Antibiotic Administration in Patients Undergoing Common Surgical Procedures in a Community Teaching Hospital: The Chaos Continues

The influence of recently published guidelines by the Surgical Infection Society (SIS) on current surgical practice are not well documented. The appropriateness of antibiotic administration in a cohort of surgical patients undergoing elective and emergency surgery in a department of surgery in an urban, community-based, private, 560-bed teaching hospital was retrospectively reviewed. The following were the criteria defining administration as appropriate as modified from SIS guidelines: Prophylactic use: (1) started prior to operation; (2) spectrum appropriate to the specific operation; (3) duration ≤ 24 hours. Therapeutic use: (1) started prior to operation; (2) spectrum appropriate to pathology; (3) Duration ≤ 24 hours for contamination or “resectable” infection and ≤ 5 days for established infection in the absence of clinical evidence of persisting infection. Any switchover from an appropriate agent to another appropriate or inappropriate agent in the same patient in the absence of microbiologic or clinical indication was considered inappropriate administration. We reviewed the charts of 211 randomly selected patients who underwent elective (n= 132) or emergency (n= 79) procedures during 1996. The operations included gastrectomy (n= 22), appendectomy (n= 27), open (n= 5) or laparoscopic (n= 27) cholecystectomy, colectomy (n= 28), hysterectomy (n= 8), laparotomy for intestinal obstruction (n= 11), mastectomy (n= 26), and ventral hernia repair (n= 37). A total of 17 antibiotics were used for prophylaxis and 21 for therapy. In 156 patients (74%) the administration was considered inappropriate. Eight patients in the inappropriate group developed diarrhea (two cases of Clostridium difficile-induced colitis) compared to two cases of diarrhea in the appropriate group (nonsignificant). The average duration of administration after elective and emergency operations was 3.3 and 5.7 days, respectively. The total expense for excessive duration of administration was $18,533. Many surgeons are not familiar with the spectrum of antimicrobials and often do not distinguish between prophylactic and therapeutic administration. Antibiotic usage in current surgical practice is often inappropriate, excessive, and chaotic.     

Optical penalization can improve vision after occlusion treatment

BACKGROUND: Optical penalization (OP) has previously been shown to successfully maintain vision in amblyopic eyes of older children when patching compliance is poor and when vision decreases once patching is discontinued. This study shows that the final vision in optically penalized eyes is often better than the vision obtained after patching alone. SUBJECTS AND METHODS: During the 5-year period from January 1992 to February 1997, 28 children aged between 3.7 and 8.2 years (average age, 6.5+/-1.1 years) were optically penalized for an average of 1.5+/-0.75 years. The maximum length of penalization was 3.3 years, whereas the minimum time was 6 months. There were 21 children with strabismic amblyopia and 7 children with anisometropic amblyopia. All 28 children had worn a patch to achieve their best visual levels and then had shown a loss of best vision when occlusion was stopped. Patching was usually resumed and continued until the previous best vision was obtained; at this point OP was started to "maintain" vision. Eighteen of the 28 children have discontinued penalization and have been followed up an average of 1(1/2) years. RESULTS: Twenty-six (93%) of the 28 patients showed an increase in best vision from that found at the conclusion of patching, and 2 patients maintained their vision at the initial level. The average visual acuity at the start of penalization was 20/50 (0.42+/-0.11 logarithm of the minimum angle of resolution [log MAR]). Final average visual acuity was 20/27 (0.15+/-0.12 log MAR). The average increase in vision was nearly 3 lines or 0.27+/-0.12 log MAR. CONCLUSION: OP alone (without the use of pharmacologic agents such as atropine) not only maintains vision after patching therapy, but also appears to improve the final visual outcome.     

Pharmacokinetics and pharmacodynamics of the aromatase inhibitor 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione in patients with postmenopausal breast cancer

Summary The pyridylglutarimide 3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione (PyG) is a novel inhibitor of aromatase that was shown to cause effective suppression of plasma oestradiol levels in postmenopausal patients. In four patients receiving oral doses of PyG (500 mg) twice daily for 3–4 days, oestradiol levels fell to 31.1%±6.3% of baseline values within 48 h and remained suppressed during treatment. Of a further six patients who received oral PyG (1 g) as a single dose, five had quantifiable oestradiol levels. Oestradiol suppression was sustained for 36 h and recovery correlated with a fall of PyG concentrations below a threshold value of ca. 2 g/ml. The pharmacokinetics of PyG were non-linear and, when fitted to the integrated Michaelis-Menten equation, yielded good parameter estimates forC _o (21.7±1.82 g/ml),K _m (2.66±0.68 g/ml) and V_max (0.86±0.06 g ml^–1 h^–1). On subsequent repeated dosing with PyG, both theK _m (4.31±0.48 g/ml) and the V_max (1.83±0.13 g ml^–1 h^–1) values increased and recovery from oestradiol suppression was more rapid, indicating that PyG induces its own metabolism.Abbreviations PyG 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione - AG aminoglutethimide - CSCC cholesterol side-chain cleavage - HPLC high-performance liquid chromatography - AUC area under the concentration versus time curve This study was supported in part by grants to the Institute of Cancer Research (Royal Cancer Hospital) from the Cancer Research Campaign and Medical Research Council     

Cutaneous Metabolism of Nitroglycerin in Vitro. II. Effects of Skin Condition and Penetration Enhancement

The effects of skin storage, skin preparation, skin pretreatment with a penetration enhancer, and skin barrier removal by adhesive tape-stripping on the concurrent cutaneous transport and metabolism of nitroglycerin (GTN) have been studied in vitro using hairless mouse skin. Storing the skin for 10 days at 4°C did not alter barrier function to total nitrate flux [GTN + 1,2-glyceryl dinitrate (1,2-GDN) + 1,3-glyceryl dinitrate (1,3-GDN)]. However, metabolic function was significantly impaired and suggested at least fivefold loss of enzyme activity. Heating skin to 100°C for 5 min appreciably damaged hairless mouse skin barrier function. The ability to hydrolyze GTN was still present, however, and remained constant over the 10-hr experimental period, in contrast to the control, which showed progressively decreasing enzymatic function with time. Pretreatment of hairless mouse skin in vivo (prior to animal sacrifice, tissue excision, and in vitro transport/metabolism studies) with 1-dodecylazacyclo-heptan-2-one (Azone), a putative penetration enhancer, significantly lowered the skin barrier to nitrate flux (relative to the appropriate control). Again, barrier perturbation resulted in essentially constant metabolic activity over the observation period. The ratio of metabolites formed (1,2-GDN/1,3-GDN) was increased from less than unity to slightly above 1 by the Azone treatment. Adhesive tape-stripping gradually destroyed skin barrier function by removal of the stratum corneum. The effects of 15 tape-strips were identical to those of Azone pretreatment: a greatly enhanced flux, a constant percentage formation of metabolites over 10 hr (once again), and an increase in the 1,2-GDN/1,3 GDN ratio. Overall, the experiments caution that, for transdermal drug delivery candidates susceptible to skin metabolism, the status of barrier function (enhancer pretreated, skin damage or disease, etc.) may significantly affect systemic availability.     

Review of elective surgical treatment of chronic duodenal ulcer

This article is a review of 20 clinical trials of various forms of elective surgical treatment of chronic duodenal ulcer conducted between 1964 and 1975, some of them prospective and others retrospective in nature. Comparisons have been made of the results following truncal vagotomy with drainage, truncal vagotomy with antrectomy, and partial gastrectomy. Additionally, selective vagotomy and truncal vagotomy have been compared in some studies and various forms of drainage, such as pyloroplasty and gastrojejunostomy, have been compared in others. In general, the results of all current forms of elective surgery for chronic duodenal ulcer have been very good, and the differences among the effects of the various procedures have been small. There have been no significant differences in the mortality rates associated with the several operations when they have been performed electively. The rate of ulcer recurrence and incidence of diarrhea have been somewhat higher after truncal vagotomy with drainage, whereas the frequency of dumping and amount of weight loss have been somewhat greater after all forms of gastric resection. Selective vagotomy appears to be associated with less frequent and severe diarrhea than does truncal vagotomy. There have been no apparent differences in the results of the various drainage procedures that have been combined with vagotomy. Highly selective vagotomy without drainage, the most recent operation for duodenal ulcer, has resulted in the lowest incidence of post-operative side effects of any surgical procedure in current use. However, the frequency of ulcer recurrence after this therapeutic measure remains to be determined by long-term studies.

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Résumé Cet article passe en revue 20 études cliniques compilées entre 1964 et 1975 sur le traitement chirurgical électif des ulcères duodénaux chroniques; certaines de ces études sont de nature prospectives, d'autres rétrospectives. On y compare les résultats obtenus par vaguotomie tronculaire avec drainage, vaguotomie tronculaire et antrectomie, et gastrectomie partielle. De plus, dans certaines études, on a comparé la vaguotomie sélective et la vaguotomie tronculaire tandis que d'autres études comparaient différentes formes de drainage, par exemple pyloroplastie et gastro-jéjunostomie. En général les résultats obtenus ont été très bons et il n'y a pas eu de différence significative entre les diverses formes de traitement chirurgical électif pour ulcère duodénal chronique. Les taux de mortalité ont été sensiblement identiques pour toutes les procédures chirurgicales lorsque pratiquées électivement. La récidive d'ulcère et la diarrhée post-opératoire se sont rencontrées plus souvent après vaguotomie tronculaire et drainage, tandis que l'incidence du syndrÔme de chasse gastrique (dumping), et la perte de poids ont été plus souvent associés avec toutes les formes de résection gastrique. La vaguotomie sélective semble s'accompagner moins souvent de diarrhée post-opératoire grave que la vaguotomie tronculaire. Les différentes procédures de drainage employées en mÊme temps que la vaguotomie n'ont pas déterminé de différence significative. La vaguotomie supra-sélective sans drainage, la dernière nouveauté dans le traitement chirurgical des ulcères duodénaux, s'est accompagnée du plus faible taux d'effets secondaires post-opératoires lorsque comparée à toutes les autres formes de traitement chirurgical couramment employés. Il faudra cependant attendre les résultats d'étude à long terme avant de connaÎtre le taux de récidive d'ulcère associé à cette nouvelle approche chirurgicale.

     

Variations in Prkdc and susceptibility to benzene-induced toxicity in mice.

Benzene, a carcinogen that induces chromosomal breaks, is strongly associated with leukemias in humans. Possible genetic determinants of benzene susceptibility include proteins involved in repair of benzene-induced DNA damage. The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), encoded by Prkdc, is one such protein. DNA-PKcs is involved in the nonhomologous end-joining (NHEJ) pathway of DNA double-strand break (DSB) repair. Here we compared the toxic effects of benzene on mice (C57BL/6 and 129/Sv) homozygous for the wild-type Prkdc allele and mice (129/SvJ) homozygous for a Prkdc functional polymorphism that leads to diminished DNA-PK activity and enhanced apoptosis in response to radiation-induced damage. Male and female mice were exposed to 0, 10, 50, or 100 ppm benzene for 6 h/d, 5 d/week for 2 weeks. Male mice were more susceptible to benzene toxicity compared with females. Hematotoxicity was evident in all male mice but was not seen in female mice. We observed similar, large increases in both micronucleated erythrocyte populations in all male mice. Female mice had smaller but significant increases in micronucleated cells. The p53-dependent response was induced in all strains and genders of mice following benzene exposure, as indicated by an increase in p21 mRNA levels in bone marrow that frequently corresponded with cell cycle arrest in G2/M. Prkdc does not appear to be a significant genetic susceptibility factor for acute benzene toxicity. Moreover, the role of NHEJ, mediated by DNA-PK, in restoring genomic integrity following benzene-induced DSB remains equivocal.     

Alcohol exposure and breast cancer: results of the women's contraceptive and reproductive experiences study.

OBJECTIVES: To explore associated biological outcomes and clarify the role of timing of exposure in the alcohol-breast cancer relationship.METHODS: In a population-based study of 4,575 women ages 35 to 64 years diagnosed with invasive breast cancer between 1994 and 1998 and 4,682 controls, we collected details of lifetime alcohol use and factors that could confound or modify the alcohol-breast cancer relationship. We used conditional logistic regression to compute the odds of breast cancer among drinkers relative to nondrinkers at all ages and at ages 35 to 49 and 50 to 64 years separately.RESULTS: Recent consumption (at reference age minus two) of >/=7 drinks per week was associated with increased risk [odds ratio (OR), 1.2; 95% CI, 1.01-1.3] and evidence of dose response was observed. Most of the excess was observed among women ages 50-64 years (OR 1.3; 95% CI, 1.1-1.6), although the test for age interaction was not statistically significant. Exposure later in life seemed more important than early exposure. Excess breast cancer associated with recent consumption was restricted to localized disease. When outcome was examined according to tumor hormone receptor status, highest risks were observed for estrogen receptor-positive/progesterone receptor-negative tumors (OR 1.6; 95% CI, 1.2-2.3).CONCLUSIONS: The effect of timing of alcohol exposure on breast cancer risk is complicated and will require additional study focused on this one issue. Further work is needed to explain how alcohol exposure, sex hormones, and tumor receptor status interact.     

Long-term neurologic and neurosensory sequelae in adult survivors of a childhood brain tumor: childhood cancer survivor study.

PURPOSE: To describe the neurologic and neurosensory deficits in children with brain tumors (BTs), compare incidence of these deficits with that of a sibling control group, and evaluate the factors associated with the development of these deficits. PATIENTS AND METHODS: Detailed questionnaires were completed on 1,607 patients diagnosed between 1970 and 1986 with a primary CNS tumor. Neurosensory and neurologic dysfunctions were assessed and results compared with those of a sibling control group. Medical records on all patients were abstracted, including radiotherapy dose and volume. RESULTS: Seventeen percent of patients developed neurosensory impairment. Relative to the sibling comparison group, patients surviving BTs were at elevated risk for hearing impairments (relative risk [RR], 17.3; P = <.0001), legal blindness in one or both eyes (RR, 14.8; P = <.0001), cataracts (RR, 11.9; P = <.0001), and double vision (RR, 8.8; P = <.0001). Radiation exposure greater than 50 Gy to the posterior fossa was associated with a higher likelihood of developing any hearing impairment. Coordination and motor control problems were reported in 49% and 26%, respectively, of survivors. Children receiving at least 50 Gy to the frontal brain regions had a moderately elevated risk for motor problems (RR, 2.0; P <.05). Seizure disorders were reported in 25% of patients, including 6.5% who had a late first occurrence. Radiation dose of 30 Gy or more to any cortical segment of the brain was associated with a two-fold elevated risk for a late seizure disorder. CONCLUSION: Children surviving BTs are at significant risk for both early and late neurologic or neurosensory sequelae. These sequelae need to be prospectively monitored.     

The Relationship of Ambulation in Labor to Operative Delivery

An abbreviated version of the Nurse-Midwifery Clinical Data Set was used to gather data on all women (n = 3,049) who began intrapartum care with a nurse-midwife in three sites. Demographic information, intrapartum care, and outcomes were recorded. The association of ambulation in labor with operative delivery was examined in a low-risk sample (n = 1,678) of women who did not receive care measures (epidural anesthesia, oxytocin induction or augmentation) that preclude mobility in labor. Women who ambulated for a significant amount of time during labor (compared with those who did not ambulate) had half the rate of operative delivery (2.7% vs. 5.5%).     

Clinical effects and pharmacokinetics of the fusion protein PIXY321 in children receiving myelosuppressive chemotherapy

A hemopoietin with the ability to accelerate both platelet and granulocyte recovery after intensive chemotherapy would have great clinical utility. The recombinant fusion protein composed of human granulocyte-macrophage colony-stimulating factor and interleukin-3 (PIXY321), showed some promise in early adult trials. However, studies for pediatric patients are limited, and there are no systematic data on the pharmacokinetics of PIXY321 given over prolonged periods at current dosage levels. Purpose: To determine the safety, clinical effects and plasma concentrations of increasing doses of PIXY321 in children treated with myelosuppressive chemotherapy. Methods: A total of 39 children with relapsed or high-risk solid tumors were enrolled in this phase I/II study. PIXY321 was administered once or twice daily by subcutaneous injection in total doses of 500 to 1000 μg/m² per day for 14 days after each course of chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). Pharmacokinetic studies were performed on day 1 of the first course in 33 patients and repeated on day 14 in 13 patients (once-daily schedule only). Results: Although mild local skin reactions and fever were frequent, no dose-limiting toxicity was identified at the maximum dose studied (1000 μg/m² per day). There were no statistically significant differences in chemotherapy-induced hematologic toxicity with increasing doses of PIXY321 or with twice-daily vs once-daily dosing. On day 1, the median PIXY321 clearance was 657 ml/min per m² (range 77–1804 ml/min per m²) and the median half-life was 3.7 h (range 2.1–20.8 h). On day 14, clearance increased in all patients studied (median increase 63%), with a corresponding decrease in the median 12-h concentration (from 1.2 to 0.25 ng/ml). Maximum concentrations were <1 ng/ml in 81% of patients, and only two patients had maximum plasma concentrations equivalent to those required for consistent activity in vitro. Conclusions: The recombinant fusion protein PIXY321 proved safe in children treated with myelosuppressive ICE chemotherapy but had no demonstrable clinical benefits. The pharmacokinetic studies suggest that the observed lack of hematologic benefit may be explained by low plasma concentrations resulting from increased clearance with prolonged administration. Moreover, the significant increase in PIXY321 systemic clearance in the absence of increased circulating myeloid cells suggests that the upregulation of either extravascular compartment hematopoietic progenitor cells or nonhematopoietic cells may play an important role in controlling circulating concentrations of this unique cytokine. These findings highlight the importance of a thorough assessment of the systemic disposition of cytokines when determining the dose and schedule necessary to achieve clinical activity in patients. Received: 29 January 1997 / Accepted: 9 May 1997