleoside compound studied in the perfusion system with a high clearance index. The transfer of the protease inhibitor amprenavir had a clearance index 2.75 times greater than the clearance index of ritonavir at peak concentration determined in a previous study. At trough concentration the clearance index was much less than at the peak concentration. A similar result was found with ritonavir.

Ex vivo human placental transfer of anti-human immunodeficiency virus compounds.

OBJECTIVE: The transfer of anti-human immunodeficiency virus (HIV) drugs has been studied in the ex vivo human placental model. There is a paucity of information on the placental transfer of these drugs because of ethical considerations and the expense involved in the use of the non-human primate model. METHODS: The standardized ex vivo human placental model was used in these studies and the clearance index in relationship to antipyrine was used to determine the role of transfer of non-nucleosides, nucleosides, and a protease inhibitor. Several of the nucleosides and ritonavir were combined with zidovudine (AZT) to determine the effect of the combinations. RESULTS: All non-nucleosides, nucleosides, and the protease inhibitor were found to cross the human placenta by simple diffusion, although at variable rates. Ritonavir did not diffuse as rapidly as the nucleosides, but some diffusion was noted at peak concentrations. CONCLUSIONS: Ex vivo perfusion studies agree with those determined in the non-human primate model and with data from existing clinical trials.

High-pressure liquid chromatographic assay of sulbactam in plasma, urine, and tissue.

A reverse-phase high-pressure liquid chromatography method for the quantitation of sulbactam in plasma, urine, and tissue is described. The assay used the formation of an imidazole derivative followed by extraction with acetonitrile and dichloromethane and used UV absorbance for detection. The mobile phase consisted of acetonitrile, tetrabutylammonium hydroxide, and phosphate buffer. The assay was linear from 100 micrograms/ml (g of tissue) to 1 microgram/ml (g). Within- and between-batch recovery was greater than 90%. The coefficient of variation was generally less than 15%. There were no interfering peaks in the quantitation of sulbactam.

Placental transfer of ritonavir with zidovudine in the ex vivo placental perfusion model.

OBJECTIVE: The object was to determine the placental transfer of ritonavir alone and in combination with zidovudine. STUDY DESIGN: Twelve placental perfusion studies were performed at trough (1-2 microg/mL) and peak (approximately 20 microg/mL) combinations of ritonavir and zidovudine. Accumulation of ritonavir was determined. RESULTS: Transfer of ritonavir at trough concentrations was undetectable (<0.025 microg/mL). The clearance index of ritonavir at peak concentration was 0.085 +/- 0.05 and was unaffected by zidovudine. The fetal concentration of ritonavir was 0.0758 +/- 0.22 microg/mL at a maternal concentration of approximately 20 microg/mL and 25.5 +/- 6.9 microg/mL at a concentration of 100 microg/mL. There was no tissue accumulation of ritonavir either alone or with zidovudine. CONCLUSION: The clearance index of ritonavir at therapeutic levels was extremely low, with little accumulation in the fetal compartment and no accumulation in placental tissue. Zidovudine does not significantly affect the transfer or accumulation of ritonavir.

Ex vivo human placental transfer of trovafloxacin.

OBJECTIVE: The purpose of this study was to determine the ex vivo human placental transfer of trovafloxacin from the maternal circulation to the fetal circulation. METHODS: Six placentas from uncomplicated, term, vaginal or cesarean deliveries were studied using the ex vivo isolated cotyledon perfusion chamber; 14C-antipyrine was used as a reference compound to determine the clearance index (CI) of trovafloxacin. RESULTS: The CI of trovafloxacin was 0.19 +/- 0.13 at a mean trough concentration of 1.38 +/- 0.22 microg/ml and 0.16 +/- 0.10 at a mean peak concentration of 7.48 +/- 2.3 microg/ml as determined by our newly developed high-pressure liquid chromatographic assay. Tissue concentration did not exceed maternal concentration, and there was little or no accumulation when the perfusion system was closed for 1 hr. CONCLUSIONS: Trovafloxacin crosses the placenta by simple diffusion and does not accumulate in the media to any extent, nor does it bind to tissue or accumulate in the placenta.

Ex vivo human placental transfer and the vasoactive properties of hydralazine.

OBJECTIVE: The purpose of this study was to determine the placental transfer and fetal vascular effects of hydralazine in an ex vivo human placental system. STUDY DESIGN: Nine placentas from uncomplicated term vaginal or cesarean deliveries were studied by means of the ex vivo single-cotyledon perfusion system. Antipyrine was used for the reference compound in the determination of the clearance index of hydralazine. Fetal vascular effects of hydralazine were determined by the effects on the perfusion pressure of the fetal artery in a constant-flow open system. Variations in fetal pressure were analyzed with the 1-sample Student t test. RESULTS: The clearance index of hydralazine ranged from 0.61 +/- 0. 18 to 0.73 +/- 0.14. The accumulation of hydralazine in the recirculated fetal compartment was linear in relationship to the maternal concentration. Fetal pressure changes were noted in 6 of the 9 placentas, or 66.6%. The mean change in pressure was -4.1 +/- 4.4 mm Hg (P =.0231). CONCLUSIONS: Hydralazine readily crosses the ex vivo human placental perfusion system.

Determination of pentamidine transfer in the in vitro perfused human cotyledon with high-performance liquid chromatography.

Pentamidine is used to treat Pneumocystis carinii pneumonia. The incidence of this infection in pregnancy has paralleled the increasing incidence of acquired immunodeficiency syndrome in pregnancy. Using the in vitro bidirectionally perfused human placenta, we studied the transfer of pentamidine across the placenta. Pentamidine was added to the maternal circulation at therapeutic concentrations (2 micrograms/ml). No transfer of pentamidine was detectable with a newly devised high-performance liquid chromatography method sensitive to 0.05 micrograms/ml of pentamidine. Increasing the pentamidine concentration tenfold produced a low level of transfer to the fetal circuit. Fetal concentrations were far below maternal perfusate concentrations. Placental tissue levels were higher than media levels. These data are suggestive of minimal drug transfer to the fetus and significant concentration of the drug in placental tissue.