Caspofungin PK in critically ill patients after the first and fourth doses: suggestions for therapeutic drug monitoring?

We describe caspofungin pharmacokinetics (PK) after the first and fourth doses in 20 critically ill septic patients. Monte Carlo simulation was used to analyze the probability of target attainment (PTA) (AUC/MIC > 865) for Candida spp. Caspofungin concentrations were analyzed by HPLC in plasma and urine. A great variability in PK parameters was observed after both doses. Patients were divided in two groups according to their AUC values (AUC ≤ 75 mg h/L cut-off). In the low-AUC group Cmax, Cmin and AUC were lower, while Vd and Cl were higher than in the high-AUC group (p < 0.05, both at day 1 and 4). The mean 24-h urinary recovery of the drug was 8 ± 6.3% (day1) and 9.8 ± 6.3 (day4). Monte Carlo simulation analysis (0.03-1 mg/L MIC-range) showed that PTA was guaranteed only for MICs ≤ 0.03 mg/L in the low-AUC group, and for MICs ≤ 0.06 mg/L in the high-AUC group. No group had a PTA ≥ 90% for 0.125 mg/L MIC (the epidemiological cut-off). Mortality was higher in low-AUC group (p < 0.01). In our 'real-world' population, no clinical data can predict which patient will have lower, suboptimal caspofungin exposure, therefore we suggest TDM to optimize caspofungin therapy and reduce the risk of selecting resistances (CEAVC, 32366/2015; OSS.15.114, NCT03798600).

Efficacy of caspofungin as secondary prophylaxis in patients undergoing allogeneic stem cell transplantation with prior pulmonary and/or systemic fungal infection.

Transplanted patients with a history of invasive fungal infection (IFI) are at high risk of developing relapse and fatal complications. Eighteen patients affected by hematological malignancies and a previous IFI were submitted to allogeneic stem cell transplantation, using Caspofungin as a secondary prophylaxis. Patients had a probable or proven fungal infection and 16 had a pulmonary localization. No side effects were recorded during treatment with Caspofungin. Compared to pre-transplant evaluation, stability or improvement of the previous IFI was observed in 16 of the 18 patients at day 30, in 13 of the 15 evaluable patients at day 180 and in 11 of the 11 evaluable patients at day 360 post transplant. In particular, all the six patients with a proven fungal infection were alive, with a stable or improved IFI after 1 year from transplant. At a maximum follow-up of 31 months, eight patients died for disease progression or transplant-related complications, but only two had evidence of fungal progression. Secondary prophylaxis with Caspofungin may represent a suitable approach to limit IFI relapse or progression, allowing patients with hematological malignancies to adhere to the planned therapeutic program.

Clinical efficacy and tolerability of caspofungin in a renal transplant patient with Aspergillus flavus lung infection: case report.

Organ transplant recipients are at increased risk for severe invasive aspergillosis, and amphotericin deoxycholate has been the standard treatment for many years. Currently, however, lipid formulations are preferred due to their few side effects. Also, a number of new antifungal drugs have been developed including new azoles and echinocandins. Caspofungin is the first of the echinocandin derivatives patented to treat patients with invasive aspergillosis who are refractory or intolerant to other therapies. A renal transplant patient on immunosuppressive treatment with chronic hepatitis B virus infection was admitted with fever, hemophthisis and lung consolidation, diagnosed to be probably caused by Aspergillus flavus. The patient developed cholestatic hepatitis most likely related to itraconazole. Clinical failure and in vitro itraconazole resistance of the isolate was also documented while the patient was receiving itraconazole at a reduced dosage. Caspofungin was administered once a day as ambulatory treatment and was well tolerated. Clinical improvement was observed after 6 weeks of treatment and no hepatic toxicity was documented. Caspofungin seems to be a potentially useful antifungal agent in renal transplant patients with invasive aspergillosis. Further evaluation of the efficacy of caspofungin is needed.

Intraoperative positive fluid balance improves tissue diffusion of ceftizoxime.

AIM OF STUDY: To demonstrate that administration of fluids and the consequent improvement of fluid balance during a surgical procedure can modify the tissue diffusion of ceftizoxime. METHODS: Twenty-eight patients (30-79 years) undergoing major abdominal surgery of the colon were administered ceftizoxime 30 mg/kg i.v. at induction of anesthesia. A sample of arterial blood was taken before administration of the drug (t0) and then again at the time of vascular occlusion of the colon segment to be removed (t1). A sample of the segment of removed colon was taken. The patients were divided into two groups on the basis of the fluid balance between t0 and t1: group A (n = 17) with a fluid balance <1,000 ml and group B (n = 11) with a fluid balance >1,000 ml. The parameters evaluated in each group were: weight, height and age of the patients, serum and tissue antibiotic concentration, percent ratio of serum and tissue concentration, time elapsed between t0 and t1, volume of administered fluids between t0 and t1, diuresis and hourly diuresis between t0 and t1 and body fluid distribution, obtained using a bioelectrical impedance analyzer. The mean results obtained in the two groups were then compared using Student's t test. RESULTS: The balance of fluids calculated up to t1 was 675 +/- 308 ml for group A and 1,411 +/- 405 ml for group B (p < 0.01). The means of the recorded values that showed statistically significant differences were: mean percent concentration ratio (43.6 +/- 8.4 vs. 84 +/- 16%; p < 0.05), concentration in the colonic segment (16.3 +/- 7.9 vs. 37.2 +/- 25.9 mg/ml; p < 0.05), urinary volume gathered up to t1 (538 +/- 557 vs. 169 +/- 104 ml; p < 0.05), hourly urinary volume up to t1 (311.1 +/- 296 vs. 97.6 +/- 77.9 ml/h; p < 0.05), percent variation of resistance (95.1 +/- 5.1 vs. 89.7 +/- 8.6; p < 0.05). The other means did not show any significant statistical differences. CONCLUSIONS: A higher tissue water level seems to facilitate the penetration of the antibiotic into the tissue according to the pharmacokinetic characteristics of ceftizoxime: high amount of free drug (not bound to plasma proteins) and high hydrosolubility.

In vivo pharmacodynamic evaluation of clarithromycin in comparison to erythromycin.

The efficacy of various dosing regimens of clarithromycin and erythromycin against recently isolated Streptococcus pneumoniae strains was determined in vivo using two animal infection models (mouse peritonitis and thigh infection). For the thigh infection model, mice received a total dose of 4 mg/Kg of either clarithromycin or erythromycin, as a single total dose or divided into 2, 4 or 8 doses/24h. After 24h of therapy S. pneumoniae organisms were killed at 2.06 to 4.03 log10 CFU/thigh by clarithromycin and the one- or two-dose regimens were significantly more effective than the four- or eight-dose regimens. Organism killing following 24h of therapy with erythromycin ranged from 1.13 to 2.31 log10 CFU/thigh, with the one- or two-dose regimens significantly less effective than the four- or eight-dose regimens. In the mouse survival study, the same dose of either clarithromycin or erythromycin was given as a single total dose or divided into two or four doses with dosing intervals of 4 and 2-times the t1/2 respectively. The results obtained in this model show that there is a significant difference in survival when clarithromycin is administered less frequently (4% deaths for the one-dose regimen in comparison to 40% deaths with the four-dose regimen, P < 0.01, Chi-square test). With erythromycin there was a trend for increased survival with the multiple-dose regimen, with significantly higher survival when concentrations exceeding the MIC were maintained for a longer time period. These results indicate that the time during which serum concentrations exceeding the MIC value of the pathogen is an important parameter for efficacy for erythromycin. On the contrary, results with both animal models demonstrate that bacterial killing and survival are significantly higher among clarithromycin-treated mice when the antibiotic is administered less frequently and the highest Cmax/MIC ratio is achieved.

Amoxicillin/clavulanate in chronic rhinosinusitis: tissue and serum distribution.

UNLABELLED: Amoxicillin/clavulanate in chronic rhinosinusitis: tissue and serum distribution. OBJECTIVE: The aim of the present study is to determine the concentrations of coamoxiclav in the sinusal mucosa of patients undergoing surgery for chronic sinusitis in comparison to serum levels after single oral administration. METHODOLOGY: 24 patients affected by chronic sinusitis, undergoing sinus surgery, were divided into three groups receiving an oral dose of 1 g of coamoxiclav (875 mg amoxicillin, 125 g of clavulanic acid, 7:1 ratio) at 2 h (first group), 4 h (second group) and 6 h (third group) before surgery. The mean concentration of amoxicillin and clavulanic acid were determined biologically in serum and in tissues. RESULTS: The highest concentrations of coamoxiclav both in serum and tissues were observed in the group which received the antibiotic 2 hours before surgery. However the tissue levels of both amoxicillin and clavulanic acid in the time period within 2-6 h after administration were higher than the Minimum Inhibitory Concentration (MIC) for the most frequent causative pathogens of sinus bacterial infections. CONCLUSIONS: Since penicillins need to maintain concentrations above the MIC for at least 40 to 60% of the interval time between administrations to be potentially effective, the Authors concluded that since both amoxicillin and clavulanic acid spread well in the ENT tissues, 1 g twice a day of the combination seems to be clinically effective even in patients suffering from acute episodes of chronic rhinosinusitis.

Postantibiotic leukocyte enhancement of meropenem against gram-positive and gram-negative strains.

The postantibiotic leukocyte enhancement (PALE) of meropenem in vitro in comparison with that of imipenem was evaluated with 24 recently isolated gram-positive and gram-negative strains. In general, pre-exposure to carbapenems (at four times the MIC for 2 h) led to increased polymorphonuclear cell phagocytic killing. The PALE of imipenem was generally significantly less than that observed with meropenem.

Cefodizime in skin suction blister fluid and serum following a single intravenous or intramuscular dose in adult patients.

Cefodizime is a third generation cephalosporin for parenteral use. The pharmacokinetics of this cephem antibiotic were determined in serum and skin suction blister fluid (SBF) after intravenous (i.v.) or intramuscular (i.m.) administration of a single 1 g dose in 8 adult patients with normal renal and hepatic function who volunteered for the study. The concentration versus time curve showed a slower elimination rate from the extravascular compartment: the half-lives were 4.4+/-0.5 and 5.4+/-0.4 hours after i.v. and i.m. route respectively. The relatively long elimination half-life in SBF with a mean residence time of about 8 hours allows the use of cefodizime once-a-day for the treatment of infections due to sensitive pathogens.

Interactions between triazoles and amphotericin B against Cryptococcus neoformans.

The interaction of amphotericin B (AmB) and azole antifungal agents in the treatment of fungal infections is still a controversial issue. A checkerboard titration broth microdilution-based method that adhered to the recommendations of the National Committee for Clinical Laboratory Standards was applied to study the in vitro interactions of AmB with fluconazole (FLC), itraconazole (ITC), and the new investigational triazole SCH 56592 (SCH) against 15 clinical isolates of Cryptococcus neoformans. Synergy, defined as a fractional inhibitory concentration (FIC) index of < or =0.50, was observed for 7% of the isolates in studies of the interactions of both FLC-AmB and ITC-AmB and for 33% of the isolates in studies of the SCH-AmB interactions; additivism (FICs, >0.50 to 1.0) was observed for 67, 73, and 53% of the isolates in studies of the FLC-AmB, ITC-AmB, and SCH-AmB interactions, respectively; indifference (FICs, >1.0 to < or =2.0) was observed for 26, 20, and 14% of the isolates in studies of the FLC-AmB, ITC-AmB, and SCH-AmB interactions, respectively. Antagonism (FIC >2.0) was not observed. When synergy was not achieved, there was still a decrease, although not as dramatic, in the MIC of one or both drugs when they were used in combination. To investigate the effects of FLC-AmB combination therapy in vivo, we established an experimental model of systemic cryptococcosis in BALB/c mice by intravenous injection of cells of C. neoformans 2337, a clinical isolate belonging to serotype D against which the combination of FLC and AmB yielded an additive interaction in vitro. Both survival and tissue burden studies showed that combination therapy was more effective than FLC alone and that combination therapy was at least as effective as AmB given as a single drug. On the other hand, when cells of C. neoformans 2337 were grown in FLC-containing medium, a pronounced increase in resistance to subsequent exposures to AmB was observed. In particular, killing experiments conducted with nonreplicating cells showed that preexposure to FLC abolished the fungicidal activity of the polyene. However, this apparent antagonism was not observed in vivo. Rather, when the two drugs were used sequentially for the treatment of systemic murine cryptococcosis, a reciprocal potentiation was often observed. Our study shows that (i) the combination of triazoles and AmB is significantly more active than either drug alone against C. neoformans in vitro and (ii) the concomitant or sequential use of FLC and AmB for the treatment of systemic murine cryptococcosis results in a positive interaction.

Pharmacokinetics of dirithromycin in patients with mild or moderate cirrhosis.

The pharmacokinetics of dirithromycin were determined over a 72-h period following oral administration of a single 500-mg dose to 8 healthy volunteers and to 16 cirrhotic patients (8 patients with class A cirrhosis and 8 patients with class B cirrhosis according to Pugh's & Child's classification). Drug levels in plasma and urine were determined by microbiological assay. The mean maximum concentrations of drug in serum obtained 3 to 4 h after administration were 0.29 +/- 0.22 mg/liter in volunteers and 0.48 +/- 0.21 and 0.52 +/- 0.38 mg/liter in patients with class A and class B cirrhosis, respectively. The elimination half-life (t1/2beta) was 23.3 +/- 7.6 h in healthy subjects and 35.2 +/- 11.8 h and 39.5 +/- 11.0 h in patients with class A and class B cirrhosis, respectively. The mean area under the concentration-time curve (AUC) and t1/2beta were significantly higher in patients with class A and B cirrhosis than in healthy controls, while total and renal clearances were markedly reduced (P < 0.01). The time to the maximum concentration of drug in serum and the volume of distribution values appeared to be similar in all groups, and the mean recovery in urine at 72 h ranged from 3.7 to 5.7%, without significant differences among groups. These results demonstrate that some dirithromycin kinetic parameters are significantly different in cirrhotic patients in comparison to those in healthy volunteers. However, an increase in the t1/2beta or AUC, which is also observed with other semisynthetic macrolides (e.g., azithromycin), does seem to be not clinically relevant if one takes into account both the high therapeutic indices of these antibiotics and the usually short duration of therapy. Therefore, on the limited basis of single-dose administration, no modifications of dirithromycin dosage seem to be required even for patients with class B liver cirrhosis.

Clinical pharmacokinetics of meropenem after the first and tenth intramuscular administration.

We investigated the pharmacokinetics of meropenem after the first and tenth i.m. administration in patients with respiratory tract infections. Ten patients (mean age 63.8 +/- 5.2 years) received meropenem 500 mg tds for at least ten doses, and plasma and urine antibiotic concentrations were determined by microbiological assay. After the first injection a mean peak plasma concentration of 7.93 +/- 1.29 mg/L was observed at 1 h. Trough levels at 8 h (0.29 +/- 0.16 mg/L) were detectable in five of ten treated patients. The mean terminal half-life was 1.08 +/- 0.2 h with an area under the curve (AUC) value of 23.8 +/- 4.59 mg/L.h, and a cumulative urinary recovery at 8 h of 48.43 +/- 3.12%. There was no evidence of change in the pharmacokinetics of meropenem after repeated i.m. administration, though the mean peak plasma concentration and AUC value were slightly increased. The accumulation ratio (assessed using AUC values) was 1.18 +/- 0.19 after multiple doses and was considered to be of little kinetic and clinical importance. Moreover, many of the trough concentrations of meropenem were below the limit of detection of the assay. After i.m. administration meropenem concentrations exceeded 0.5 mg/L for longer than previously described following i.v. infusion. No adverse events were reported.

In vitro postantibiotic effect and postantibiotic leukocyte enhancement of tobramycin.

The occurrence of a postantibiotic effect (PAE) and postantibiotic leukocyte enhancement (PALE) of tobramycin, a natural aminoglycoside clinically used since the early 1970s, has been investigated in comparison to gentamicin on recent clinical isolates of Staphylococcus aureus (both methicillin-susceptible and -resistant strains) and of Gram-negative fermenting and non-fermenting rods. A concentration-dependent PAE was observed with both antibiotics, regardless of the bacterial species used, with some variability based on their intrinsic resistance. Tobramycin, at concentrations equal to or higher than the minimum inhibitory concentration (MIC), exhibited a rather long PAE (ranging from 1.9 to 10.9 h) which was often significantly longer than that observed with gentamicin (ranging from 1.0 to 7.5h). Moreover, pre-exposure to tobramycin led to enhanced polymorphonuclear leukocyte phagocytosis and killing with a 2- to 27-fold increase in activity compared to controls. These results suggest that tobramycin might be conveniently used with once-daily dosing for the treatment of infections due to sensitive pathogens.

Betalactam therapy and intestinal flora.

Betalactams, mainly when orally administered, may lead to intestinal flora modifications related to their spectrum of activity, rate of absorption and degradation. therefore it is important to investigate the possible influence of recently developed oral cephem derivatives on normal human microflora. We have investigated the impact on normal human intestinal flora in a 10-day course with cefetamet-pivoxil (CET, 500 mg BID) in comparison to cefixime (CFX, 400 mg qD) or cefuroxime axetil (CA, 250 mg BID) in 24 patients suffering from acute exacerbation of chronic bronchitis. Stool specimens were taken before (day 0), at the end (day 10) and 14 days after treatment (day 24) and quali-quantitative microflora composition was determined with a detection limit of 10 CFU/g dry weight. Treatment with CET caused slight and non-significant modifications of normal intestinal flora. On the contrary CFX and CA significantly affect Enterobacteriaceae and clostridia with a concomitant increase in enterococci for CFX. With both CFX and CA there was a new appearance of Salmonella spp. as well as Clostridium difficile in 4 and 2 cases, respectively. Therefore CET seems to affect normal bowel flora minimally in comparison to other oral cephalosporins. This aspect might contribute to the low incidence of GI related side effects in patients treated with CEt for longer than 1 week.

Regional and systemic prophylaxis with teicoplanin in monolateral and bilateral total knee replacement procedures: study of pharmacokinetics and tissue penetration.

Twenty-four patients undergoing monolateral or bilateral total knee replacement (TKR) procedures were randomized to receive teicoplanin (T) either systemically or regionally. Subjects scheduled for systemic prophylaxis and undergoing monolateral (six patients) or bilateral (five patients) TKR received a single 800-mg dose of T in 100 ml of saline as a 5-min infusion into a forearm vein 2.5 h before surgery. For regional prophylaxis, patients undergoing monolateral surgery (eight subjects) received 400 mg of T in 100 ml of saline as a 5-min infusion into a foot vein of the leg to be operated on immediately after the tourniquet was inflated. For the five patients scheduled for bilateral operation and regional prophylaxis, the administration of T was also repeated for the second knee operation. The tourniquet, as the standard TKR surgical technique, was inflated to 400 mm Hg (c. 50 kPa) in all 24 patients immediately before the beginning of surgery and kept in place for the duration of the operation. Samples of serum, bone, skin, synovia, and subcutaneous tissue were collected at timed intervals during surgery. They were microbiologically assayed for T by using Bacillus subtilis as the test organism. Overall, the mean T concentrations obtained with regional route prophylaxis were found to be 2 to 10 times higher than those achieved following systemic prophylaxis. Moreover, peak levels in different tissues after regional prophylaxis were significantly higher (P < 0.05). None of the patients experienced adverse effects due to regional or systemic T administration; no prosthetic or wound infections were observed in the follow-up period (from 12 to 26 months).

Pharmacokinetics and blister fluid penetration of brodimoprim in adults.

We investigated the pharmacokinetic properties of brodimoprim (B), a new diaminopyrimidine, including its penetration into suction blister fluid (SBF) after a single or multiple oral dose in 15 patients with a mean age of 61.5 +/- 9.3 yrs, suffering from respiratory tract infections with normal renal and hepatic function. Patients were divided into 3 groups of 5 cases each, according to treatment plan: Group I = B 400 mg single dose day 1; Group II = B 400 mg qD day 1 and 200 mg qD days 2 to 4; Group III = B 200 mg BID day 1 and 200 mg qD days 2 to 4. Concentrations were determined microbiologically using B. subtilis ATCC 6633 as the test organism with a lower limit of sensitivity of 0.37 mg/l. With a single oral dose of 400 mg (Group I) a computed serum Cmax of 2.9 +/- 0.6 mg/l was observed 5.6h after administration, with a elimination half-life (t1/2 beta) of 32.3 +/- 4.1 h. In SBF a mean peak of 1.9 +/- 0.6 mg/l was reached after 6h with a t1/2 beta of 34.7 +/- 5.4 h and a penetration index (Pl), obtained by the AUCSBF/AUCs percent ratio of 61%. With multiple doses serum peak concentrations increased significantly, while the time to reach the peak (Tmax) was shorter (3.7-4.2 h) than after a single dose. Main kinetic parameters, such as t1/2 beta, mean residence time (MRT), elimination rate constant (Kel) and AUC, were significantly higher in Group II and III patients than in Group I cases. Similar differences were observed among the main SBF kinetic parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro effects of brodimoprim on human polymorphonuclear leukocyte functions. Preliminary results.

The in vitro effects of brodimoprim and trimethoprim on the functions of human polymorphonuclear (PMN) leukocytes have been studied comparatively evaluating chemotaxis, phagocytosis and production of superoxide anion. No significant effects of both diaminopyrimidines on chemotaxis and phagocytic activity of PMNs have been observed while both brodimoprim and trimethoprim enhanced the oxidative burst. A synergistic activity between the host immune system and the direct antimicrobial action of brodimoprim may occur while using this diaminopyrimidine in vivo.

Pharmacokinetics of azithromycin in patients with impaired hepatic function.

The pharmacokinetics of azithromycin were determined over a 192-h period following oral administration of a single 500-mg dose to six healthy volunteers and to 16 cirrhotic patients (ten class A and six class B; Pugh's classification). Plasma and urinary levels were determined by microbiological assay. The mean Cmax, obtained 2-3 h after administration, was 0.29 mg/L in volunteers, and 0.39 and 0.51 mg/L in class A and class B cirrhosis, respectively. The elimination half-life was 53.5 h in control subjects, and 60.6 and 68.1 h in class A and class B cirrhotic patients, respectively. The mean residence time was significantly higher in class B patients, but AUC, Vd, Cltot and Clr values appeared to be similar in all groups. The mean urinary recovery of azithromycin at 192 h varied from 11-15.7%, and did not differ significantly among groups. These results demonstrate that azithromycin pharmacokinetics do not differ consistently in patients with mild or moderate hepatic impairment in comparison with healthy volunteers. Therefore, no dosage modifications of azithromycin seem to be required for patients with class A or B liver cirrhosis.