F. Gudiol

A SHORT-TERM STUDY OF THE SAFETY, PHARMACOKINETICS, AND EFFICACY OF RITONAVIR, AN INHIBITOR OF HIV-1 PROTEASE

BACKGROUND Reverse-transcriptase inhibitors have only moderate clinical efficacy against the human immunodeficiency virus type 1 (HIV-1). Ritonavir is an inhibitor of HIV-1 protease with potent in vitro anti-HIV properties and good oral bioavailability. METHODS We evaluated the antiviral activity and safety of ritonavir in a double-blind, randomized, placebo-controlled phase 1 and 2 study of 84 HIV-positive patients with 50 or more CD4+ lymphocytes per cubic millimeter. The patients were randomly assigned to one of four regimens of ritonavir therapy, or to placebo for four weeks and then (by random assignment) to one of the ritonavir regimens. RESULTS During the first 4 weeks, increases in CD4+ lymphocyte counts and reductions in the log number of copies of HIV-1 RNA per milliliter of plasma were similar among the four dosage groups, but in the three lower-dosage groups there was a return to base-line levels by 16 weeks. After 32 weeks, in the seven patients in the highest-dosage group (600 mg of ritonavir every 12 hours), the median increase from base line in the CD4+ lymphocyte count was 230 cells per cubic millimeter, and the mean decrease in the plasma concentration of HIV-1 RNA (as measured by a branched-DNA assay) was 0.81 log (95 percent confidence interval, 0.40 to 1.22). In a subgroup of 17 patients in the two higher-dosage groups, RNA was also measured with an assay based on the polymerase chain reaction, and after eight weeks of treatment there was a mean maximal decrease in viral RNA of 1.94 log (95 percent confidence interval, 1.37 to 2.51). Adverse events included nausea, circumoral paresthesia, elevated hepatic aminotransferase levels, and elevated triglyceride levels. Ten withdrawals from the study were judged to be related to ritonavir treatment. CONCLUSIONS In this short-term study, ritonavir was well tolerated and had potent activity against HIV-1, but its clinical benefits remain to be established.

Risk Factors and Response to Antibiotic Therapy in Adults with Bacteremic Pneumonia Caused by Penicillin-Resistant Pneumococci

We retrospectively studied 24 adults with bacteremic pneumonia (25 episodes) due to penicillin-resistant pneumococci, for which the minimal inhibitory concentrations (MICs) of penicillin G were 0.12 to 8.0 micrograms per milliliter; 79 percent of the strains showed multiple antibiotic resistance. As compared with 48 control patients with bacteremic pneumonia caused by penicillin-sensitive pneumococci, the 24 patients with penicillin-resistant pneumococci had a significantly higher incidence of use of beta-lactam antibiotics during the previous three months (65 vs. 17 percent, P = 0.0008), hospitalization during the previous three months (58 vs. 21 percent, P = 0.0038), nosocomial pneumonia (37 vs. 6 percent, P = 0.0032), episodes of pneumonia during the previous year (29 vs. 4 percent, P = 0.010), and factors on initial presentation that were associated with a poor prognosis (an initially critical condition) (67 vs. 27 percent, P = 0.0030). Their overall mortality rate was significantly higher (54 vs. 25 percent, P = 0.0298). Eleven of 19 episodes of pneumonia due to organisms for which MICs were 0.12 to 2.0 micrograms per milliliter, which were treated with penicillin G (10 episodes) or another beta-lactam agent (9 episodes), resulted in recovery (2 of 10 patients in an initially critical condition recovered, as compared with all of 9 not initially in a critical condition, P = 0.0012). Two patients who had penicillin-resistant pneumococci for which MICs were 4.0 and 8.0 micrograms per milliliter did not respond to ampicillin and ticarcillin therapy, respectively. Our study suggests that pneumonia due to penicillin-resistant pneumococci may occur more often in a population with some identifiable risk factors, and may respond to intravenous high-dose penicillin therapy if MICs are less than or equal to 2 micrograms per milliliter. Cases involving higher resistance may require an alternative antibiotic.

Evaluation of vancomycin for therapy of adult pneumococcal meningitis.

The emergence of pneumococci resistant to penicillin and other agents prompted us to evaluate intravenous vancomycin for the therapy of pneumococcal meningitis, which has an overall mortality of 30%. Eleven consecutive adult patients with cerebrospinal fluid (CSF)-culture-proven pneumococcal meningitis and positive initial CSF Gram stain were given intravenous vancomycin (usual dosage, 7.5 mg/kg every 6 h for 10 days). The MBCs of vancomycin ranged from 0.25 to 0.5 micrograms/ml. Early adjunctive therapy with intravenous dexamethasone, mannitol, and sodium phenytoin was also instituted. After 48 h of therapy, all 11 patients showed a satisfactory clinical response, although the CSF culture remained positive in one case; median trough CSF and serum vancomycin levels were 2 and 5.1 micrograms/ml, respectively, and trough CSF bactericidal titers ranged from less than 1:2 to 1:16. On day 3, one patient died of acute heart failure. Four patients had clinical failure at on days 4 (two patients), 7 (one), and 8 (one) of therapy; they all immediately responded to a change in antibiotic therapy. The remaining six patients were cured after 10 days of vancomycin therapy. At this point, median peak CSF and serum vancomycin levels were 1.9 and 18.5 micrograms/ml, respectively. A transient alteration of renal function occurred in two patients, and persistent slight hypoacusia occurred in three patients. In summary, 11 adults with pneumococcal meningitis were treated with vancomycin and early adjunctive therapy including dexamethasone. All patients initially improved, and 10 were ultimately cured of the infection. However, four patients experienced a therapeutic failure, which led to a change in vancomycin therapy.

Characteristics and antibiotic therapy of adult meningitis due to penicillin-resistant pneumococci

Of 66 episodes of pneumococcal meningitis seen in Bellvitge Hospital, Barcelona, Spain (January 1981 to June 1987), 15 (23 percent) were due to penicillin-resistant pneumococci [minimal inhibitory concentrations (MICs) of 0.1 to 4 micrograms/ml]. Fifty percent of these strains were also resistant to chloramphenicol. Most were sporadic community-acquired cases. Clinical characteristics were similar in both penicillin-resistant and penicillin-sensitive cases. Those cases with MICs of greater than 1 microgram/ml did not show a response to penicillin therapy. Of nine patients treated with cefotaxime (200 to 350 mg/kg per day) with penicillin G MICs of 0.1 to 4 micrograms/ml and cefotaxime MICs of less than or equal to 0.03 to 1 microgram/ml, seven recovered, one experienced a relapse after 14 days of therapy and the infection was cured with intravenous vancomycin, and one patient died with sterile cerebrospinal fluid. Thus, adults with meningitis due to penicillin-resistant pneumococci may be adequately treated with high doses (around 300 mg/kg per day) of intravenous cefotaxime if MICs of penicillin G are less than or equal to 4 micrograms/ml. Cases with higher resistance may require another antibiotic such as vancomycin.

Treatment of Human Brucellosis with Doxycycline plus Rifampin or Doxycycline plus Streptomycin: A Randomized, Double-Blind Study

OBJECTIVE To compare the effectiveness of doxycycline-rifampin (DR) combination therapy with that of the classic doxycycline-streptomycin (DS) combination in patients with brucellosis. DESIGN A randomized, double-blind study, with a mean follow-up of 15.7 months. SETTING A 1000-bed teaching hospital in Barcelona, Spain. PATIENTS Ninety-five patients (68 men and 27 women; mean age, 39 years) diagnosed with brucellosis on the basis of both clinical and serologic findings; 81 of these patients had blood cultures positive for Brucella melitensis. INTERVENTIONS Forty-four patients received doxycycline, 100 mg every 12 hours, and rifampin, 15 mg/kg body weight per day in a single morning dose, for 45 days; 51 patients received the same dose of doxycycline for 45 days plus streptomycin, 1 g/d for 15 days. MAIN OUTCOME MEASURES Therapeutic failure and relapse during the follow-up period. RESULTS The mean time to defervescence was 4.2 days for the DR group and 3.2 days for the DS group (P greater than 0.2). The actuarial probability of therapeutic failure or relapse at 12 months of follow-up (Kaplan-Meier) was 14.4% in the DR group and 5.9% in the DS group (difference, 8.5%; 95% Cl, -4.8% to 21.6%; P greater than 0.2). All three patients with spondylitis in the DR group failed therapy compared with one of four patients in the DS group. Excluding patients with spondylitis, the actuarial failure rate was 4.9% and 4.3% in the DR and DS groups, respectively, at 12 months of follow-up (difference, 0.6%; Cl, -8.1% to 9.4%; P greater than 0.2). CONCLUSIONS Doxycycline-rifampin combination therapy for 45 days is as effective as the classic DS combination in most patients with brucellosis; however, DR therapy might be less effective in those patients with spondylitis.

Risk factors for nosocomial bacteremia due to methicillin-resistantStaphylococcus aureus

In a prospective surveillance study (February 1990–December 1991) performed at a 1000-bed teaching hospital to identify risk factors for nosocomial methicillin-resistantStaphylococcus aureus (MRSA) bacteremia, 309 patients were found to be colonized (n=103; 33 %) or infected (n=206; 67 %) by MRSA. Sixty-three of them developed bacteremia. Compared with 114 patients who had nosocomial bacteremia caused by methicillin-sensitiveStaphylococcus aureus during the same period of time, MRSA bacteremic patients had more severe underlying diseases (p<0.01), were more often in intensive care units (p<0.01) and had received prior antibiotic therapy more frequently (p<0.01). To further identify risk factors for MRSA bacteremia, univariate and multivariate analyses of this series of 309 patients were performed using the occurrence of MRSA bacteremia as the dependent variable. Among 14 variables analyzed, intravascular catheterization, defined as one or more intravascular catheters in place for more than 48 h, was the only variable selected by a logistic regression model as an independent risk factor (OR=2.7, CI=1.1–6.6). The results of this study reinforce the concept that recent antibiotic therapy may predispose patients to MRSA infection and suggest that among patients colonized or infected by MRSA, those with intravascular catheters are at high risk of developing MRSA bacteremia.

Efficacy of Colistin versus β-Lactams, Aminoglycosides, and Rifampin as Monotherapy in a Mouse Model of Pneumonia Caused by Multiresistant Acinetobacter baumannii

ABSTRACT The treatment of life-threatening infections due to carbapenem-resistant Acinetobacter baumannii has become a serious challenge for physicians worldwide. Often, only colistin shows in general good in vitro activity against these carbapenem-resistant strains, but its antibacterial efficacy in comparison with the antibiotics most used in clinical practice is not well known. We studied the efficacy of colistin versus those of imipenem, sulbactam, tobramycin, and rifampin in an experimental pneumonia model with immunocompetent mice. We used three strains of A. baumannii corresponding to the main clones (A, D, and E) involved in the outbreaks of our hospital, with different grades of resistance to imipenem (imipenem MICs of 1, 8, and 512 μg/ml, respectively) and to the other antibiotics. The MIC of colistin was 0.5 μg/ml for the three strains. Reduction of log10 CFU/g in lung bacterial counts, clearance of bacteremia, and survival versus results with controls were used as parameters of efficacy. Imipenem and sulbactam (Δlung counts: −5.38 and −4.64 log10 CFU/ml) showed the highest level of bactericidal efficacy in infections by susceptible and even intermediate strains. Tobramycin and rifampin (−4.16 and −5.15 log10 CFU/ml) provided good results against intermediate or moderately resistant strains, in agreement with killing curves and pharmacodynamics. On the contrary, colistin showed the weakest antibacterial effect among the antibiotics tested, both in killing curves and in the in vivo model (−2.39 log10 CFU/ml; P < 0.05). We conclude that colistin did not appear as a good option for treatment of patients with pneumonia due to carbapenem-resistant A. baumannii strains. Other alternatives, including combinations with rifampin, may offer better therapeutic profiles and thus should be studied.

Risk factors for faecal carriage of Klebsiella pneumoniae producing extended spectrum β-lactamase (ESBL-KP) in the intensive care unit

In the course of an outbreak of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae (ESBL-KP) in an intensive care unit (ICU), we conducted active surveillance to determine the risk factors for ESBL-KP faecal colonization of patients. We used weekly rectal samples during a four-month period. ESBL-KP was found in the faeces of 72 of 188 (38%) patients, and 42 (58%) of them were colonized within the first week of admission to the ICU. The probability of remaining free of faecal colonization was less than 20% at 30 days of ICU admission. The risk factors associated with ESBL-KP faecal colonization were clinical severity score at admission (P = 0.004), arterial catheterization (P = 0.002), total parenteral nutrition (P = 0.04), urinary catheterization (P = 0.01), mechanical ventilation (P < 0.001), and previous antibiotic therapy (P = 0.04). A logistic regression analysis identified duration of urinary catheterization (OR:3.5; 95% CI 1.2-10.3) and mechanical ventilation (OR:4.6; 95% CI 1.1-19.3) as independent risk factors for ESBL-KP faecal colonization. Our results suggest that in an ESBL-KP prevalent environment, manipulations that facilitate cross-infection are the most relevant in the acquisition of the micro-organism and risk increases throughout hospitalization.

Factors Associated with Complications and Mortality in Adult Patients Hospitalized for Infectious Cellulitis

The aim of this study was to analyze medical outcomes, including risks for complications and mortality, in 332 adult patients hospitalized for cellulitis. The infection was documented microbiologically in 128 cases (39%). Staphylococcus aureus (46 cases) and Streptococcus pyogenes (22 cases) were the most frequent causative pathogens. Overall, 63 patients (19%) were discharged early (≤4 days) and 166 patients (50%) were hospitalized for more than 4 days without developing any complications. One hundred three patients (31%) had one or more complications or died. Of these, 78 required surgical debridement, 10 required plastic surgery, 7 underwent amputation, and 15 had shock on presentation. When comparing the three study groups (patients discharged early, patients hospitalized for ≤4 days without complications, and patients who developed 1 or more complication or who died), patients who were discharged early (low risk) were more frequently female and were less likely to have multiple comorbid conditions, hypoalbuminemia, renal insufficiency, and/or cutaneous necrosis at presentation. Overall mortality (<30 days) was 5% (16/332 patients). Factors associated with death were male sex, presence of multiple comorbid conditions, congestive heart failure, morbid obesity, hypoalbuminemia, renal insufficiency, shock, and Pseudomonas aeruginosa cellulitis. These findings can be used to stratify patients with acute cellulitis according to risks for complications and mortality and may be helpful when deciding the most appropriate means of care, i.e. outpatient treatment or hospitalization.

Prospective study of 288 episodes of bacteremia in neutropenic cancer patients in a single institution

Trends in causative organisms and sources of infection were studied in a series of 288 episodes of bacteremia in neutropenic cancer patients observed in a single institution from 1986 to 1993. The incidence of bacteremia increased significantly from 20 episodes per 1000 admissions in 1986 to 50 episodes per 1000 admissions in 1993 (p=0.00001). Over the study period, a continuous increment in gram-positive bacteremia, which reached 81% of episodes in 1993 (p=0.000001), was observed. Conversely, the incidence of gram-negative bacteremia remained stable. Coagulase-negative staphylococci and viridans group streptococci were the most commonly isolated pathogens. Bacteremia caused by coagulase-negative staphylococci increased from 3 episodes per 1000 admissions to 19 episodes per 1000 admissions (p=0.0001), and viridans group streptococci bacteremia increased from 0 episodes per 1000 admissions to 19 episodes per 1000 admissions (p=0.000001). The upward trend in gram-positive bacteremia appeared to be related to a significant increase in both intravascular catheters (p=0.003) and oral mucositis (p=0.003) as sources of infection. Specific strategies to prevent chemotherapy-induced mucositis and catheter-related bacteremia merit further investigations.