Comparative effects of ciprofloxacin and ceftazidime on cytokine production in patients with severe sepsis caused by gram-negative bacteria.

In the present study the effect of ciprofloxacin versus ceftazidime on concentrations of pro- and anti-inflammatory cytokines in the sera of patients with severe sepsis was evaluated. The study included 58 previously healthy patients suffering from severe sepsis caused by gram-negative bacteria, treated with either ciprofloxacin or ceftazidime after thorough clinical and microbiological evaluation and followed up for clinical outcome. Levels of the proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha), interleukin-1b (IL-1b), IL-6, and IL-8 and of the anti-inflammatory cytokine IL-10, as well as of IL-1 receptor antagonist and soluble TNF receptors I and II, in serum were measured at baseline and 24 and 48 h after the first antimicrobial dose. Mean SAPS-II scores, development of septic shock, and mortality rates were similar in the two groups (43.2 +/- 9.2, 21.4%, and 14.3% in the ceftazidime group versus 49.8 +/- 11.3, 20%, and 13.3% in the ciprofloxacin group). Serum TNF-alpha and IL-6 levels at 24 and 48 h were significantly lower in the ciprofloxacin group, while the IL-10/TNF-alpha ratio was significantly higher, than those for the ceftazidime group. Among patients with high baseline TNF-alpha levels, there were significant increases in the IL-10/TNF-alpha ratio at both 24 and 48 h over that at admission for the ciprofloxacin group, while no differences were noted in the ceftazidime group. These results indicate that ciprofloxacin may have an immunomodulatory effect on septic patients by attenuating the proinflammatory response, while there is no evidence that differences in the cytokines measured have any impact on the final outcome.

Remote abscess formation during interferon-alpha therapy for viral hepatitis.

Abscess formation at the injection site is an unusual infectious complication of interferon-alpha (IFN-alpha) treatment of chronic hepatitis C virus (HCV) infection, but remote abscess formation during IFN-alpha therapy is very rare. In the present communication, we report three cases of remote abscess formation detected among 68 patients with chronic viral hepatitis treated with IFN-alpha, and review the pertinent English literature. We believe that, as fever and constitutional symptoms are common side effects of IFN-alpha treatment, a high index of suspicion is indicated to exclude abscess formation in cases of unexplained fever during IFN-alpha therapy.

Interleukin-6 and C-reactive protein as early markers of sepsis in patients with diabetic ketoacidosis or hyperosmosis.

AIMS/HYPOTHESIS: An early diagnosis of sepsis in patients with diabetic ketoacidosis and hyperosmolar non-ketotic coma is crucial and could save lives. We studied serum C-reactive protein and interleukin-6 to find out how useful these might be for identifying sepsis. METHODS: Sixty one diabetic patients with ketoacidosis or hyperosmolar non-ketotic coma were enrolled. Patients with signs and symptoms of systemic inflammatory response syndrome were identified. Acute-phase reactants, including C-reactive protein and interleukin-6, the main cytokine responsible for the induction of acute-phase proteins, were measured on admission and when patients had clinically improved and were euglycaemic. RESULTS: A total of 49 out of 61 patients with diabetic ketoacidosis or hyperosmosis had signs of systemic inflammatory response syndrome. Another 27 patients had systemic inflammatory response syndrome and no signs of infection and 22 patients had systemic inflammatory response syndrome due to proven infection. We detected a significant increase in serum C-reactive protein and interleukin-6 values in patients infected compared with patients not infected with systemic inflammatory response syndrome SIRS. Patients who finally died had much higher levels of these proteins, while there was a prompt reduction of serum C-reactive protein and interleukin-6 early during remission. CONCLUSION/INTERPRETATION: Diabetic ketoacidosis and hyperosmolar non-ketotic coma can often cause a clinical syndrome resembling systemic inflammatory response syndrome. Determination of serum C-reactive protein and interleukin-6 levels is a useful way of excluding an underlying infection early on as well as confirming and monitoring sepsis.

Polymorphonuclear leukocyte rigidity is defective in patients with chronic renal failure.

BACKGROUND: The purpose of the study was to investigate the rigidity of polymorphonuclear leukocytes (PMNs) in non-dialysed chronic renal failure (CRF) and haemodialysis (HD) patients. METHODS: PMN rigidity as well as tumour necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta) plasma levels were assessed in 10 early-stage CRF, 10 late-stage non-HD, and 10 HD patients, before and during dialysis. In HD patients both cellulose acetate and polysulphone membranes were used. Ten healthy subjects served as controls. Rigidity was tested by counting the deformability in morphologically passive PMNs by the micropipette method. Cytokine levels were measured by enzyme-linked immunosorbent assay. RESULTS: PMN rigidity was significantly increased in end-stage CRF patients regardless of HD but not in early-stage CRF. In HD patients PMN rigidity increased significantly 60 min after initiation of HD. There was an increase of TNF-alpha and IL-1beta levels in end-stage non-HD and HD patients and a further increase at 60 min after initiation of HD. The percentage of morphologically activated PMNs was increased only during dialysis. The nature of the HD membrane had no influence on rigidity, PMN activation, or cytokine production. CONCLUSIONS: The results indicate that PMN rigidity is defective in end-stage chronic CRF patients and is further increased 60 min after initiation of HD, regardless of the nature of the HD membrane used. PMN activation, increased TNF-alpha and IL-1beta levels, or a direct PMN impairment may cause the observed cell rigidity.

Monotherapy with intravenous followed by oral high-dose ciprofloxacin versus combination therapy with ceftazidime plus amikacin as initial empiric therapy for granulocytopenic patients with fever.

The aim of the present study was to obtain clinical experience with the use of high-dose ciprofloxacin as monotherapy for the treatment of febrile neutropenia episodes (granulocyte count, <500/mm(3)) compared to a standard regimen and to clarify whether ciprofloxacin administration may be switched to the oral route. In a prospective randomized study ciprofloxacin was given at 400 mg three times a day (t.i.d.) for at least 72 h followed by oral administration at 750 mg twice a day (b.i.d). That regimen was compared with ceftazidime given intravenously at 2 g t.i.d. plus amikacin given intravenously at 500 mg b.i.d. The frequency of successful clinical response without modification at the end of therapy was almost identical for ciprofloxacin (50% [62 of 124 patients]) compared with that for ceftazidime plus amikacin (50.8% [62 of 122 patients]) in an intent-to-treat analysis; the frequencies were 48.3% (57 of 118 patients) versus 49.6% (56 of 113 patients), respectively, in a per-protocol analysis (P values for one-sided equivalence, 0.0485 and 0.0516, respectively; delta = 10%), with no significant differences among patients with bacteremia and other microbiologically or clinically documented infections and fever of unknown origin. For 82 (66.1%) patients, it was possible to switch from parenteral ciprofloxacin to the oral ciprofloxacin, and the response was successful for 61 (74.4%) patients. The efficacies of the regimens against streptococcal bacteremias were 16.6% (one of six patients) for the ciprofloxacin group and 33.3% (one of three patients) for the combination group (it was not statistically significant), with one breakthrough streptococcal bacteremia observed among the ciprofloxacin-treated patients. Adverse events were mostly self-limited and were observed in 27 (20.6%) ciprofloxacin-treated patients and 26 (19.7%) patients who were receiving the combination. This study demonstrates that high-dose ciprofloxacin given intravenously for at least 3 days and then by the oral route is therapeutically equivalent to the routine regimen of intraveneous ceftazidime plus amikacin even in febrile patients with severe neutropenia (polymorphonuclear leukocyte count, <100 mm(3)). However, it is very important that before an empirical therapy is chosen each hospital determine bacteriologic predominance and perform resistance surveillance.

Effect of cytokines and colony-stimulating factors on passive polymorphonuclear leukocyte deformability in vitro.

Cytokines are potent polymorphonuclear leukocyte (PMN) activators and can decrease their deformability. We evaluated passive PMN deformability using the micropipette method after incubation with different concentrations of lipopolysaccharide (LPS), interleukins (IL-) 1, 6, 8 and 10, tumour necrosis factor (TNF), granulocyte (G) and granulocyte-macrophage (GM) colony-stimulating factors (CSF). TNF, IL-1, G-CSF, GM-CSF and, to a lesser degree, IL-6 significantly and in a dose-dependent fashion decrease PMN deformability. LPS had no direct effect on PMN deformability. When cytokines at concentrations with no effect on deformability were combined they increased PMN rigidity. The findings suggest that several cytokines and CSF impair directly, and not by activation alone, PMN deformability.

Neutrophil deformability in patients with sepsis, septic shock, and adult respiratory distress syndrome.

OBJECTIVE: To investigate the deformability of morphologically active and passive neutrophils in patients with sepsis (SP), septic shock (SS), and adult respiratory distress syndrome (ARDS). DESIGN: Prospective, observational study. SETTING: A university hospital intensive care unit and research laboratory. PATIENTS: Six patients with sepsis, six patients with septic shock, and six patients with ARDS. Eight healthy volunteers and eight ventilated but noninfected patients served as controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Morphologically passive and active neutrophil deformability as defined by the micropipette method was significantly decreased in patients with SP, SS, and ARDS associated with sepsis as compared with both control groups. Neutrophils from SS and ARDS patients were significantly more rigid as compared with neutrophils from SP patients but they did not differ from each other. The percentage of activated neutrophils was significantly higher in SP, SS, and ARDS patients. Increased passive neutrophil rigidity was significantly attenuated after coincubation with cytochalasin D. Tumor necrosis factor-alpha and interleukin-1beta serum levels were significantly higher in SP, SS, and ARDS patients. CONCLUSIONS: The entire neutrophil population is less deformable in SP, SS, and ARDS patients. The decreased deformability of passive neutrophils suggests that a direct mechanism involving actin polymerization, distinct from cell activation, is involved. These observations may be important in the mechanism of impaired vascular flow in patients with sepsis.

Management of brain abscesses with sequential intravenous/oral antibiotic therapy.

Eight patients with brain abscesses who refused prolonged hospitalisation were treated with a short course (6-12 days) of intravenous antibiotics followed by prolonged treatment (15-19 weeks) with an oral antibiotic regimen consisting of metronidazole, ciprofloxacin and amoxicillin. All patients responded favourably as shown clinically and in imaging studies. No severe adverse events or sequelae were noted. On admission all patients had a normal or mildly impaired mental status, abscesses less than 3 cm in diameter and no serious predisposing factors. Although combined surgical/medical treatment remains the standard approach in management of these patients, the findings suggest that oral antibiotic therapy only subsequent to a short course of intravenous antibiotics may be an acceptable alternative in selected cases.

Pro- versus anti-inflammatory cytokine profile in patients with severe sepsis: a marker for prognosis and future therapeutic options.

Serum concentrations of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6, and the anti-inflammatory cytokine Il-10, and IL-1 receptor antagonists (IL-1ra) and soluble TNF receptors (sTNFRs) were measured in 65 patients with severe sepsis. All patients were evaluated clinically and microbiologically and were followed up for clinical outcome. Levels of both pro- and anti-inflammatory cytokines were significantly elevated in patients with sepsis. Elevated serum IL-10 and TNF-alpha levels and a high IL-10 to TNF-alpha ratio were associated with death, whereas higher levels of TNF-alpha, IL-6, IL-1ra, and sTNFR were detected in patients with an early hemodynamic deterioration. Interleukin-10 and IL-10:TNF-alpha ratio remained higher in nonsurvivors, whereas IL-10 paralleled the sepsis score. Although both the inflammatory and anti-inflammatory response is profoundly augmented in patients with severe sepsis, the sustained overproduction of the anti-inflammatory cytokine IL-10 is the main predictor of severity and fatal outcome.

Five day moxifloxacin therapy compared with 7 day clarithromycin therapy for the treatment of acute exacerbations of chronic bronchitis.

In this multinational, randomized, double-blind study, the efficacy and safety of a 5 day course of moxifloxacin 400 mg orally od was compared with that of a 7 day course of clarithromycin 500 mg orally bd. in 750 patients with acute exacerbations of chronic bronchitis, characterized by at least two of the symptoms: sputum purulence, increased sputum volume or increased dyspnoea. Seven days after the end of therapy, clinical cure was achieved for 89% (287 of 322) of efficacy-evaluable patients in the moxifloxacin group and 88% (289 of 327) of patients in the clarithromycin group (95% CI, -3.9%, 5.8%). At follow-up (21-28 days post-treatment), the continued clinical cure rates were 89% (256 of 287) for moxifloxacin and 89% (257 of 289) for clarithromycin. A total of 342 pathogenic bacteria were isolated from the sputum of 287 patients. The most common pathogens were Haemophilus influenzae (37%), Streptococcus pneumoniae (31%) and Moraxella catarrhalis (18%). Seven days post-treatment, a successful bacteriological response was obtained for 77% (89 of 115) of patients in the moxifloxacin group and 62% (71 of 114) of patients in the clarithromycin group, indicating superiority of moxifloxacin (95% CI, 3.6%, 26.9%). Both treatments were well tolerated with few adverse events. This study demonstrated that for the treatment of acute exacerbations of chronic bronchitis a 5 day course of moxifloxacin 400 mg od was clinically equivalent and bacteriologically superior to a 7 day course of clarithromycin 500 mg bd.

Cost-minimisation analysis of sequential treatment with ofloxacin or ciprofloxacin in hospitalised patients.

This study evaluated the cost of sequential treatment with once-daily ofloxacin or twice-daily ciprofloxacin in 474 hospitalised patients in different countries. The patients were treated intravenously for at least 3 days, then orally for 7 to 10 days or for 3 days beyond the disappearance of infection-related symptoms. The overall clinical cure rate (86.8% with ofloxacin and 89.6% with ciprofloxacin) and the overall bacteriological response rate (89.9 and 89.0%, respectively) were similar, and a cost-minimisation analysis was conducted. The acquisition costs for ofloxacin and ciprofloxacin in Greece, Israel, Slovenia and Turkey were used and converted to Deutschmarks (DM), and the costs of administration were analysed for each hospital. The different cost categories for oral and intravenous (IV) treatment (e.g. antimicrobial acquisition, drug monitoring, drug delivery costs) were used to identify any differences. The total costs per patient varied between the countries involved, but were higher for ciprofloxacin (ofloxacin: DM239 to DM724; ciprofloxacin: DM540 to DM976). In a sensitivity analysis using identical daily acquisition costs for the 2 fluoroquinolones, the total cost of treatment was higher for ciprofloxacin, as a result of the lower cost of administration of ofloxacin in the once-daily regimen. Continuing IV therapy would be approximately 50% more expensive than switching to oral administration; however, whenever possible, both drugs can be switched from IV to oral treatment.

Absorption of ciprofloxacin in patients with diabetic gastroparesis.

The purpose of this study was to assess the pharmacokinetic profile of ciprofloxacin in 12 patients with diabetic gastroparesis. Patients received both a single 500-mg oral (p.o.) dose and a single 400-mg intravenous (i.v.) dose of ciprofloxacin separated by a 1-week washout period. Pharmacokinetic parameters (means +/- standard deviations) for the p.o. and i.v. doses were as follows: areas under the concentration-time curve from 0 h to infinity, 9.74 +/- 2.59 and 11.78 +/- 3.18 micrograms.h/ml, respectively; maximum concentrations of drug in serum, 2.13 +/- 0.67 and 4.21 +/- 1.07 micrograms/ml, respectively; and half-lives, 4.03 +/- 0.58 and 4.20 +/- 0.58 h, respectively. The ratio of the areas under the concentration-time curves from 0 h to infinity for the p.o. and i.v. doses was 0.84, with a 90% confidence interval of 0.68 to 0.98; the mean absolute bioavailability was calculated to be 67% (range, 43 to 82%). From these data it appears that ciprofloxacin is adequately absorbed in patients with diabetic gastroparesis.

Adherence of Candida albicans to epithelial cells from normal and cancerous urinary bladders.

Patients with malignancies are at high risk to develop infections by Candida albicans. We have compared the adherence of C. albicans isolated from urine cultures to bladder epithelial cells obtained from healthy volunteers and patients with cancer of the bladder. The mean number of C. albicans adhering per epithelial cell from areas infiltrated from cancer was significantly higher as compared to cells obtained from intact areas of cancerous bladders and from normal bladders. The increased adherence of C. albicans to cancerous epithelial cells suggests that malignancies are associated with alterations of the epithelial cell surface which render the cells more susceptible to colonization by C. albicans. The increased colonization may predispose these patients to C. albicans infections.

In vivo potentiation of polymorphonuclear leukocyte chemotaxis by clindamycin.

Polymorphonuclear leukocyte (PMNL) chemotaxis was evaluated in ten healthy volunteers who had received 600 mg of clindamycin intramuscularly. Serum obtained 3 hours after the administration of clindamycin significantly increased PMNL chemotaxis. Serum obtained at 12 and 24 hours after the administration of the drug did not induce significant increase in PMNL chemotaxis. The administration of clindamycin had no direct effect on the PMNLs in terms of their chemotactic activity. These results demonstrate serum-associated augmentation of PMNL chemotaxis by clindamycin in vivo which may be of potential clinical benefit in the outcome of infections.

In vivo potentiation of polymorphonuclear leukocyte function by ciprofloxacin.

Ciprofloxacin was administered to 10 healthy volunteers at a dose of 250 mg orally. Serum and polymorphonuclear leukocytes (PMNLs) were obtained from all subjects before the administration of the drug and 12 hours after the administration. In addition serum was obtained from all subjects at 24 and 48 hours after ciprofloxacin administration. All sera and PMNLs were used for the chemotactic, phagocytic and killing determinations of the PMNLs. The results demonstrated that serum obtained 12 hours after the administration of ciprofloxacin potentiates PMNL chemotactic activity (chemotactic index (CI) = 33.0 +/- 4.2 microns (means +/- S.D.)) as compared to the chemotactic activity generated by serum obtained prior to administration of the drug, CI = 20.4 +/- 4.4 microns (p < 0.01). Serum obtained 24 and 48 hours after ciprofloxacin administration did not stimulate PMNL function. The administration of ciprofloxacin did not have any direct influence on the PMNLs in terms of their chemotactic response. Furthermore, serum obtained after the administration of ciprofloxacin markedly enhanced PMNL phagocytosis and killing of all organisms tested. Ciprofloxacin also acted directly on the PMNLs and increased their bactericidal activity. These results demonstrate that ciprofloxacin potentiates PMNL function in vivo which may be of potential clinical benefit.

Three cases of varicella thrombophlebitis as a complication of varicella zoster virus infection.

Three cases of deep venous thrombosis following varicella infection are described which were successfully treated with bed rest and anticoagulants. Two of these patients had severe pulmonary manifestations of varicella and the third was complicated by pulmonary embolism. Deep vein thrombosis is an uncommon systemic manifestation of varicella, possibly associated with vascular endothelium wall damage caused by varicella zoster virus infection.

Primary sternal osteomyelitis.

Primary sternal osteomyelitis is a rare condition. Only few cases have been reported in the English literature. We describe the case of a young woman presenting with persistent fever and chest pain. Radionuclide bone scan and computed tomography of the chest were consistent with metastatic neoplasm. Surgical intervention, however, revealed primary staphylococcal osteomyelitis and the patient was successfully treated with combined extensive surgical debridement and intravenous antibiotics.

Varicella pneumonia in adults. A review of pulmonary manifestations, risk factors and treatment.

Pneumonia is a rare but serious and occasionally fatal complication of varicella. Two cases of varicella pneumonia were successfully treated with acyclovir in our department. We reviewed the pulmonary manifestations of varicella, the risk factors and the effect of acyclovir on varicella pneumonia on immunocompetent adults. Early, aggressive therapy with acyclovir seems to abort the catastrophic consequences of varicella pneumonia, while oral acyclovir chemoprophylaxis is probably beneficial in high-risk populations with chickenpox.

A comparative study on aztreonam, ceftazidime and amikacin in the treatment of complicated urinary tract infections.

In a prospective, randomized trial, aztreonam (1 g intravenously or intramuscularly, twice daily) was compared with ceftazidime (1 g intravenously or intramuscularly, twice daily) and amikacin (500 mg intravenously or intramuscularly, twice daily) in 76 patients aged 24 to 84 years (mean, 59.7 years) with complicated urinary tract infections. Initial pathogens included Escherichia coli (47.5%), Pseudomonas aeruginosa (22.5%), Klebsiella spp. (9%), Proteus spp. (7.5%) and Enterobacter spp (6%). In four patients initial urine cultures yielded more than one organism. All pathogens were sensitive to the three study drugs. Including performance of 4- to 6-week follow-up cultures, eradication of the pathogens occurred in 72% of patients treated with aztreonam, in 74% of those treated with ceftazidime and in 71% treated with amikacin (p greater than 0.05). Clinical success was observed in 84% of patients treated with aztreonam, in 82% of those treated with ceftazidime and in 85% treated with amikacin (p greater than 0.05). All drugs were well tolerated. It is concluded that aztreonam, ceftazidime and amikacin are equally effective and safe for the treatment of complicated urinary tract infections due to susceptible organisms.

Penetration of ciprofloxacin into human cerebrospinal fluid in patients with inflamed and non-inflamed meninges.

The penetration of ciprofloxacin into the cerebrospinal fluid (CSF) in 25 patients with non-inflamed meninges and in 9 patients with inflamed meninges was studied. In the patients with non-inflamed meninges plasma and CSF were obtained 1-10 h after the second dose of ciprofloxacin and in the patients with inflamed meninges 1, 2, 3, 5, 7 and 9 h after the second dose. In the first group (non-inflamed meninges) data from 6 patients were obtained 4, 5 and 6 h post-dose. Mean ciprofloxacin concentrations in the CSF ranged from 0.073 mg/l to 0.106 mg/l during this observation time, while in the second group (inflamed meninges) they ranged from 0.089 to 0.260 mg/l. These results demonstrate that ciprofloxacin diffuses into the CSF at concentrations which exceed the MICs of Neisseria meningitidis and most gram-negative aerobic bacilli.