Master V, Roberts G W, Coulthard K P, Baghurst P A, Martin A, Roberts M E, Onishko C R, Martin A J, Linke R J, Holmes M, Jarvinen A, Kennedy D, Colebatch K A, Hansman D, Parsons D W
Department of Pulmonary Medicine, Adelaide Women's and Children's Hospital, North Adelaide, South Australia, Australia.
Pediatr Pulmonol. 2001 May;31(5):367-76. doi: 10.1002/ppul.1060.
Our objective was to compare the efficacy, safety, and microbiology of once-daily intravenous (IV) tobramycin with conventional 8-hourly tobramycin/ceftazidime IV therapy for acute Pseudomonas aeruginosa (PA) pulmonary exacerbations in cystic fibrosis (CF). CF patients with PA-induced pulmonary exacerbations were allocated to receive either once-daily tobramycin (Mono) or conventional therapy with tobramycin/ceftazidime given 8-hourly (Conv). The two longitudinal groups received therapy in a double-blind, randomized manner over a period of 2 years. Tobramycin doses were adjusted to achieve a daily area under the time-concentration curve of 100 mg x hr/L in both groups. Results were assessed for both short-term changes (efficacy and safety after 10 days of IV antibiotics during acute exacerbations) and long-term changes (efficacy, safety, and sputum microbiology between study entry and exit). Pulmonary function tests (PFTs) on admission were similar in both groups. After 10 days of IV antibiotics, absolute mean improvements in percent of predicted PFTs were 12.8, 12.1, and 13.7 for forced expiratory volume in 1 sec (FEV(1)), forced vital capacity (FVC), and forced expired flow between 25--75% of FVC (FEF(25--75%)) in the Conv group (n = 51 admissions) compared to 10.6, 9.9, and 10.6 in the Mono group (n = 47)(P<0.05 for all). Sixteen percent in the Conv group and 15% of patients in the Mono group did not respond to therapy by day 10. Long-term PFT patterns were similar for the Conv and Mono groups. The time between admissions did not differ. The Mono group showed a significant increase in tobramycin minimum inhibitory concentrations (MICs) against PA from study entry to study exit (P = 0.02, n = 27 strains); this failed to reach significance in the Conv group (P = 0.08, n = 25). There was no significant increase in the number of isolates, with MIC> or =8 mg/L in both groups. No short- or long-term changes in audiology or serum creatinine were found in either group. After 10 days of IV therapy, the urinary enzyme N-acetyl-beta-d-glucosaminidase/creatinine ratios increased in both groups (P0.05). This increase was greater in the Conv compared to the Mono group (P < 0.05). We conclude that this pilot study indicates once-daily tobramycin therapy to be as effective and safe as conventional 8-hourly tobramycin/ceftazidime therapy. Combination antibacterial therapy appears to offer no clinical advantage over once-daily tobramycin monotherapy. Tobramycin once-daily monotherapy is a potential alternative to conventional IV antibacterial therapy which deserves further investigation, including the impact on susceptibility of PA to tobramycin.
我们的目的是比较每日一次静脉注射妥布霉素与传统的每8小时一次静脉注射妥布霉素/头孢他啶疗法治疗囊性纤维化（CF）患者急性铜绿假单胞菌（PA）肺部加重的疗效、安全性和微生物学情况。PA引起肺部加重的CF患者被分配接受每日一次妥布霉素治疗（单药组）或每8小时一次给予妥布霉素/头孢他啶的传统治疗（传统组）。这两个纵向组在2年的时间里以双盲、随机的方式接受治疗。两组均调整妥布霉素剂量，以使时间-浓度曲线下的每日面积达到100mg·hr/L。评估了短期变化（急性加重期静脉使用抗生素10天后的疗效和安全性）和长期变化（研究开始至结束期间的疗效、安全性和痰液微生物学情况）。两组入院时的肺功能测试（PFTs）相似。静脉使用抗生素10天后，传统组（n = 51例入院患者）1秒用力呼气容积（FEV(1)）、用力肺活量（FVC）和FVC 25%至75%之间的用力呼气流量（FEF(25--75%)）相对于预测PFTs百分比的绝对平均改善分别为12.8、12.1和13.7，而单药组（n = 47）分别为10.6、9.9和10.6（所有比较P<0.05）。传统组16%的患者和单药组15%的患者在第10天时对治疗无反应。传统组和单药组的长期PFT模式相似。两次入院之间的时间无差异。单药组从研究开始至结束时，针对PA的妥布霉素最低抑菌浓度（MICs）显著增加（P = 0.02，n = 27株）；传统组未达到显著水平（P = 0.08，n = 25）。两组中MIC≥8mg/L的分离株数量均无显著增加。两组在听力学或血清肌酐方面均未发现短期或长期变化。静脉治疗10天后，两组的尿酶N-乙酰-β-D-氨基葡萄糖苷酶/肌酐比值均升高（P<0.05）。传统组的升高幅度大于单药组（P < 0.05）。我们得出结论，这项初步研究表明每日一次妥布霉素治疗与传统的每8小时一次妥布霉素/头孢他啶治疗一样有效且安全。联合抗菌治疗似乎并不比每日一次妥布霉素单药治疗具有临床优势。每日一次妥布霉素单药治疗是传统静脉抗菌治疗的一种潜在替代方案，值得进一步研究，包括对PA对妥布霉素敏感性的影响。
