Worldwide clinical data on efficacy and safety of ciprofloxacin

During the clinical trials 8,861 patients have been treated with ciprofloxacin worldwide. 3,822 of the therapeutic courses were valid for analysis of efficacy according to FDA standards. The following dosages were usually administered: UTI: 100 to 500 mg twice daily orally or 100 mg twice daily intravenously; RTI: 250 to 1000 mg twice daily orally or 200 mg twice daily intravenously; septicemia: 200 mg intravenously twice daily; gonorrhea: 250 to 500 mg single tablet orally; all other infections: 500 to 1000 mg twice daily orally or 200 mg twice daily intravenously. Ciprofloxacin was administered to 762 courses of lower RTI, 88 courses of upper RTI, 108 courses of bacteremia, 766 courses of skin structure infection, 142 courses of bone and joint infections, 149 courses of intra-abdominal infections, 33 courses of gastrointestinal infections, 1,633 courses of UTI, 49 courses of pelvic infections, 279 courses of STD, mainly gonorrhea, and three courses of meningitis. The clinical response was resolution in 76%, improvement in 18% and failure in only 6%. Bacteriologic response by all sites evaluable: pathogens were eradicated from 74%, markedly reduced in 2%, persisted in 10%. Relapse occurred in 4% and reinfection was observed in another 6%. The overall response was favourable for 90% of the patients. Drug safety was established on a data base of 8,861 courses worldwide. The following side-effects according to COSTART terminology were observed: digestive 5%, metabolic nutritional 4.6%, central nervous 1.6%, skin 1.4%, hemic and lymphatic 1%, cardiovascular 0.4%, body as a whole 0.4%, urogenital 0.3%, special senses 0.3%, musculo-skeletal 0.1%, respiratory 0.08%. Several courses had more than one reaction. Thus the total incidence of side-effects for the treated patient population was 10.2%. Ciprofloxacin is a highly effective drug and a breakthrough in several areas of medical interest. It is relatively safe and side-effects are usually mild or moderate in intensity and transient.Weltweit wurden 8861 Behandlungsverläufe während der klinischen Prüfung mit Ciprofloxacin dokumentiert. Nach FDA-Kriterien waren 3822 Behandlungsverläufe auswertbar für die Beurteilung der Wirksamkeit. Die nachfolgenden Dosierungen wurden üblicherweise angewandt: Harnwegsinfektionen: 100 bis 500 mg oral, zweimal pro Tag oder 2 × 100 mg intravenös; Atemwegsinfektionen: 250 bis 1000 mg oral zweimal pro Tag oder 2 × 200 mg intravenös; Sepsis: zweimal pro Tag intravenös 200 mg; Gonorrhoe: 1 Tablette zu 250 oder 500 mg; alle anderen Infektionen 500 bis 1000 mg zweimal pro Tag oral oder zweimal 200 mg intravenös. Bei folgenden Indikationen wurde Ciprofloxacin geprüft: Infektionen des Respirationstraktes — tiefe 762 Fälle, obere 88 Fälle, Sepsis — 108 Fälle, Haut- und Weichteilinfektionen — 766 Fälle, Knochen-und Gelenkinfektionen — 142 Fälle, intraabdominale Infektionen 149 Fälle, gastrointestinale Infektionen — 33 Fälle, Harnwegsinfektionen — 1633 Fälle, gynäkologische Infektionen — 49 Fälle, venerische Erkrankungen (hauptsächlich Gonorrhoe) — 279 Fälle und bei 3 Fällen mit Meningitis. Klinische Heilung wurde in 76% und deutliche Besserung in 18% aller Fälle erreicht, in nur 6% der Fälle versagte die Therapie. Bei 74% wurden die Bakterien eliminiert und bei weiteren 2% deutlich reduziert; sie persistierten bei 10% der Patienten. Ein Rückfall wurde bei 4% beobachtet und eine Reinfektion bei 6%. Das Gesamturteil (klinisches und bakteriologisches Ergebnis) war günstig für 90% der Patienten. Für die Beurteilung der Verträglichkeit konnten 8861 Behandlungsverläufe herangezogen werden. Die folgenden Nebenwirkungen (nach COSTART Organsystem) wurden beobachtet: Verdauungstrakt 5%, Metabolismus 4,6%, ZNS 1,6%, Haut 1%, Blut- und Lymphsystem 1%, Herz-Kreislauf 0,4%, Gesamtkörperreaktionen 0,4%, Urogenital 0,3%, Sinnesorgane 0,3%, Gelenk- und Muskeln 0,1% und Atemwege 0,08%. Bei mehreren Behandlungsverläufen wurde mehr als eine Nebenwirkung beobachtet, so daß die Gesamtinzidenz, bezogen auf die Patientenzahl, nur 10,2% beträgt. Ciprofloxacin ist hochwirksam und ein therapeutischer Durchbruch auf vielen Gebieten der Infektiologie. Es ist relativ gut verträglich; die beobachteten Nebenwirkungen waren in der Regel nur leicht oder mäßig schwer und vorübergehend.     

Safety of long-term therapy with ciprofloxacin: data analysis of controlled clinical trials and review.

We reviewed the literature and the manufacturer's U.S. clinical data pool for safety data on long-term administration of ciprofloxacin (Bayer, West Haven, CT). Only controlled clinical trials including patients treated for >30 days were selected. We identified 636 patients by literature search and 413 patients in the Bayer U.S. database who fulfilled our search criteria; the average treatment duration for these patients was 130 and 80 days, respectively. Main indications for long-term therapy were osteomyelitis, skin and soft-tissue infection, prophylaxis for urinary tract infection, mycobacterial infections, and inflammatory bowel disease. Adverse events, premature discontinuation of therapy, and deaths occurred at a similar frequency in both treatment arms. Most adverse events occurred early during therapy with little increase in frequency over time. As with short-term therapy, gastrointestinal events were more frequent than central nervous system or skin reactions, but pseudomembranous colitis was not observed. No previously unknown adverse events were noted. We conclude that ciprofloxacin is tolerated as well as other antibiotics when extended courses of therapy are required.     

Overstitch在临床应用中的安全性评价

Overstitch内镜缝合系统是近年来逐渐应用于临床的内镜下空腔脏器全层缝合设备,该设备扩大了消化内镜手术的治疗范围,推进了临床手术治疗的微创化。近年来关于该设备的临床试验层出不穷,展示了Overstitch应用于临床治疗的潜力,但时见其相关并发症及不良反应报道,Overstitch相关手术的安全性尚待验证。本文就Overstitch的临床应用及安全性进行综述和讨论,旨在揭示该设备用于治疗消化系统疾病的优势及不足,进而评价这一新兴内镜缝合设备在临床应用中的安全性。     

Anticoagulant factor concentrates in disseminated intravascular coagulation: rationale for use and clinical experience.

Natural inhibitors of coagulation, in other words, antithrombin (AT), the protein C system, and tissue factor pathway inhibitor (TFPI), play an important role in controlling the activation of coagulation during disseminated intravascular coagulation (DIC). Furthermore, they may not only influence coagulation but also attenuate inflammatory responses during sepsis. Low circulating levels of AT and protein C have been associated with poor outcome. Replacement therapy with AT, activated protein C (APC), and TFPI has been shown to attenuate thrombin generation and to reduce mortality in experimental sepsis models. Experience with AT and APC in patients is promising. Data from large phase III trials of AT and APC as treatment of patients with severe sepsis will soon be available. Recombinant TFPI is currently in phase II clinical trials for severe sepsis.     

Radiological approaches in the evaluation of joint disease in children

In summary, the newer technologies in radiology have allowed us to visualize more clearly the manifestation of joint disease in children. The presence of small erosions and cartilage damage can be seen much better with magnetic resonance imaging than with any other modality short of arthrography, a much more invasive examination. Joint effusion, although sometimes visualized with conventional radiography, is probably best recognized with ultrasound or magnetic resonance imaging, although it can be detected with computed tomography as well. For the evaluation of avascular necrosis that can be associated with steroid use in joint disease, bone scintigraphy is a simple, sensitive method. Magnetic resonance may be as or more sensitive and gives additional information as well. In the detection of change with time, conventional radiography probably will remain the standard as it is still the simplest, least expensive examination; however, it has many limitations in specific cases. Bone scintigraphy may be of value in selected cases. Although we have still not had enough experience with magnetic resonance imaging to use it as a way of evaluating progress of joint disease, it promises to be the most sensitive radiologic measure of evaluating progress as small anatomical changes can be detected within the cartilage, which cannot be done easily with other means.     

Primary myelodysplastic syndrome in children: the clinical experience in 33 cases

We describe the clinicomorphological features in 33 cases of primary myelodysplastic syndrome classified according to the FAB classification which presented to a single centre over a 12 year period. Presenting features were typically related to pancytopenia although hepatosplenomegaly and granulocytic sarcomas were far more prevalent than in the adult population. Morphological assessment of the peripheral blood and the bone marrow showed seven patients had refractory anaemia (RA), 13 patients had RA with excess of blasts (RAEB), nine patients had RAEB in transformation (RAEB-t) and four patients had chronic myelomonocytic leukaemia (CMML). The overall mean survival was short (9.9 months) in all the subgroups and the leukaemic transformation rate was high. None of the patients scored 0-1 according to the Bournemouth Scoring System; four patients scored 2 whereas 29 patients scored 3 to 4. We conclude that unlike adults, the myelodysplastic syndromes in children run an aggressive clinical course, irrespective of the FAB subtype, and the pathogenesis of these diseases in paediatric practice warrants scientific scrutiny. Intensive chemotherapy such as the one used in de novo-AML lead to complete remission in some children and these early results suggest that this should be the treatment of choice in paediatric MDS.     

Safety evaluation of the use of femural percutaneous closure systems with simultaneous use of abciximab.

INTRODUCTION: The growing use of abciximab during coronary angioplasty, with 12 hours of intravenous perfusion, prolongs hospital stay and increases the risk of hemorrhage after sheath removal at the puncture site. Femoral percutaneous closure devices can reduce immobilization time, but their safety in the presence of abciximab in respect to hemorrhage has not been clearly determined. OBJECTIVES: To evaluate the safety and efficacy of the Perclose system in patients undergoing angioplasty with abciximab. POPULATION AND METHODS: The Perclose system was used in 79 patients undergoing angioplasty, with abciximab in 31 patients (58.6 +/- 12.2 years, 90% male, p = NS)--Group 1, and 48 pts without abciximab (61.8 +/- 10.9 years, 79% male, p = NS)--Group 2. We compared heparin dose, sheath diameters, primary success rate, coronary care unit admissions and minor and major complications. One patient was previously anticoagulated with warfarin and all the others were on oral antiplatelet therapy before and after angioplasty. RESULTS: Primary success with the use of the Perclose system was 78%. We found no significant statistical differences between groups in respect to the presence of diabetes, sheath diameter or referral for intervention. Heparin dosage was slightly higher in group 2 (p = 0.09) and ACT was also higher in group 2 (p = 0.01). More patients in group 1 had delayed ambulation (p = 0.04) due to abciximab perfusion. In 7 patients in group 1 and 9 in group 2, additional manual/mechanical compression was needed for moderate bleeding in the first hours (p = NS). One rupture of the femoral artery with need for surgical repair (primary failure) and another delayed rupture (48 hours) occurred in group 1 (both with an associated infection), and 1 pseudoaneurysm in a patient from group 2, without abciximab but taking warfarin (p = NS). None of the variables analyzed determined the occurrence of complications. Only oral anticoagulation determined the occurrence of major complications. CONCLUSIONS: User of the Perclose system for percutaneous closure of the femoral artery in patients undergoing coronary angioplasty with simultaneous use of abciximab was not associated with greater morbidity than in patients without glycoprotein IIb/IIIa receptor antagonists.     

Safety evaluation of tocainide in the American emergency use program

This is a report of the safety evaluation of tocainide in the first 369 patients entered into the American Tocainide Emergency Use Program. This humanitarian protocol has made tocainide available for emergency use in the treatment of life-threatening, intractable ventricular arrhythmias in patients who were unresponsive to or unable to take the approved antiarrhythmic drugs. The most frequent adverse experiences reported were neurologic and gastrointestinal in nature and included dizziness, lightheadedness, tremors, nausea, vomiting, and anorexia. Adverse experiences resulted in the discontinuation of tocainide in 16% of these patients and were transient and reversible with no conclusive evidence of permanent organ injury. Adverse experiences having special relevance to the safety assessment of new antiarrhythmic agents are discussed, including congestive heart failure, arrhythmias and conduction disturbances, convulsions, lupus erythematosus-like illness, and deaths while on therapy. No significant abnormal trends were observed in routine hematologic and biochemical laboratory screening tests or in ophthalmologic or chest x-ray examinations. An evaluation of the effects of chronic tocainide administration on ECG intervals showed no significant change in P-R or QRS intervals but demonstrated a statistically significant decrease in Q-T duration. It is concluded that in patients with life-threatening ventricular arrhythmias, tocainide is a safe agent with a favorable risk-benefit ratio.     

Long-term oral ciprofloxacin: experience in the treatment of incurable infective endocarditis

Acute septic infective endocarditis caused by Pseudomonas aeruginosa, in two patients with conditions that made it incurable, was treated with long-term orally administered ciprofloxacin. Bacteremia and symptoms cleared, resulting in subjective well-being without cure for three and one half and 22 months, respectively. Large amounts of ciprofloxacin, 150 and 1,440 g, respectively, were given continuously without apparent adverse reactions. Blood isolates of P. aeruginosa after treatment had limited progression of resistance to ciprofloxacin. Use of orally administered ciprofloxacin provides new opportunities for the long-term treatment of serious infections with restricted risk of bacterial drug resistance and no appreciable side effects.     

Major joint replacement. A model for antithrombotic drug development: from proof-of-concept to clinical use

AIM: Development of antithrombotic compounds has traditionally been performed in patients undergoing total hip and knee replacement surgery. A high number of asymptomatic deep-vein thromboses are radiologically detectable, and bleeding and other adverse events (AE) are easy to observe. However, standardization of study procedures and endpoints in early proof-of-concept studies and late pure clinical endpoint studies has been lacking. This has made comparison between studies difficult, economic analyses speculative and potential benefits of applying the drug regimen in non-selected patients uncertain. In this paper, the International Surgical Thrombosis Forum proposes a strategy for the clinical investigation of new pharmacological agents for the prophylaxis of postoperative thrombotic events. METHODS: First, dose titration safety studies of short duration, in highly selected patients using objective venographic endpoints are recommended. Bleeding should be divided into the quantified volume of surgical bleeding and other adjudicated clinical bleeding events. The number of AE should be described for each dose step and classified according to International Coding of Diagnoses (ICD). Second, a dose confirmatory study of moderate exposure period and sufficient follow-up time is recommended. The exclusion criteria should be restricted to contraindications of the compared drugs and technical procedure. RESULTS: The efficacy, bleeding and AE should be similar to those used in dose-titration studies. In addition, the failure rate of the drug to exert its effect and the net clinical benefit should be calculated. CONCLUSION: Finally, trials with simple clinical endpoints and long follow-up should be conducted to evaluate the potential benefits of the drug-regimen in non-selected populations.     

Chronic thrombocytopenia of childhood: use of non-invasive methods in clinical evaluation

OBJECTIVES: An unselected group of 21 children with chronic thrombocytopenia was investigated to understand the patients' platelet abnormality better. METHODS: Platelet counts, mean platelet volumes (MPV), membrane glycoproteins and Fcgamma receptor type IIA (FcgammaRIIA) polymorphism H131R, reticulated platelets (% RP), antiplatelet antibodies and plasma thrombopoietin (TPO) were measured. RESULTS: Sixteen patients had idiopathic thrombocytopenic purpura (ITP) (group 1: platelets < 50 x 10(9)/L, n = 6; group 2: 50-99 x 10(9)/L, n = 4; group 3: 100-149 x 10(9)/L, n = 4; group 4: splenectomised patients with normal platelet counts, n = 2). Five patients had familial thrombocytopenia. Six healthy children were studied as a reference. In the 19 thrombocytopenic patients, the platelets were significantly larger and % RP and TPO levels were significantly higher than those in the controls. Increased megakaryocytosis at diagnosis was associated with larger MPV and higher % RP but not with platelet level or TPO. The % RP was remarkably high in all ITP patients of group 1 indicating a brisk production of platelets despite low peripheral count. In all patients with familial thrombocytopenia, TPO was increased suggesting that the syndrome was not because of defective TPO production. The distribution of FcgammaRIIA alleles in the patients was similar to that in the controls. CONCLUSIONS: A combined application of % RP and TPO could be helpful in classifying patients with chronic thrombocytopenia into different categories. The observations may be of value in the clinical evaluation of ITP patients and lead to avoidance of invasive examinations at least in some patients.     

Benign cutaneous polyarteritis nodosa in children below 10 years of age--a clinical experience.

OBJECTIVE--To report 10 children younger than 10 years of age with benign cutaneous polyarteritis nodosa (BCPAN). METHODS--Ten children aged 1.25-10 years (mean 4.7 years; M:F = 7:3) were admitted with an unusual vasculitis. The clinical features, laboratory investigations, treatment and follow up data were analysed. RESULTS--Clinical features of these patients included: fever (10), peripheral gangrene (eight), livido reticularis (four), ulceration, nodules and vesiculobullous lesions alone or in combination (10), black necrotic patches over limbs and trunk (three), and arthralgia or swelling of large joints (seven). Cryoglobulinaemia was transient in three children, lasting for eight months in one of them. Histopathology of the skin lesions revealed vasculitis of small and occasionally medium sized blood vessels in nine of the 10 children. Possible association of BCPAN was noted with diphtheria-pertussistetanus immunisation (one), drugs (two), streptococcal infection (two), wasp sting (one), and falciparum malaria (one). The clinical course was interspersed with remissions and exacerbations. Response to corticosteroids alone occurred in seven patients, while three children needed cytotoxic drugs in addition. In a follow up of 5.6 years (mean) no evidence of systemic involvement was noted. CONCLUSIONS--A rare form of vasculitis, BCPAN, is reported in children. The features that distinguished our patients from those reported earlier were onset in the first decade of life and higher incidence of peripheral gangrene.     

Infections and anti-TNF therapy: strategies for screening based on clinical experience

SIR, We read with interest the article by Kroesen et al. [1]and the editorial by Moots et al. [2]. Both papers highlightthe need for awareness of severe infections in patients on anti-tumournecrosis factor (TNF) therapy and the importance of developingstrategies to prevent such events. In our region we