35．复达欣注射剂
出处：按学科分类—医药、卫生 军事医学科学出版社《临床常用进口药物手册》第181页（29343字）
【中文释文】：
〔成分〕
复达欣注射剂的供应是瓶装白色至淡黄色的药粉，分装500mg，1g及2g头孢噻甲羧肟(形式为五水化物)，并含碳酸钠(每克头孢噻甲羧肟含118mg)，当加入注射用水时，复达欣注射剂便泡腾溶解成为注射用溶液。
复达欣注射剂每克头孢噻甲羧肟约含钠52mg(2．3mmol)。116mg五水化物头孢噻甲羧肟相当于100mg头孢噻甲羧肟游离酸。
〔适应证〕
头孢噻甲羧肟是杀菌性头孢子菌抗生素，对多种β内酰胺酶有抵抗力，并对广谱的革兰阳性及阴性细菌有效。
复达欣适用于由敏感细菌所引发的单一感染及混合感染。由于头孢噻甲羧肟有宽广的抗菌谱，故于敏感试验尚未有结果的时候，作为首选药物可单独地使用。它还可与氨基糖甙类或其他β内酰胺抗生素伍用。在怀疑是脆弱拟杆菌之时，亦可与另一抗厌氧菌的抗生素同用。
适应证包括：
严重的感染：例如败血病，菌血症，腹膜炎，脑膜炎，免疫受抑制病人的感染及需要严密监护的病人，例如感染性烧伤的病人。
呼吸道感染：包括患有囊性纤维化的病人的肺部感染，耳，鼻及喉部感染，泌尿道感染，皮肤及软组织感染，胃肠，胆及腹部感染，骨及关节感染。
血和腹膜透析及不卧床之连续腹膜透析(CAPD)而并发的感染。
预防治疗：前列腺手术(经尿道的切除术)。
〔细菌学〕
头孢噻甲羧肟是杀菌剂，其作用在于阻止细菌细胞壁的合成。体外试验中，广泛范围的病原菌株和分离菌，包括抗庆大霉素和其他抗氨基糖甙类的菌株都对头孢噻甲羧肟敏感。其对绝大多数临床上重要的革兰阳性及革兰阴性细菌所产生的β内酰胺酶都具高度的稳定性，因而对很多抗氨苄青霉素及头孢噻吩的菌株都有效。头孢噻甲羧肟于体外试验显具高度内在活性，在窄小的最低抑制浓度范围内对绝大多数的菌属有效，且于不同的接种水平下其最低抑制浓度改变极微。体外试验中头孢噻甲羧肟及氨基糖甙类抗生素伍用则显示功效是相加的；而在一些试验的菌株中亦表现出协同作用。在体外试验头孢噻甲羧肟对下列的细菌有效。
革兰阴性：大肠杆菌、克雷白杆菌种(包括肺炎杆菌)、奇异变形菌、普通变形菌、摩氏摩根氏菌(前称摩氏变形菌)、雷氏变形菌、假单胞菌种如绿脓杆菌、普罗威登斯菌、肠杆菌属、枸椽酸杆菌属、沙雷菌属、沙门菌属、志贺菌、小肠结肠炎耶氏菌、出血败血性巴斯德菌、不动杆菌属、淋病奈瑟菌、脑膜炎奈瑟菌、流感嗜血杆菌和副流感嗜血杆菌(包括抗氨苄青霉素的菌株)。
革兰阳性：金黄色葡萄球菌和白色表皮葡萄球菌(对二甲氧苯青霉素敏感的菌株)、细球菌属、酿脓链球菌、无乳链球菌、肺炎链球菌、缓症链球菌、链球菌属(粪链球菌除外)。
厌氧菌菌株：消化球菌种、消化链球菌属、链球菌属、丙酸杆菌属、产气荚膜梭状芽胞杆菌、梭杆菌属、拟杆菌属(很多脆弱拟杆菌株已有抗药性)。
于体外试验，头孢噻甲羧肟对二甲氧苯青霉素有抗药性的葡萄球菌，粪链球菌及多种其他的肠球菌，难辨梭状芽胞杆菌，单核细胞增多性李司特菌及弯曲杆菌属无作用。
〔剂量〕
复达欣是供非肠道的给药方法使用，剂量依感染的严重程度，敏感性、部位和种类及病人的年龄，体重和肾功能而定。
成人：头孢噻甲羧肟的成人剂量范围是每天1～6g，分2或3次作静脉注射或肌肉注射。对使泌尿道及许多较轻的感染症，一般每12h500mg或1g已足够。对大多数感染，应使用每8h1g或每12h2g的剂量。对非常严重的感染，特别是免疫受抑制的病人，包括那些嗜中性白细胞减少者，应使用每8h或12h2g的剂量。
囊性纤维化症：在纤维囊性而患有假单胞菌类肺部感染之成人，应使用100～150mg／(kg·d)的高剂量，分3次给药。
当用作预防剂于前列腺手术时，1g的剂量应用于诱导麻醉，第二剂剂量则应考虑用于除去导管时。在肾功能正常的成人中使用过9g／d的剂量，而无病症。
婴儿及儿童(超过两个月大的儿童)：一般的剂量范围是30～100mg／(kg·d)，分2或3次给药。对免疫受抑制或患有囊性纤维化或脑膜炎的儿童，可使用剂量高至150mg／(kg·d)，分3次给药(最高为6g／d)。
新生至两个月大婴儿：25～60mg／(kg·d)，分2次给药。头孢噻甲羧肟在新生婴儿的血清半衰期能是成人的3～4倍。
老年病人：鉴于急性患病的老年人头孢噻甲羧肟清除率有所减低，尤其在年龄超过80岁的病人，其剂量通常不能超过3g／d。
在肾功能损害情况下的剂量：头孢噻甲羧肟以原型从肾脏排泄的，因此对肾功能损害的病人，推荐的剂量需减低。可使用的首次负荷剂量为1g，然后应做肾小球过滤率来决定适当的维持剂量。
肾功能不全病人建议的头孢噻甲羧肟维持剂量
在患有严重感染的病人，上表所列的单剂量是可以增加50%或适当地增加给药频率。对这些病人，应监测头孢噻甲羧肟的血清水平，而最低的水平不应超过40mg／l。
儿童的肌酐清除率应根据体表面积作调整。
正在接受血透析治疗的病人剂量：在血透析过程中，头孢噻甲羧肟的血清半衰期范围是3～5h，随后每一血液透析期均应重复上表建议的维持剂量。头孢噻甲羧肟可用于腹膜透析及不卧床之连续腹膜透析。除静脉注射之外，头孢噻甲羧肟可混入透析液一起用(通常2升透析液用125～250mg)。
正在特护治疗接受连续动静脉血液透析或高流速血液过滤法的肾衰竭病人，剂量为1g／d，可分一次或多次给药。
至于用低流速血液过滤法的病人，则请依照上列肾功能不全的建议剂量。
〔用法〕
头孢噻甲羧肟可作静脉给药或深肌内注射，注射部位是臀大肌之上外四分之一或大腿的外侧部位。供应复达欣注射剂的小瓶是经过减压的。在配制时会释发二氧化碳，正压力因而产生。
〔配制指南〕
表12 头孢噻甲羧肟溶液的配制
*注：配制静脉输注液应分4个阶段(参照本文)
当病人接受非肠道液体时，可直接将头孢噻甲羧肟溶液注入静脉或给药器的管道内。
头孢噻甲羧肟与常用的静脉注射溶液都可配伍。使用时建议采用下列配制法。
〔配制肌肉注射液或静脉大剂注射液〕
1．将针插过瓶封口，并注入推荐量的稀释液；
2．将针拔出，摇动药瓶至药液成为一清澈的溶液；
3．将瓶倒置，将注射推进器完全压下，再把针插过瓶封口，并保持针在溶液内，将全部溶液吸入注射器内；
4．注射器内所含的细小二氧化碳气泡可以不需理会。
〔配制静脉输注液〕
1．将针头插过瓶封口，并注入10ml稀释液；
2．将针头拔出，摇动药瓶至瓶内溶液变成清澈；
3．将一支放气针插入药瓶封口以释出瓶内的气压；
4．当放气针仍留在原位时，便加入余量的稀释液，拔出放气针及注射器针，摇动小瓶，便可如常地供输注用。
注：为保存产品的无菌状况，必须注意放气针在产品溶解前不可插过瓶封口。
〔禁忌证〕
头孢噻甲羧肟禁用于对头孢菌素类有过敏的病人。
〔警告〕
如用其他的β内酰胺抗生素类一样，在用头孢噻甲羧肟治疗前应小心询问对头孢噻甲羧肟，头孢子菌素类，青霉素类或其他药物的过敏反应病史。对青霉素有Ⅰ型或直接过敏反应的病人，使用头孢噻甲羧肟应特别谨慎。倘若有对头孢噻甲羧肟产生过敏的反应，便停止用药。如发生严重的过敏反应情况，可能需要采用肾上腺素，氢化可的松，抗组织胺药或其他紧急处理。
〔注意事项〕
对于正在接受肾毒性药物例如氨基糖甙抗生素类或强效的利尿剂如呋喃苯胺酸作合并治疗的病人，使用高剂量的头孢类抗生素应谨慎，因这些药合用对肾功能有不良的作用。头孢噻甲羧肟的临床经验证明在推荐的剂量水平下，这情况是不成问题的。没有证据表明头孢噻甲羧肟于正常的治疗剂量时会对肾功能有不良的影响。但是，一如所有经由肾排泄的抗生素类，剂量需要根据肾功能的减低程度而相应地减低。有报道，当剂量没有得到适当减低时，有时会有神经上的一些后遗症。
没有任何实验证明头孢噻甲羧肟可影响胚胎发育或畸胎形成，但一如所有药物，在妊娠的最初数月中，应小心使用。低浓度的头孢噻甲羧肟进人乳汁中排出，因此，给哺乳妇女服用头孢噻甲羧肟时应小心谨慎。
头孢噻甲羧肟不干扰糖尿的酶试验，但用铜还原法(Benedict′s，Fehling′s，Clinitest)则可能观察到轻微的干扰。头孢噻甲羧肟在肌酐的碱性苦味酸测定中不产生干扰。约有5%病人在与使用头孢噻甲羧肟有关的Coombs′试验中显示阳性，这可能会干扰血液的交叉配型。
一如其他广谱的抗生素类，长期使用头孢噻甲羧肟可能会引致非敏感菌过度生长(例如念珠菌属，肠球菌)，因而可能需要中止疗法或采用适当的护理方法。重复评估病人的情况是必要的。在体外显示氯霉素对头孢噻甲羧肟及其他头孢子菌素类有拮抗作用，这一发现临床意义尚不清楚，但若打算同时使用头孢噻甲羧肟和氯霉素时，便须考虑拮抗作用的可能性。
〔副作用〕
临床经验显示一般对头孢噻甲羧肟的耐受良好。
稀有的副作用包括：
局部：因静脉给药造成静脉炎或血栓性静脉炎；肌肉注射后有疼痛和／或炎症。
过敏：斑丘疹或荨麻疹，发热，瘙痒和血管性水肿罕有及过敏性反应(包括支气管痉挛和／或低血压)。与其他头孢菌素类一样，偶有毒性表皮坏死溶解。
胃肠道的：腹泻，恶心，呕吐，腹痛和罕见的鹅口疮或结肠炎。与其它头孢菌素一样，结肠炎可能与难辨梭状芽胞杆菌有关，并可能会以伪膜性结肠炎出现。
生殖泌尿道：念珠菌病，阴道炎。
中枢神经系统：头痛，眩晕，感觉异常和味觉障碍。曾有报道，肾损害的病人，其头孢噻甲羧肟的剂量并没有适当地减低而发生神经后遗症的报告包括：震颤，肌阵挛病，抽搐和脑病。
实验室检验改变：一过性头孢噻甲羧肟治疗期间的改变包括：
嗜酸性粒细胞增多，Coombs′试验阳性，溶血性贫血(罕见)，血小板增多及一种或多种肝酶，ALT(SGPT)，AST(SGOT)，LDH，GGT和碱性磷酸酯酶活性增高。
一如其他的头孢类抗菌素，偶然观察到血尿素，血尿素氮和／或血清肌酐的一过性增高。白细胞减少，嗜中性白细胞减少，血小板减少症及淋巴细胞增多罕见。
〔用药过量〕
用头孢菌素过量会导致神经系统后遗症如脑病，抽搐，昏迷。血清头孢噻甲羧肟水平可通过血液透析法或腹膜透析法来减低。
〔药物制剂注意事项〕
供应复达欣注射剂的小瓶是减压的。在配制时会释放二氧化碳，正压力因而产生。有关配制方法，请参阅用法一栏。
瓶装的复达欣注射剂应贮于25℃以下，必要时不超过30℃以上，贮存两个月对产品没有损害。未配制的小瓶应避光保存。
用注射用水(英国药典)或相容的液体配制的头孢噻甲羧肟溶液，在室温下保存18h，在电冰箱内保存7d，药效均良好。
头孢噻甲羧肟与常用的静脉注射溶液相容。
头孢噻甲羧肟于碳酸氢钠注射液内的稳定性不如其他的静脉用液体，所以并不推荐用其作稀释液。
头孢噻甲羧肟与氨基糖甙类不应混合于同一给药器或注射器内。
曾有报道当万古霉素加入头孢噻甲羧肟溶液后出现沉淀的情况，所以为审慎起见，对使用这两种药物之间需先冲洗给药器和输注管。
溶液从淡黄色至琥珀色，依浓度，稀释液及贮藏情况而定。产品的药效并不受这种颜色变更的影响。
头孢噻甲羧肟浓度在介于1～40mg／ml之间与下列溶液相容：
0．9%氯化钠注射液(英国药典)；
M／6氯化钠注射液(英国药典)；
复合乳酸钠注射液(英国药典)(Hartmann溶液)；
5%葡萄糖注射液(英国药典)；
0．225%氯化钠+5%葡萄糖注射液(英国药典)；
0．45%氯化钠+5%葡萄糖注射液(英国药典)；
0．9%氯化钠+5%葡萄糖注射液(英国药典)；
0．18%氯化钠+4%葡萄糖注射液(英国药典)；
10%葡萄糖注射液(英国药典)；
右旋糖酐40注射液(英国药典)10%于0．9%氯化钠注射液(英国药典)内；
右旋糖酐40注射液(英国药典)10%于5%葡萄糖注射液(英国药典)内；
右旋糖酐70注射液(英国药典)6%于0．9%氯化钠注射液(英国药典)内；
右旋糖酐70注射液(英国药典)6%于5%葡萄糖注射液(英国药典)内；
头孢噻甲羧肟的浓度在0．05～0．25mg／ml与腹膜内透析液(乳酸盐)相容，作肌肉注射用的头孢噻甲羧肟可用0．5%或1%盐酸利多卡因注射液(英国药典)来配制。
当头孢噻甲羧肟浓度在4mg／ml时，与下列溶液混合一起，两者仍会保持良好的药效。
氢化可的松(氢化可的松磷酸钠)1mg／ml于0．9%氯化钠注射液(英国药典)或于5%葡萄糖注射液(英国药典)内；
头孢呋肟(头孢呋肟钠)3mg／ml于0．9%氯化钠注射液(英国药典)内；
邻氯青霉素(邻氯青霉素钠)4mg／ml于0．9%氯化钠注射液(英国药典)内；
肝素10U／ml或50U／ml于0．9%氯化钠注射液(英国药典)内；
氯化钾10μg／1或40μg／l于0．9%氯化钠注射液(英国药典)内；
复达欣注射剂瓶装500mg，以1．5ml的注射用水配制后，可加入甲硝哒唑注射液(500mg于100ml内)，而两者均保存其活性。
〔药代动力学〕
头孢噻甲羧肟于非肠道途径给药后便达到高而持久的血清水平，及后随着半衰期约2h而下降。肌肉注射500mg及1g后，血清峰值迅即分别达到18mg／l及37mg／l，静脉大剂量推注500mg，1g及2g5min后，血清水平分别达到46mg／l，87mg／l及170mg／l。静脉及肌肉注射后8～12h，血清中仍见有效的治疗浓度。头孢噻甲羧肟与血清蛋白的结合率约为10%。
头孢噻甲羧肟不在体内代谢而是以原型经由肾小球滤过而排泄入尿中。在24h内约80%～90%的剂量可于尿中复见。对于肾功能受损的病人，其排除功能降低，故应降低剂量，经胆汁排泄不到1%，这明显地限制了进入肠内的份量。
在骨，心，胆汁，痰，眼房水，滑液，胸膜液及腹膜液中，头孢噻甲羧肟的浓度能超过最小抑菌浓度。头孢噻甲羧肟很容易经胎盘转移，在人奶中排泄。头孢噻甲羧肟不易穿过完整的血脑屏障，所以在不存在炎性情况的时候，其在脑脊髓液中的水平是很低。当脑膜发炎时，脑脊髓液内则会达到4～20mg／l或更高的治疗水平。
复达欣为葛兰素集团所拥有之商标。
〔生产厂家〕
英国葛兰素集团
(附本品别名：头孢他啶，Ceftazidime Pentahydrate，GR20263，kefadim，SN401，头孢噻甲羧肟，噻甲羧肟头孢菌素，头孢齐定，凯复定)
【外文释文】：
Presentation
Fortum Injection is supplied as a white to faintly yellow powder in vials contanining 500mg，1 g and 2 g ceftazidime(as pentahydrate)with sodium carbonate(1 18 milligram per gram of ceftazidime)．On the addition of water for injections，Fortum Injection dissolves with effervescence to produce a solution for injection．
Fortum Injection contains approximately 52 mg(2．3 mmol)of sodium per gram of ceftazidime．
116 mg cefazidime pentahydrate is equivalent to 100mg ceftazidime free acid．
Indications
Ceftazidime is a bactericidal cephalosporin antibiotic which is resistant to most beta-lactamases and is active against a wide range of Gram-positive and Gram-negative bacteria．
It is indicated for the treatment of single or multiple infections caused by susceptible organisms．
Ceftazidime，because of its broad antibacterial spectrum，may be used alone as first choice drug，pending sensitivity test results．It may be used in combination with an aminoglycoside or most other beta-lactam antibiotics．It may also be used with an antibiotic against anaerobes when the presence of bacteroides fragilis is suspected．
Indications include：
Severe infections e．g．septicaemia，bacteraemia，peritonitis，meningitis，infections in immunosuppressd patients，infection in patients in intensive care，e．g．infected burns．
Respiratory tract infections including lung infections in cystic fibrosis．
Ear，nose and throat infections．
Urinary tract infections．
Skin and soft tissue infections．
Gastrointestinal，biliary and abdominal infections．
Bone and joint infections．
Infections associated with haemo-and peritoneal dialysis and with continuous ambulatory peritoneal dialysis(CAPD)．
Prophylaxis：Prostatic surgery(transurethral resection)．
Bacteriology
Ceftazidime is bactericidal in action．It acts by inhibiting bacterial cell wall synthesis．A wide range of pathogenic strains and isolates are susceptible in vitro including strains resistant to gentamicin and other aminoglycosides．It is highly stable to most clinically important betalactamases produced by both Gram-positive and Gram-negative organisms and consequently is active against many ampicillin-and cephalothin-resistant strains．Ceftazidime has high intrinsic activity in vitro and acts within a narrow MIC range for most genera with minimal changes in MIC at varied inoculum levels．In vitro，the activities of ceftazidime and aminoglycosides in combination are additive．There is evidence of synergy in some strains．
Ceftazidime is active in vitro against the following organisms：
Gram-negative：E．Coli，Klebsiella spp．(including K1 pneumoniae)，Proteus mirabilis，Proteus vulgaris，Morganella morganii(formerly Proteus morganii)，Proteus rettgeri，Pseudomonas spp．(including Ps aeruginosa)，Providencia spp．，Enterobacter spp．，Citrobacter spp．，Serratia spp．，Salmonella spp．，Shigella spp．，Yersinia enterocolitica，Pasteurella multocida，Acinetobacter spp．，Neisseria gonorrhoeae，Neisseria meningitidis，Haemophilus influenzae(including ampicillin resistant strains)，Haemophilus parainfluenzae(including ampiclilin resistant strains)．
Grem-positive：Staphylococcus aureus(methicillin-sensitive strains)，Staphylococcus epidermidis(methicillin-sensitive strains)，Micrococcus spp．，Streptococcus pyogenes(Group A beta-haemolytic streptococci)，Streptococcus Group B(Strept agalactiae)，Streptococcus pneumoniae，Streptococcus mitis，Streptococcus spp．(excluding Enterococcus(Streptococcus)faecalis)．
Anaerobic strains：Peptococcus spp．，Peptostreptococcus spp．，Streptococcus spp．，Propionibacterium spp．，Clostridium perfringens，Fusobacterium spp．，Bacteroides spp．(many strains of Bacteroides fragilis are resistant)．
Ceftazidimel is not active in vitro against methicillin-resistant staphylococci，Enterococcus(Streptococcus)faecalis and many other Enterococci，Clostridium difficile，Listeria monocytogenes，Campylobacter spp．
Dosage
Fortum is to be used by the parenteral route，the dosage depending upon the severity，sensitivity and site and type of infection and upon the age，weight and renal function of the patient．
Adults：
The adult dosage range is 1-6 g／d in 2 or 3 divided doses by i．v．or i．m．injection．
Urinary tract and less severe infections，500 mg or 1 g 12-hourly is usually adequate．For most infecions，．1 g 8-hourly or 2 g 12-hourly should be given．
Very severe infections，especially in immunocompromised patients，including those with neutropenia，2 g 8 or 12-hourly should be administered．
Fibrocystic adult with pseudomonal lung infections，high doses of 100 to 150 mg／(kg·d)in 3 divided doses should be used．
When used as a prophylactic agent in prostatic surgery 1 g should be given at the induction of anaesthesia．A second dose should be considered at the time of catheter removal．
In adults with normal renal function，9 g／d has been used without ill effect．Infants and children(>2 months)： The usual dosage range is 30 to 100 mg／(kg·d)，given in 2 or 3 divided doses．Doses up to 150 mg／(kg·d)(maximum 6 g daily)in 3 divided doses may be given to infected immunocompromised or fibrocystic children or children with meningitis．
Neonates(0-2)months：
The usual dose range is 25-60 mg／(kg·d)given in 2 divided doses．In neonates the serum half-life of ceftazidime can be 3-4 times that in adults．
Use in the Elerly：
In view of the reduced clearance of ceftazidime in acutely ill elderly patients，the daily dosage should not normally exceed 3g，especially in those over 80 years of age．
Renal Impaiment：
Ceftazidime is excreted unchanged by the kidneys．Therefore，in patients with impaired renal function，it is recommended that the dosage of ceftazidime should be reduced to compensate for its slower excretion．An initial loading dose of 1 g should be given．
Maintenance doses should be based on GFR：
Recommended maintenance doses of ceftazidime in renal insuficiency are shown below：
Table 12
In patients with severe infections，the unit dose given in the table should be increased by 50%or the dosing frequency increased．In such patients the ceftazidime serum levels should be monitored and trough levels should not exceed 40 mg／l．
In children，the creatinine clearance should be adjusted for body surface area or lean body mass．
Haemodialysis：The serum half-life during haemodialysis ranges from 3-5 hours．Following each haemodialysis period the maintenance dose of ceftazidime recommended in the above table should be repeated．
Peritoneal dialysis：Ceftazidime may be used in peritoneal dialysis and continuous ambulatory peritoneal dialysis(CAPD)．
In addition to i．v．use，ceftazidime can be incorporated into the dialysis fluid(usually 125-250mg for 2 litres of dialysis solution)．
For patients with renal failure on continuous arteriovenous haemodialysis or high-flux haemofiltration in intensive therapy units，1 g daily either as a single dose or in divided doses．For low-flux haemofiltration follow the dosage recommended under impaired renal function．
Administration
Ceftazime may be given intravenously or by deep intramuscular injection into a large muscle mass such as the upper outer quadrant of the gluteus maximus or lateral part of the thigh．
All sizes of vials as supplied are under reduced pressure．As the product dissolves，carbon dioxide is released and a positive pressure develops．
Instructions for constitution：
Table 13
＃：Preparation should be in four stages(see text)．
Ceftazidime solutions may be given directly into the vein or introduced into the tubing of a giving set if the patient is receiving parenteral fluids．Ceftazidime is compatible with most commonly used intravenous fluids．For ease of use，it is recommended that the following techniques of constitution are adopted．
Preparation of solutions for i．m．or i．v．bolus injection：
1．Introduce the syringe needle through the vial closure and inject the recommended volume diluent．
2．Withdraw the needle and shake the vial to give a clear solution．
3．Invert the vial with the syringe piston fully depressed，insert needle through the vial closure and withdraw the total volume of solution into the syringe ensuring that the needle remains in the solution．
4．Small bubbles of carbon dioxide in the syringe may be disregarded．
Preparation of solutions for i．v．infusion：
1．Insert the syringe needle through the vial closure and inject 10 ml of diluent．
2．Withdraw the needle and shake the vial to give a clear solution．
3．Insert a gas relief needle through the vial closure to relieve the internal pressure．
4．With the gas relief needle in place add the remainder of the diluent．Remove both the gas relief and syringe needles，shake the vial and set up for infusion use in the normal way．
Note：To preserve product sterility，it is important that the gas relief needle is not inserted through the vial closure before the producet has dissolved．
Contraindications
Ceftazidime is contraindicated in patients with known hypersensitivity to cephalosporin antibiotics．
Warnings
As with other beta-lactam antiblotics，before therapy with ceftazidime is instituted，careful inquiry should be made for a history of hypersensitivity reactions to ceftazidime，cephalosporins，penicillins，or other drugs．Ceftazdime should be given only with special caution to patients with type l or immediate hypersensitivity reactions to penicillin．If an allergic reaction to ceftazidime occurs，discontinue the drug．Serious hypersensitivity reactions may require epinephrine(adrenaline)，hydrocortisone，antihistamine or other emergency measures．
Precautions
Cephalosporin antibiotics at high dosage should be given with caution to patients receiving concurrent treatment with nephrotoxic drugs such as aminoglycosides，or potent diuretics such as frusemide，as these combinations may adversely affect renal function．Clinical experience with ceftazidime has shown that this is not likely to be a problem at the recommended dose levels．There is no evidence that ceftazidime adversely affects renal funtion at normal therapeutic doses．However，as for all antibiotics eliminated via the kidneys，it is necessary to reduce the dosage according to the degree of reduction in renal function(see Dosage in Re hal impairment)to avoid the clinical consequences of elevated antibiotic levels．Neurologicalsequelae have occasionally been reported when the dose has not been reduced appropriately．
There is no experimental evidence of embryopathic or teratogenic effects attributable to ceftazidime but，as with all drugs，its should be administered with caution during the early months of pregnancy and in early infancy．Ceftazidim is excreted in human milk in small quantities and consequently caution should be exercised when ceftazidime is administered to nursing mothers．
Ceftazidime does not interfere with enzyme-based tests for glycosuria but slight interference may occur with copper reduction methods(Benedict’s，Fehling’s，Clinitest)．Ceftazidime does not interfere in the alkale picrate assay for creatinine．
The development of a positive Coombs’test associated with the use of ceftazime in about 5% of patients may interfere with the cross-matching of blood．
As with other broad spectrum antibiotics，prolonged use of ceftazidime may result in the overgrowth of non-susceptible organisms(e．g．Candida，Enterococci)which may require interruption of treatment or adoption of appropriate measures．Repeated evaluation of the patient’s condition is essential．
Chloramphenicol is antagonistic in vitro with ceftazidime and other cephalosporins．The clinical relevance of this finding is unknown，but if concurrent administration of ceftazidime with chloramphenicol is proposed，the possibility of antagonism should be considered．
Side effects
Ceftazidime is generally well tolerated．
Adverse reactions are infrequent and include：
Local：
Phlebitis or thrombophlebitis with i．v．administration；pain and／or inflammation after i．m．injection．
Hypersensitivity：
Maculopapular or urticarial rash，fever，pruritus，and very rarely angioedema and anaphylaxis(including bronchospasm and／or hypotension)．As with other cephalosporins，there have been rare reports of toxic epidermal necrolysis．
Gastrointestinal：
Diarrhoea，nausea，vomiting，abdominal pain，and very rarely oral thrush or colitis．As with other cephalosporins，colitis may be associated with Clostridium difficile and may pesent as pseudomembranous colitis．
Genito-urinary：
Candidiasis，vaginitis．
Central Nervous System：
Headache，dizziness，paraesthesia and bad taste．There have been reports of neurologi cal sequelae including tremor，myoclonia，convulsions，and encephalopathy occurring in patients with renal impairment in whom the dose of ceftazidime has not been appropriately reduced．
Laboratory test changes：
Transient changes noted during ceftazidime therapy include：eosinophilia，positive Coombs’test，very rarely haemolytic anaemia，thrombocy tosis and elevations in one or more of the hepatic enzymes．ALT(SGPT)，AST(SGOT)，LDH，GGT and alkaline phosphatase．
As with some other cephalosporins，transient elevations of blood urea，blood ureanitrogen and／or serum creatinine have been observed occasionally．Very rarely，leucopenia，neutropenia，agranulocytosis，thrombocytopenia and lymphocytosis have been reported．
Overdosage
Overdosage can lead to neurological sequelae including encephalopathy，convulsions and coma．Serum levels of ceftazidime can be reduced by haemodialysis or peritoneal dialysis．
Pharmaceutical precautions
Vials of Fortum injection are supplied under reduced pressure；a positive pressure is produced on constitution due to the release of carbon dioxide．See Administration section above for recommended techniques of constitution．
Vials of Fortum Injection should be stored at a temperature below 25℃．Occasional storage at temperature not higher than 30℃ for up to 2 months is not detrimental to the product．
Unconstituted vials should be protected from light．
Solutions of ceftazidime in water for injections or compatible fluids retain satisfactory potency for 18 hours at room temperature or 7 days in a refrigerator．
Compatibility：
Ceftazidime is compatible with most commonly used intravenous fluids．
Ceftazime is less stable in Sodium Bicarbonate Injection than in other intravenous fluids．It is not recommended as a diluent．
Ceftazidime and aminoglycosides should not be mixed in the same giving set or syringe．
Precipitation has been reported when vancomycin has been added to ceftazidime in solution．Therfore，it would be prudednt to flush giving sets and intravenous lines between administration of these two agents．
Solutions range from light yellow to amber depending on concentration，diluent and storage conditions used．Within the stated recommendations，product potency is not adversely affected by such colour variations．
Ceftazidime at concentrations between 1 mg／ml and 40mg／ml is compatible with：
0．9%Sodium Chloride Injection BP
M／6 Sodium Chloride Injection BP
Compound Sodium Lactate Injection BP(Hartmann’s Solution)
5%Dextrose Injection BP
0．225%Sodium Chloride and 5%Dextrose Injection BP
0．45%Sodium Chloride and 5%Dextrose Injection BP
0．9%Sodium Chloride and 5%Dextrose Injection BP
0．18%Sodium Chloride and 4%Dextrose Injection BP
10%Dextrose Injection BP
Dextran 40 Injection BP 10%in 0．9%Sodium Chloride Injection BP
Dextran 40 Injection BP 10%in 5%Dextrose Injection BP
Dextran 70 Injection BP 6%in 0．9%Sodium Chloride Injection BP
Dextran 70 Injection BP 6%in 5%Dextrose Injection BP
At concentrations between 0．05 mg／ml and 0．25 mg／ml，Ceftazidime is compatible with Intraperitoneal Dialysis Fluid(Lactate)．
Ceftazidime may be constituted for intramuscular use with 0．5%or 1%Lidocaine Hydrochloride Injection BP．
When ceftazidime is admixed at 4 mg／ml with the following，both components retain satisfactory potency：
Hydrocortisone(hydrocortisone sodium phosphate)1 mg／ml in 0．9%Sodium Chloride Injection BP or 5%Dextrose Injection BP
Gefuroxime(cefuroxime sodium)3 mg／ml in 0．9%Sodium Chloride Injection BP
Cloxacillin(cloxacillin sodium)4 mg／ml in 0．9%Sodium Chloride Injection BP
Heparin 10 U／ml or 50 U／ml in 0．9%Sodium Chloride Injection BP
Potassium Chloride 10μg／l or 40μg／l in 0．9%Sodium Chloride Injection BP
The contents of a 500 mg vial of Fortum Injection constituted with 1．5 ml water for injections，may be added to metronidazloe injection(500 mg in 100 ml)and both retain their activities．
Pharmacokinetics
Ceftazidime administered by the parenteral route produces high and prolonged serum levels which decrease with a half-life of about 2 hours．
After i．m．administration of 500 mg and 1 g，peak levels of 18 mg／l and 37 mg／l respectively are rapidly achieved．Five minutes after an intravenous bolus injection of 500 mg，1 g or 2 g，serum levels are respectively 46 mg／l，87 mg／l and 170 mg／l．
Therapeutically effective concentrations are still found in the serum 8-12 hours after either i．v．or i．m．administration．
The serum protein binding of ceftazidime is about 10%．
Ceftazidime is not metabolized in the body and is excreted unchanged in the active form into the urine by glomerular filtration，approximately 80%-90%of the dose is recovered in the urine with in 24 hours．Elimination of ceftazidime is decreased in patients with impaired renal function and the dose should be reduced．See section on renal impairment．Less than 1%is excreted via the bile which limits the amount entering the bowel．
Concentrations in excess of the Minimum Inhibitory Levels(MIC)for common pathogens can be achieved in tissues such as bone，heart，bile，sputum，aqueous humour，synovial，pleural and peritoneal fluids．
Transplacental transfer of ceftazidime readily occurs．Ceftazidime is excreted in the breat milk．Ceftazidime penetrates the intact blood-brain-barrier poorly and low levels are achieved in the CSF in the absence of inflammation．Therapeutic levels of 4-20 mg／l or more are achieved in the CSF when the meninges are inflamed．
Manufacturer
Fortum is a trade mark owned by the Glaxo Group of Companies．
Made for Glaxo Group ltd by
Glaxo Operations UK Ltd
Greenford，England