舒普深sulperazon
舒普深（注射用头孢哌酮钠舒巴坦钠）是唯一的β-内酰胺酶不可逆抑制剂舒巴坦与第三代头孢菌素头孢哌酮的复方制剂。它不仅对临床上日益增多的各种耐药菌的抗菌作用明显加强，而且还扩大了第三代头孢菌素的抗菌谱。

名称：舒普深 Sulperazon

制造商：辉瑞制药有限公司

药物分类：Y1.1.1．青霉素类

简介：
舒普深® ※
品名与成份
正式品名：注射用舒巴坦钠/头孢哌酮钠
英文名：Sulbactam Sodium/Cefoperazone Sodium(1:1) for injection

性状
本品是舒巴坦钠/头孢哌酮钠1:1组成的白色或类白色结晶粉末，易溶于水。

适应证
本品适用于治疗敏感细菌所引起的下列感染：
上呼吸道与下呼吸道感染；上泌尿道与下泌尿道感染；腹膜炎、胆囊炎、胆管炎和其他腹腔内感染；败血症；脑膜炎；皮肤和软组织感染；骨骼及关节感染；盆腔炎、子宫内膜炎、淋病和其他生殖器、尿道感染。

用法与用量
成人每日常用量为2-4克（即头孢哌酮1-2克/日），分等量每12小时静脉或肌内注射一次，严重或难治性感染，剂量可增至8.0克/日（即每日4克头孢哌酮），分等量每12小时静脉注射一次，舒巴坦最大推荐剂量为4.0克/日（即本品8克），即使在未知细菌敏感性试验结束的情况下，也可用本品进行治疗。
严重肾功能不全的患者（肌肝清除率<30毫升/分钟），使用本品时应调整给药方案，以补偿舒巴坦清除率的降低，肌酐清除率在16-30毫升/分钟之间的患者，每12小时的舒巴坦最高剂量为1克（即本品最大剂量为2.0克/日）。肌酐清除率<15毫升/分钟的患者，每12小时的舒巴坦最高剂量为500毫克（即本品最大剂量为1克/日），如遇严重感染，可另行加用头孢哌酮。
儿童本品常用量为每日40-80毫克/公斤（即头孢哌酮每日20-40毫克/公斤），等分2-4次给药。遇严重或难治性感染，本品剂量可增至每日160毫升/公斤（即头孢哌酮每日80毫克/公斤），等分2-4次给药。
新生儿出生第一周内，应每隔12小时给药一次；儿科舒巴坦最高剂量不得超过每日80毫克/公斤（本品每日160毫克/公斤）。若头孢哌酮的需要量超过每日80毫克/公斤时，应另行加用头孢哌酮。

静脉注射法：
采用静脉滴注时，先将每瓶本品溶于适量（见上表）5%葡萄糖液、0.9%氯化钠注射液或灭菌注射用水；然后再用同一溶媒稀释至50-100毫升供静脉滴注、滴注时间为30-60分钟。

肌内注射法：
应使用灭菌注射用水配制肌内注射液。当注射液中头孢哌酮浓度在250毫克/毫升可以上时，需采用二步稀释法，具体步骤如下：
1. 先加适量灭菌注射用水溶解。
2. 再以2%利多卡因注射液稀释，使最终溶液的利多卡因浓度为0.5%。

不良反应
一般而言，患者对本品耐受性良好，大多数不良反应为轻至中度，继续治疗，不良反应会消失。
胃肠道-与其它抗生素一样，使用本品时最常见的副作用是胃肠道反应，据报道，腹泻（稀便）最为常见，其次是恶心及呕吐，发生率为3.6-10.8%。
皮肤反应-与所有青霉素类和头孢菌素类一样，本品可引起过敏反应，表现为斑丘疹、荨麻疹、嗜酸粒细胞增多和药物热。发生率为0.8-1.3%，易发生于有过敏病史，特别是对青霉素过敏的中性粒细胞轻度下降病人。
血液-与其它β-内酰胺类抗生素一样，长期使用本品有导致可逆性中性粒细胞减少症的可能，一些病人曾对直接库存姆斯试验呈阳性反应。曾报导血红蛋白及红细胞压积的降低，曾发现有一过性的嗜酸粒细胞增多和血小板减少现象，低凝血酶原血症也曾有报道。
其它不良反应：小于1%的患者中出现头痛、发热、注射部位疼痛、寒战等不良反应。
实验室异常现象：在所报导的病例中有6.3-10%的病例谷草转氨酶、谷丙转氨酶、碱性磷酸酶或血胆红素有一过性的升高。
局部反应：肌内注射时，本品耐受性良好，偶有一过性的疼痛，与其它头孢菌素类和青霉素一样，用静脉插管输注时，有些患者会有输液部位静脉炎。

禁忌证
对青霉素或头孢菌素抗生素过敏者禁用。

规格与包装
1.0克瓶装，外套纸盒，每瓶含舒巴坦钠相当于舒巴坦500毫克；头孢哌酮钠相当于头孢哌酮500毫克。

【原产地英文商品名】:SULPERAZON (500/500)mg/bottle
【原产地英文药品名】:SULBACTAM SODIUM/CEFOPERAZONE SODIUM
【中文参考商品译名】:舒普深 (500/500)毫克/瓶
【中文参考药品译名】:舒巴坦钠/头孢哌酮钠
【生产厂家中文参考译名】:辉瑞
【生产厂家英文名】:PFIZER 

 
Trade name: Sulperazon

Pharmaceutical form: powder for solution for injection in 1.0 g vials

Description: white powder

Composition
Sulbactam sodium/cefoperazone sodium combination is available as a dry powder for reconstitution in a 1:1 ratio in terms of free SBT/CPZ (1000 mg + 1000 mg).

Pharmacotherapeutic group
Antibiotic, cephalosporin + inhibitor of beta-lactamases [J01CR].

Pharmacological properties
Pharmacodynamics
The anti-bacterial component of sulbactam/cefoperazone is cefoperazone, a third generation cephalosporin, which acts against sensitive organisms during the stage of active multiplication by inhibiting biosynthesis of cell wall mucopeptide. Sulbactam does not possess any useful antibacterial activity, except against Neisseriaceae and Acinetobacter. However, biochemical studies with cell-free bacterial systems have shown it to be an irreversible inhibitor of most important beta-lactamases produced by beta-lactam antibiotic-resistant organisms.

The potential for sulbactam`s preventing the destruction of penicillins and cephalosporins by resistant organisms was confirmed in whole-organism studies using resistant strains in which sulbactam exhibited marked synergy with penicillins and cephalosporins. As sulbactam also binds with some penicillin binding proteins, sensitive strains are also often rendered more susceptible to sulbactam/cefoperazone than to cefoperazone alone.

The combination of sulbactam and cefoperazone is active against all organisms sensitive to cefoperazone. In addition it demonstrates synergistic activity in a variety of organisms, most markedly the following: Haemophilus influenzae, Bacteroides species, Staphylococcus species, Acinetobacter calcoaceticus, Enterobacter aerogenes, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Citrobacter diversus.

Sulbactam/cefoperazone is active in vitro towards a wide spectrum of clinically significant microorganisms:

Gram-positive microorganisms
Staphylococcus aureus (penicillinase and non-penicillinase producing strains), Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes (beta-hemolytic A group streptococcus), Streptococcus agalactiae (beta-hemolytic B group streptococcus), most strains of beta-hemolytic streptococci, many strains of Streptococcus faecalis (enterococci).

Gram-negative microorganisms
Escherichia coli, Klebsiella species, Enterobacter species, Citrobacter species, Haemophilus influenzae, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia rettgeri, Providencia species, Serratia species (including S. marcescens), Salmonella and Shigella species, Pseudomonas aeruginosa and some other Pseudomonas species, Acinetobacter calcoaceticus, Neisseria gonorrhoeae, Neisseria meningitides, Bordetella pertussis, and Yersinia enterocolitica.

Anaerobic organisms
Gram-negative organisms (including Bacteroides fragilis, other Bacteroides species, and Fusobacterium species)

Gram-positive and gram-negative cocci (including Peptococcus, Peptostreptococcus and Veillonella species)

Gram-positive bacilli (including Clostridium, Eubacterium and Lactobacillus species)

Pharmacokinetics
Both sulbactam and cefoperazone are smoothly distributed in various tissues and fluids including biles, bladder, skin, appendage, fallopian tubes, ovaries, uterus, etc.

Mean peak sulbactam and cefoperazone concentrations after the administration of 2 grams of sulbactam/cefoperazone (1 g sulbactam, 1 g of cefoperazone) intravenously over 5 minutes were 130.2 and 236.8 mcg/ml respectively. This reflects the larger volume of distribution for sulbactam (Vd = 18.0-27.6 L) compared to cefoperazone (Vd = 10.2-11.3 L).

There are no data on the pharmacokinetic interaction between sulbactam and cefoperazone when administered together in the form of sulbactam/cefoperazone.

Approximately 84% of the sulbactam dose and 25% of the cefoperazone dose administered with sulbactam/cefoperazone is excreted by the kidney. Most of the remaining dose of cefoperazone is excreted in the bile. After sulbactam/cefoperazone parenteral administration the mean half-life for sulbactam is about 1 hour while that for cefoperazone is 1.7 hours. Serum concentrations have been shown to be proportional to the dose administered.

After multiple dosing no significant changes in the pharmacokinetics of either component of sulbactam/cefoperazone have been reported and no accumulation has been observed when administered every 8 to 12 hours.

Use in patients with hepatic impairment
Cefoperazone is extensively excreted in bile. The serum half-life of cefoperazone is usually prolonged and urinary excretion of the drug increased in patients with hepatic diseases and/or biliary obstruction. Even with severe hepatic dysfunction, therapeutic concentrations of cefoperazone are obtained in bile and only a 2- to 4-fold increase in half-life is seen.

Use in Renal Dysfunction
In patients with different degrees of renal function administered sulbactam/cefoperazone, the total body clearance of sulbactam was highly correlated with estimated creatinine clearance. Patients who are functionally anephric showed a significantly longer half-life of sulbactam (mean 6.9 and 9.7 hours in separate studies). Hemodialysis significantly altered the half-life, total body clearance, and volume of distribution of sulbactam.

Use in Elderly
The pharmacokinetics of sulbactam/cefoperazone have been studied in elderly individuals with renal insufficiency and compromised hepatic function. Both sulbactam and cefoperazone exhibited longer half-life, lower clearance, and larger volumes of distribution when compared to data from normal volunteers. The pharmacokinetics of sulbactam correlated well with the degree of renal dysfunction while for cefoperazone there was a good correlation with the degree of hepatic dysfunction.

Use in Children
Studies conducted in pediatrics have shown no significant changes in the pharmacokinetics of the components of sulbactam/cefoperazone compared to adult values. The mean half-life in children has ranged from 0.91 to 1.42 hours for sulbactam and from 1.44 to 1.88 hours for cefoperazone.

Therapeutic indications
Sulbactam/cefoperazone is indicated for the treatment of the following infections when caused by susceptible organisms:
respiratory tract infections (upper and lower)
urinary tract infections (upper and lower)
peritonitis, cholecystitis, cholangitis, and other intra-abdominal infections
septicemia
meningitis
skin and soft tissue infections
bone and joint infections
pelvic inflammatory disease, endometritis, gonorrhea, and other infections of the genital tract

Posology and Method of Administration
Use in Adults
Daily dosage recommendations for sulbactam/cefoperazone in adults are as follows:

Ratio SBT/CPZ (g) Sulbactam (g) Cefoperazone (g)
-----------------------------------------------------------------------------------------
1:1 2.0 - 4.0 1.0 - 2.0 1.0 - 2.0
------------------------------------------------------------------------------------------

Doses should be administered every 12 hours in equally divided doses.

In severe or refractory infections the daily dosage of sulbactam/cefoperazone may be increased up to 8 g of the 1:1 ratio (i.e., 4 g cefoperazone activity) or 12 g of the 1:2 ratio (i.e., 8 g cefoperazone activity). Patients receiving the 1:1 ratio may require additional cefoperazone administered separately. Doses should be administered every 12 hours in equally divided doses.

The recommended maximum daily dosage of sulbactam is 4 g.

Use in Renal Dysfunction

Patients with creatinine clearances between 15 and 30 ml/min should receive a maximum of 1 g of sulbactam administered every 12 hours (maximum daily dosage of 2 g sulbactam), while patients with creatinine clearances of less than 15 ml/min should receive a maximum of 500 mg of sulbactam every 12 hours (maximum daily dosage of 1 g sulbactam). In severe infections it may be necessary to administer additional cefoperazone.

The pharmacokinetic profile of sulbactam is significantly altered by hemodialysis. The serum half-life of cefoperazone is reduced slightly during hemodialysis. Thus, dosing should be scheduled to follow a dialysis period.

Use in Children
Daily dosage recommendations for sulbactam/cefoperazone in children are as follows:
SBT/CPZ Sulbactam Cefoperazone
Ratio mg/kg/day Dose mg/kg/day Dose mg/kg/day
--------------------------------------------------------------------------------------------------
1:1 40 - 80 20 - 40 20 - 40
---------------------------------------------------------------------------------------------------

Doses should be administered every 6 to 12 hours in equally divided doses.

In serious or refractory infections, these dosages may be increased up to 160 mg/kg/day of the 1:1 ratio. Doses should be administered in two to four equally divided doses.

Use in Neonates
For neonates in the first week of life, the drug should be given every 12 hours. The maximum daily dosage of sulbactam in pediatrics should not exceed 80 mg/kg/day.

Preparation of solutions for parenteral administration
Intravenous Administration
Lactated Ringer’s Solution is a suitable vehicle for intravenous infusion, however, not for initial reconstitution because of incompatibility of the mixture. A two-step dilution is required using sterile water for injection (shown in table above) further diluted with lactated Ringer’s solution.

For intermittent infusion, each vial of sulbactam/cefoperazone should be reconstituted with the appropriate amount of 5% dextrose in water, 0.9% sodium chloride Injection or sterile water for Injection and then diluted to 20 ml with the same solution followed by administration over 15 to 60 minutes.

For intravenous injection, each vial should be reconstituted as above and administered over a minimum of 3 minutes.

Intramuscular Administration
Initial reconstitution with 2% lidocaine HCl solution should be avoided since this mixture has been shown to be incompatible. However, a two step dilution process involving initial reconstitution in water for injection will result in a compatible mixture when further diluted with 2% lidocaine HCl solution.

Preparation of the solution
-----------------------------------------------------------------------------------------------------
Total Equivalent dosage of Volume of Maximum Final
Dosage (g) sulb. + cefoperazone (g) Diluent (ml) Conc. (mg/ml)
2.0 1.0 + 1.0 6.7 125 + 125
------------------------------------------------------------------------------------------------------

Sulbactam/cefoperazone has been shown to be compatible with water for injection, 5% dextrose, normal saline, 5% dextrose in physiological solution at concentrations of 10 mg cefoperazone and 10 mg sulbactam per ml and up to 250 mg/ml cefoperazone and 250 mg/ml sulbactam per ml.

Lactated Ringer’s Solution
Sterile water for injection should be used for reconstitution (see the table above). A two step dilution is required using sterile water for Injection (shown in table above) further diluted with lactated Ringer’s solution to a sulbactam concentration of 5mg/ml (use 2 ml initial dilution in 50 ml or 4 ml initial dilution in 100 ml lactated Ringer’s solution).

Lidocaine
Sterile water for Injection should be used for reconstitution. For a concentration of cefoperazone of 250 mg/ml or larger, a two step dilution is required using sterile water for Injection (shown in table above) further diluted with 2% lidocaine to yield solutions containing up to 250 mg/ml cefoperazone and 250 mg/ml sulbactam in approximately a 0.5% lidocaine HCl solution.

Pregnancy and lactation
This drug should be used during pregnancy and lactation only if clearly needed.

Adverse events
Anaphylactoid reactions: shock

Gastrointestinal tract: vomiting, nausea, pseudomembranous colitis.

Dermatological reactions: maculopapular rash, pruritus, itching, and Stevens-Johnson syndrome. These reactions are more likely to occur in patients with a history of allergies, particularly to penicillin.

Hematology: Decrease in neutrophile count. As with other beta-lactam antibiotics, reversible neutropenia may occur with prolonged administration. Some individuals have developed a positive direct Coombs test during treatment. Decreased hemoglobin or hematocrit have been reported. Transient eosinophilia, leukopenia and thrombocytopenia have occurred, and hypo-prothrombinemia has been reported.

Other: headache, fever, pain at the injection site, chills, hematuria, and vasculitis.

Laboratory tests: Transient elevations of liver function tests, ACT, ALT, alkaline phosphatase and bilirubin levels have been noted.

Local reactions: Sulbactam/cefoperazone is well tolerated following intramuscular administration. Occasionally, transient pain may follow administration by this route. As with other cephalosporins and penicillins, when sulbactam/cefoperazone is administered by an intravenous catheter some patients may develop phlebitis at the infusion site (0.1%).

Contraindications
Sulbactam/cefoperazone is contraindicated in patients with known allergy to penicillins, sulbactam, cefoperazone, or any of the cephalosporins

Special warnings and special precautions
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam or cephalosporin therapy. These reactions are more apt to occur in individuals with a history of hypersensitivity reactions to multiple allergens. If an allergic reaction occurs, the drug should be discontinued and the appropriate therapy instituted.

Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should be administered as indicated.

Dose modification may be necessary in cases of severe biliary obstruction, severe hepatic disease or in cases of renal dysfunction coexistent with either of those conditions.

In patients with hepatic dysfunction and concomitant renal impairment, cefoperazone serum concentrations should be monitored and dosage adjusted as necessary. In these cases dosage should not exceed 2 g/day of cefoperazone without close monitoring of serum concentrations.

As with other antibiotics, Vitamin K deficiency has occurred in a few patients treated with cefoperazone. The mechanism is most probably related to the suppression of gut flora, which normally synthesize this vitamin. Those at risk include patients with poor diet, malabsorption states (e.g., cystic fibrosis) and patients on prolonged intravenous alimentation regimens. Prothrombin time should be monitored in these patients, and patients receiving anticoagulant therapy, and exogenous vitamin K administered as indicated.

As with other antibiotics, overgrowth of non-susceptible organisms may occur during prolonged use of sulbactam/cefoperazone. Patients should be observed carefully during treatment. As with any potent systemic agent, it is advisable to check periodically for organ system dysfunction during extended therapy; this includes renal, hepatic, and hematopoietic systems. This is particularly important in neonates, especially when premature, and other infants.

Cefoperazone does not displace bilirubin from plasma protein binding sites.

Overdosage
Limited information is available on the acute toxicity of cefoperazone sodium and sulbactam sodium in humans. Overdosage of the drug would be expected to produce manifestations that are principally extensions of the adverse reactions reported with the drug. The fact that high CSF concentrations of β-lactam antibiotics may cause neurologic effects, including seizures, should be considered. Because cefoperazone and sulbactam are both removed from the circulation by hemodialysis, these procedures may enhance elimination of the drug from the body if overdosage occurs in patients with impaired renal function.

Interaction with other drugs and other forms of interaction
Alcohol
A reaction characterized by flushing, sweating, headache, and tachycardia has been reported when alcohol was ingested during and as late as the fifth day after cefoperazone administration. A similar reaction has been reported with certain other cephalosporins and patients should be cautioned concerning ingestion of alcoholic beverages in conjunction with administration of sulbactam/cefoperazone. For patients requiring artificial feeding orally or parenterally, solutions containing ethanol should be avoided.

Drug Laboratory Test Interactions
A false-positive reaction for glucose in the urine may occur with Benedict`s or Fehling`s solution.

Aminoglycosides
Solutions of sulbactam/cefoperazone and aminoglycosides should not be directly mixed, since there is a physical incompatibility between them. If combination therapy with sulbactam/cefoperazone and an aminoglycoside is contemplated this can be accomplished by sequential intermittent intravenous infusion provided that separate secondary intravenous tubing is used, and that the primary intravenous tubing is adequately irrigated with an approved diluent between doses. It is also suggested that doses of sulbactam/cefoperazone be administered throughout the day at times as far removed from administration of the aminoglycoside as possible.

Nature and contents of container
Sulbactam/cefoperazone is available in vials of 2.0 g (1 g of the active component). Dark glass colorless vials with halobutyl rubber stoppers coverd with teflone and aluminum foil.

Shelf life
2 years.

Check out the expiry date before opening the vial. Do not use the drug after the expiry date shown on the pack.

Storage conditions
Store below 250C.
Keep out of reach of children.

Dispensing conditions
Rx

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