Increased risk of breakthrough infection among cytomegalovirus donor-positive/recipient-negative kidney transplant recipients receiving lower-dose valganciclovir prophylaxis.

OBJECTIVE: We compared the effectiveness of lower-dose (LD) (450 mg/day for 6 months) to standard-dose (SD) (900 mg/day for 6 months) valganciclovir (VGCV) prophylaxis for prevention of cytomegalovirus (CMV) infection and disease in high-risk CMV donor-positive/recipient-negative (D+/R-) kidney recipients. METHODS: We performed a single-center, retrospective cohort study, in a 750-bed academic medical center, involving a total of 90 evaluable CMV high-risk kidney recipients. All patients were retrospectively followed from day of transplantation to November 1, 2012, or to the development of CMV infection or disease, death, or loss to follow-up. CMV screening was only done if suggestive symptoms or abnormal laboratory values were present. Our immunosuppressive protocol otherwise did not differ between periods. RESULTS: In total, 45 consecutive eligible patients initiated SD prophylaxis in the 22 months before the institutional protocol change regarding CMV prophylaxis. One patient developed CMV infection in the setting of non-adherence. In the 16 months after the protocol update, 45 consecutive eligible patients receiving LD prophylaxis were evaluated: 6 developed CMV infection while receiving prophylaxis (P = 0.11). Ganciclovir (GCV)-resistant infection was confirmed in 1 patient in the LD prophylaxis group. Late-onset CMV infection or disease occurred in 11 patients (24%) in the SD group and in 12 patients (27%) in the LD group (P = 0.86). More patients in the SD group developed leukopenia (75% vs. 44%, P < 0.01). During the study period, no significant differences were seen between the groups in mean mg/kg exposure to rabbit anti-thymocyte globulin induction courses, mean tacrolimus troughs, number of rejection episodes, mean estimated renal function, graft survival, or patient survival. Overall mean follow-up (± standard deviation) was 357 days (± 53) in the SD group and 320 days (± 103) in the LD group (P = 0.03). CONCLUSION: Breakthrough CMV infection while receiving VGCV prophylaxis occurred more often after the institutional protocol revision to LD VGCV prophylaxis. Given our concern for increased risk of breakthrough infection and GCV resistance when prophylaxis is under-dosed, our institutional protocols were revised back to SD prophylaxis for all CMV D+/R- kidney transplant recipients.

Mycotic splenic artery aneurysm secondary to Coxiella burnetii endocarditis.

Mycotic artery aneurysms are rare but potentially lethal vascular lesions due to their high risk of rupture. Bacterial endocarditis as well as trauma and inadequate immunity are predisposing factors. Surgery remains the treatment of choice, although alternative methods have been used. We report the first known case of a 6 cm mycotic splenic artery aneurysm proximal to the splenic hilum, secondary to bacterial endocarditis from Coxiella burnetii. Resection of the aneurysm, splenectomy, and distal pancreatectomy were performed. In all patients with culture-negative endocarditis and mycotic aneurysm, C. burnetii infection should be ruled out.

In vitro release of fusidic acid and teicoplanin from cancellous bone allografts.

The characteristics of cancellous bone allografts as carriers of fusidic acid and teicoplanin are described. Particles of cancellous bone were compressed into a wiremesh cylinder; five replicas were impregnated for one hour into fusidic acid; and another five for one hour into teicoplanin. Elution was estimated daily. Concentrations of fusidic acid and teicoplanin were determined by a microbiological assay. Both antibiotics were eluted at very high concentrations within the first days. Allografts impregnated in fusidic acid provided concentrations above 20 microg/ml for 20 days. Eluted teicoplanin after day 4 was below 10 microg/ml. It is concluded that cancellous bone allografts may allow adequate in vitro elution of fusidic acid but not of teicoplanin. The latter results support their application in experimental models of osteomyelitis.

Pharmacokinetics of fluoroquinolones in uncompensated cirrhosis: the significance of penetration in the ascitic fluid.

In order to study the penetration of routinely used fluoroquinolones in the ascitic fluid of patients with uncompensated cirrhosis the following doses were given. Three patients received three consecutive iv doses of 200 mg of ciprofloxacin, six patients, three consecutive iv doses of 300 mg of ciprofloxacin, seven others, three consecutive iv doses of 400 mg of pefloxacin and six, three consecutive iv doses of 400 mg of ofloxacin. Drug levels in serum and the ascitic fluid were monitored at regular time intervals. Peak levels of the 200 mg dose of ciprofloxacin, of the 300 mg dose of ciprofloxacin, of pefloxacin and of ofloxacin in serum were 2.11,2.45,9.21 and 8.86 microg/ml, respectively and in the ascitic fluid 0.67, 0.45, 6.09 and 5.83 microg/ml, respectively T(1/2) was 3.19+/-0.73, 3.55+/-1.68, 15.60+/-12.40 and 9.45+/-3.14 h, respectively with AUC of 3.62+/-4.02, 7.39+/-4.70, 137.85+/-63.96 and 119.8+/-16.83 mg/l h. Urinary excretion of ciprofloxacin and of ofloxacin was similar to healthy individuals but pefloxacin showed a mean urinary excretion of 30.11%. It is concluded that pefloxacin and ofloxacin at the administered iv doses result in serum and ascitic fluid levels above the MICs of the common pathogens causing spontaneous bacterial peritonitis and that they should be administered to cirrhotic patients in dosing regimens similar to those in patients with normal hepatic function. The use of ciprofloxacin requires further studies to define the appropriate dose.

Visceral leishmaniasis in a patient with acquired hypogammaglobulinemia.

A case of visceral leishmaniasis in a 26-year-old man with acquired IgA and IgG2 hypogammaglobulinemia, secondary to carbamazepine therapy given because of a previous head injury, is presented. The patient's clinical picture was otherwise typical, although hypogammaglobulinemia resulted in a delay in diagnosis, and response to therapy was excellent. This case is noteworthy because it is the first reported case of visceral leishmaniasis in a hypogammaglobulinemic patient and also because it is the fifth case of hypogammaglobulinemia due to carbamazepine reported worldwide.

Treatment of experimental osteomyelitis caused by methicillin-resistant Staphylococcus aureus with a biodegradable system of lactic acid polymer releasing pefloxacin.

A novel biodegradable system of D-,L-dilactide delivering pefloxacin was implanted in 104 rabbits with experimental osteomyelitis caused by methicillin-resistant Staphylococcus aureus (MRSA), 26 serving as controls. Animals were killed on each third day and viable bacterial counts and levels of pefloxacin in bone tissue were determined. A 99. 9% decrease in viable count of bacteria was achieved by day 12 and complete bacterial eradication on day 33. Pefloxacin was released gradually, reaching its peak on day 15 at levels 100 times the MIC of pefloxacin for MRSA. The biodegradable system described may have a future role in the therapeutic approach to osteomyelitis.

Chronic osteomyelitis caused by multi-resistant Gram-negative bacteria: evaluation of treatment with newer quinolones after prolonged follow-up.

We evaluated ciprofloxacin, ofloxacin and pefloxacin regimens for the treatment of chronic osteomyelitis due to Gram-negative multiresistant organisms. The study was open, nonrandomized and included 28, 21 and 16 patients, respectively. The 4-fluoroquinolone regimens were 1000 mg, 400 mg and 400-800 mg bd, for a mean duration of 137, 163 and 134 days, respectively. Pseudomonas aeruginosa was the most common pathogen, isolated in 33 individuals. Patients were followed clinically, bacteriologically and radiologically during treatment and for 2-5 years after discontinuation of therapy. Clinical outcome at the end of therapy was successful in 79%, 81% and 75%, improvement occurred in 11%, 10% and 19%, and the failure rate was 11%, 10% and 6%, while 11%, 5% and 6% relapsed, respectively. At the end of follow-up the bacterial eradication rate was 68%, 76% and 69%, respectively. Fluoroquinolone resistance emerged in 18%, 19% and 13% of ciprofloxacin, ofloxacin and pefloxacin recipients, respectively. The newer quinolones were safe and well tolerated and should be considered as the contemporary treatment of choice for chronic Gram-negative osteomyelitis, particularly whenever P. aeruginosa is implicated.

The in vitro activity of FCE 22101 against gram-negative aerobic isolates resistant to third generation cephalosporins.

The in vitro activity of FCE 22101 against 97 Gram-negative aerobic nosocomial isolates was compared with that of ceftriaxone using the agar dilution method. Thirty-four (79%) of the 43 ceftriaxone resistant (MIC > 16 mg/l) isolates were found to be FCE 22101 susceptible (MIC < or = 8 mg/l), while of the ceftriaxone susceptible isolates, only seven Enterobacter cloacae and one Serratia spp strain were FCE 22101 resistant. The new penem may offer an alternative for treating nosocomial infections due to aerobic Gram-negative strains resistant to third generation cephalosporins, provided that clinical studies confirm its clinical usefulness.

Pefloxacin versus ceftazidime in the treatment of a variety of gram-negative-bacterial infections.

In a prospective open randomized trial, pefloxacin was given to 53 patients and ceftazidime was given to 50 patients suffering from bronchopneumonia (n = 29), deep soft tissue infection (n = 19), urinary tract infection (n = 28), chronic osteomyelitis in exacerbation (n = 15), chronic otitis media in exacerbation (n = 3), malignant external otitis (n = 3), abdominal abscess (n = 2), septic arthritis (n = 1), acute cholangitis (n = 1), bacterial endocarditis (n = 1), and subacute sinusitis (n = 1). Underlying aggravating factors coexisted in 45 and 41 patients in the pefloxacin and ceftazidime groups, respectively, with 32 and 33 infections characterized as nosocomial and severe in each group, respectively. Pefloxacin was given at a dose of 400 mg intravenously (i.v.) (n = 16) or per os (n = 23) every 8 or 12 h, as well as i.v. followed by per os (n = 14), for 7 to 180 days; and ceftazidime was given at 2 g i.v. every 8 h (n = 45) or 1 g intramuscularly every 8 h (n = 5) for 7 to 56 days. Pseudomonas aeruginosa and various members of the family Enterobacteriaceae predominated in culture specimens. Clinical cure was observed in 38 and 39 patients given pefloxacin and ceftazidime, respectively; 10 and 7 patients were improved; and in 5 and 4 patients treatment failed. Pathogen eradication was observed in 42 and 39 patients, respectively; persistence was observed in 8 and ll patients, respectively, followed by the emergence of resistance in five and four P. aeruginosa strains, respectively (P = not significant). With the exception of photosensitivity rash in seven patients given pefloxacin, all side effects observed in eight and three patients in the pefloxacin and ceftazidime groups, respectively (P < 0.01), were not important and were self-limited. It is concluded that pefloxacin is as effective as ceftazidime in moderate to severe gram-negative-bacterial infections, with similar trends toward development of resistance during therapy.

Poor efficacy of teicoplanin in treatment of deep-seated staphylococcal infections.

Teicoplanin in a 400 mg intravenous loading dose followed by 200 mg/day intravenously or intramuscularly was given to 19 patients with deep-seated staphylococcal infections. Only eight patients (44.4%) were considered cured, failure mostly being observed in patients with osteomyelitis, endocarditis and bacteremia. Poor tissue kinetics of teicoplanin and the presence of foreign bodies are probable explanations for the reported failures. Future trials using a higher dose of teicoplanin with or without the addition of rifampicin or gentamicin seem to be justified.

Use of intravenous ciprofloxacin in difficult-to-treat infections.

Intravenous ciprofloxacin was administered to 54 patients who were either critically ill or in whom oral administration was not possible. The 31 males and 23 females ranged in age from 20 to 89 years (mean, 53.2 +/- 17.8 years). Patients had "difficult-to-treat" infections, i.e., respiratory infections (15), abscesses (four intraabdominal, three lung, two soft tissue, and one intrahepatic), deep soft tissue infections (10), chronic post-traumatic osteomyelitis in exacerbation (nine), upper urinary tract infection (five), malignant external otitis (two), catheter-related bacteremia (two), and infectious endocarditis (one). Thirty patients (56 percent) had serious associated medical problems. Pathogens included Pseudomonas aeruginosa (38 isolates), Acinetobacter species (10 isolates), Enterobacter cloacae (eight isolates), Escherichia coli (two isolates), Proteus mirabilis (one isolate), Kingella kingae (one isolate), Bacteroides fragilis (eight isolates), and Peptostreptococcus species (five isolates). Minimal inhibitory concentrations of ciprofloxacin ranged from 0.003 to 2 micrograms/ml. In 39 patients, the isolated microorganisms were multi-resistant; resistance included ceftazidime and amikacin in 32 patients. In 24 patients, ciprofloxacin was given exclusively by the intravenous route at a dose of 200 mg every 12 hours; in 30 patients, treatment was completed after discontinuation of the parenteral drug with the oral preparation of ciprofloxacin at a dose of 750 mg every 12 hours. The duration of parenteral treatment ranged from six to 40 days (mean, 14.9 days). A successful clinical response was observed in 49 patients (91 percent), while five (9 percent) failed to show a response. Bacteriologic outcomes were as follows: eradication of pathogen in 33 patients (61.1 percent), persistence in 18 (33.3 percent), and relapse in three (5.6 percent), with development of resistance to ciprofloxacin in nine patients (16.7 percent) and superinfection in two patients (3.7 percent). Side effects included vein irritation at the site of the infusion (three patients), abnormal elevation in liver enzyme levels (two patients), reversible renal failure (one patient), and nausea (one patient). Parenteral ciprofloxacin is a safe, well-tolerated, and effective therapy for the critically ill patient, and can be replaced with the oral form when clinically appropriate.

Evaluation of imipenem/cilastatin against nosocomial infections and multiresistant pathogens.

Thirty-five patients suffering from soft tissue infections (12), upper UTIs (6), bronchopneumonia (6), septicaemia (2), chronic osteomyelitis (2), intra-abdominal abscess (2), liver abscess (1), lung abscess (1), acute cholangitis (1), thoracic empyema (1) and chronic prostatitis (1) were given imipenem/cilastatin for 6-21 days. In 22 patients several aggravating factors coexisted, while infection in 16 patients was polymicrobial. The following pathogens were implicated: Pseudomonas aeruginosa (21), Escherichia coli (15), Enterobacter cloacae (6), Proteus spp. (3), Klebsiella pneumoniae(3), Citrobacter freundii (1), Salmonella enteritidis (1), Acinetobacter spp. (4), Haemophilus influenzae (2), Bacteroides fragilis (1) and Peptococcus saccharolyticus (1) with MICs to imipenem ranging between 0.5 and 8 mg/l. A successful clinical response was observed in 91.4% of the patients, while pathogens were eradicated in 75.9%, persisted in 24.2% and recurred, in 9.1% of patients, with development of resistance to imipenem in two Ps. aeruginosa strains. Against 150 multiresistant strains of Ps. aeruginosa, 40% of which were resistant to amikacin, 86.4% and 88.9% were found sensitive to ceftazidime and imipenem respectively. It is concluded that imipenem provides the possibility of treating successfully multiresistant and polymicrobial infections with a single antimicrobial.

Evaluation of ciprofloxacin in the treatment of Pseudomonas aeruginosa infections.

The efficacy and safety of ciprofloxacin in the treatment of Pseudomonas aeruginosa infections was evaluated in 72 patients suffering from upper urinary tract infection (19 patients), deep soft tissue infection (16), chronic osteomyelitis (12), abscess (7), chronic otitis media (6), otitis externa (3) and bronchopneumonia (9). Forty-eight patients received an oral dose of 500 mg or 750 mg b.i.d. and five patients an i.v. dose of 200 mg b.i.d., while 19 patients were given both oral and parenteral doses. The duration of therapy ranged from seven days to more than four months. The MICs of ciprofloxacin for the Pseudomonas aeruginosa strains isolated were in the range less than 0.06-2 mg/l; 36% of the strains were resistant to all other available antibiotics. At follow-up after a minimum of six months the clinical success rate was 75% and the infecting organism was permanently eradicated in 49% of the patients. In nine patients the organism developed resistance, particularly when the initial MIC was higher than 0.5 mg/l. No significant adverse reactions were observed. Ciprofloxacin is the first antipseudomonal antimicrobial agent which can be administered orally and therefore fulfills a need in chemotherapy.

Evaluation of aztreonam in difficult-to-treat infections with prolonged posttreatment follow-up.

Aztreonam at doses of 1 or 2 g given intramuscularly or intravenously every 8 h for 7 to 42 days was given to 55 patients, most of them suffering from difficult-to-treat infections either because the isolated pathogens were multiresistant or because of the location of the infection. Infections included: urinary tract (23 cases), deep soft tissue phlegmon (12 cases), chronic osteomyelitis in exacerbation (7 cases), abscesses (7 cases), pneumonia (4 cases), and external otitis (2 cases). In culture specimens, Pseudomonas aeruginosa (24 isolates) and various Enterobacteriaceae species (37 isolates) were isolated with MICs ranging from 0.25 to 16 micrograms/ml. Clinically, at the completion of treatment and after a 6-week posttreatment follow-up, 45 (81.6%) patients were cured, 4 (7.2%) improved, 3 (5.6%) relapsed, and 3 (5.6%) failed to respond to therapy. Bacteriologically, at the end of treatment, the pathogen was eradicated in 50 patients (91%) and persisted in 5 (9%). After a 6-week follow-up, cultures remained sterile in 33 patients (60.0%), 16 (29.1%) relapsed, in 6 (10.9%) bacteria persisted, and superinfection was reported in 4 (7.3%) patients. No appreciable adverse effects or toxicity was observed. From the reported results, it is concluded that aztreonam is a valuable addition to the field of antimicrobial chemotherapy that can be used effectively and safely in the treatment of a variety of gram-negative infections.

Aztreonam versus cefamandole in the treatment of urinary tract infections.

The in vivo efficacy and safety of aztreonam compared to that of cefamandole was randomly and prospectively studied in the treatment of 30 patients suffering from recurrent urinary tract infections with a patient ratio of 2 aztreonam to 1 cefamandole. The mean age was 51.6 +/- 15.4 and 59.8 +/- 13 years respectively. Both antibiotics were given at a dose of 1 g, 8 hourly i.m. for 7-13 days. Sixty-seven percent versus 70% of the patients given aztreonam and cefamandole respectively were suffering from upper urinary tract infections. X ray abnormalities predisposing to relapse or reinfections were present in 88% vs 80% of the patients, while all patients had typical symptoms of urinary tract infections, with high fever (greater than or equal to 38.5 degrees C) reported in 70% and 60% of the patients in the two treatment groups respectively. Escherichia coli and Proteus mirabilis were the predominant isolates in urine cultures. During treatment all patients responded favourably both clinically and bacteriologically, while after a 6-week follow-up 20% versus 30% relapsed clinically with 15% vs 30% bacteriologic relapses in the two groups, but only in patients suffering from upper urinary tract infections. No development of bacterial resistance was observed in the relapses, while mainly Enterococcus spp was implicated in reinfections. No appreciable side effects of toxicity were observed. It was concluded that aztreonam is a promising new antibiotic that deserves further clinical trials in systemic infections.