Virological and Social Outcomes of HIV-Infected Adolescents and Young Adults in The Netherlands Before and After Transition to Adult Care.

BACKGROUND: As a result of effective combination antiretroviral therapy (cART) and advanced supportive healthcare, a growing number of human immunodeficiency virus (HIV)-infected children survive into adulthood. The period of transition to adult care is often associated with impaired adherence to treatment and discontinuity of care. We aimed to evaluate virological and social outcomes of HIV-infected adolescents and young adults (AYAs) before and after transition, and explore which factors are associated with virological failure. METHODS: We included 59 HIV-infected AYAs from the Netherlands who had entered into pediatric care and transitioned from pediatric to adult healthcare. We used HIV RNA load and cART data from the Dutch Stichting HIV Monitoring database (1996-2014), and collected social and treatment data from patients' medical records from all Dutch pediatric HIV treatment centers and 14 Dutch adult treatment centers involved. We evaluated risk factors for virological failure (VF) in a logistic regression model adjusted for repeated measurements. RESULTS: HIV VF occurred frequently during the study period (14%-36%). During the transition period (from 18 to 19 years of age) there was a significant increase in VF compared with the reference group of children aged 12-13 years (odds ratio, 4.26 [95% confidence interval, 1.12-16.28]; P = .03). Characteristics significantly associated with VF were low educational attainment and lack of autonomy regarding medication adherence at transition. CONCLUSIONS: HIV-infected AYAs are vulnerable to VF, especially during the transition period. Identification of HIV-infected adolescents at high risk for VF might help to improve treatment success in this group.

An itchy holiday.

A 33-year-old Dutch woman developed itchy skin lesions during a beach holiday in Thailand. She was treated for various diagnoses, without success. Finally she was successfully treated for a clinically suspected hookwormrelated folliculitis. A brief overview of hookworm-related folliculitis is given.

[Sexual transmission of hepatitis C in homosexual men]. / Seksuele overdracht van hepatitis C bij homoseksuele mannen.

An acute hepatitis C infection was diagnosed in three HIV-positive gay men, aged 43, 48 and 30 years, respectively. In all three, unprotected sexual intercourse and fisting was a universal risk factor for the infection. They all denied having used drugs intravenously, which is the most common risk factor. The third man had a documented proctitis (lymphogranuloma venereum) at the time when the HCV transmission must have taken place. No serious complications occurred during the acute HCV infection. Because the infection did not resolve spontaneously after a few months, all three men were treated with pegylated interferon and ribavirin. Recently, the number of cases of acute HCV infection has been seen to increase in The Netherlands. This may be due primarily to an increase in unprotected sexual intercourse and fisting. This hypothesis is supported by a documented increased prevalence of sexually transmissible diseases among gay men in The Netherlands. As acute infections may turn into chronic infections, treatment of an acute infection should be considered in order to prevent the chronic disease.

Killing of Pseudomonas aeruginosa during continuous and intermittent infusion of ceftazidime in an in vitro pharmacokinetic model.

An in vitro pharmacokinetic model mimicking human serum drug concentrations, based on a dialyzer unit, was developed to study the efficacies of continuous infusion and intermittent administration of ceftazidime over a period of 36 h. The daily dose of ceftazidime was 300 mg/liter/24 h given either as a continuous infusion or as three bolus doses. The intermittent dosing regimen yielded peak and trough concentrations after the fourth dose of 92.3 (standard deviation, 8.0) and 1.4 (standard deviation, 0.9) mg/liter, respectively. Continuous administration yielded concentrations of approximately 20 mg/liter. To study efficacy, three Pseudomonas aeruginosa strains, ATCC 27853, CF4, and CF16, were used. The MICs of ceftazidime for these strains were 1, 4, and 16 mg/liter, respectively. Strain CF16 was killed initially during both regimens and then started to regrow. At the end of the fourth dosing interval, i.e., after 32 h, viable counts showed no difference between the regimens. Strains ATCC 27853 and CF4 were killed initially during both dosing schedules, and after the first dosing interval viable counts were similar. However, after the fourth interval, there was a marked difference between bacterial counts during continuous and intermittent infusion, being 2.2 and 2.8 log10, respectively, demonstrating a greater efficacy during continuous infusion. The results indicate that, in the absence of other factors, a sustained level of ceftazidime around or slightly above the MIC is not high enough to maintain efficacy over more than one (8-h) dosing interval. When sustained concentrations higher than four times the MIC are employed, continuous administration in this model is more efficacious than intermittent dosing.

Emergence of antibiotic resistance amongst Pseudomonas aeruginosa isolates from patients with cystic fibrosis.

We investigated the emergence of resistance to 15 anti-pseudomonal antibiotics amongst Pseudomonas aeruginosa isolates from 34 chronically colonized patients with cystic fibrosis by comparing the susceptibilities of strains isolated before 1987 and after 1989 from the same patients. Strains obtained after 1989 from a further 19 patients who were newly colonized served as controls. The 34 pairs of isolates demonstrated a marked increase in resistance which could not be accounted for by a general increase in resistance during the intervening years since the susceptibility patterns of strains isolated before 1987 were similar to those of strains isolated from patients in the control group. There was a strong correlation between this increase in resistance and both the frequency of admissions to and the number of days spent in hospital. Cluster analysis of the changes in susceptibility for individual antibiotics revealed four distinct patterns of resistance: the fluoroquinolones, with the exception of ofloxacin; the aminoglycosides; the ureidopenicillins and aztreonam; and the cephalosporins, carbapenems, carboxypenicillins and ofloxacin. We conclude that the long-term administration of anti-pseudomonal antibiotics to patients who are chronically colonized with P. aeruginosa is associated with the development of resistance.

Use of pharmacodynamic parameters to predict efficacy of combination therapy by using fractional inhibitory concentration kinetics.

Combination therapy with antimicrobial agents can be used against bacteria that have reduced susceptibilities to single agents. We studied various tobramycin and ceftazidime dosing regimens against four resistant Pseudomonas aeruginosa strains in an in vitro pharmacokinetic model to determine the usability of combination therapy for the treatment of infections due to resistant bacterial strains. For the selection of an optimal dosing regimen it is necessary to determine which pharmacodynamic parameter best predicts efficacy during combination therapy and to find a simple method for susceptibility testing. An easy-to-use, previously described E-test method was evaluated as a test for susceptibility to combination therapy. That test resulted in a MICcombi, which is the MIC of, for example, tobramycin in the presence of ceftazidime. By dividing the tobramycin and ceftazidime concentration by the MICcombi at each time point during the dosing interval, fractional inhibitory concentration (FIC) curves were constructed, and from these curves new pharmacodynamic parameters for combination therapy were calculated (i.e., AUCcombi, Cmax-combi, T>MIC-combi, and T>FICi, where AUCcombi, Cmax-combi, T>MIC-combi, and T>FICi are the area under the FICcombi curve, the peak concentration of FICcombi, the time that the concentration of the combination is above the MICcombi, and the time above the FIC index, respectively). By stepwise multilinear regression analysis, the pharmacodynamic parameter T>FICi proved to be the best predictor of therapeutic efficacy during combination therapy with tobramycin and ceftazidime (R2 = 0.6821; P < 0.01). We conclude that for combination therapy with tobramycin and ceftazidime the T>FICi is the parameter best predictive of efficacy and that the E-test for susceptibility testing of combination therapy gives promising results. These new pharmacodynamic parameters for combination therapy promise to provide better insight into the rationale behind combination therapy.

Duration and clinical relevance of postantibiotic effect in relation to the dosing interval.

The influence of half-life on the postantibiotic effect (PAE) of tobramycin against Pseudomonas aeruginosa and Staphylococcus aureus was investigated during one dosing interval. Tobramycin half-lives of 0.5 to 2.5 h were simulated in an in vitro model, and the PAE was determined by an enzymatic inactivation method at different time points, i.e., when the tobramycin concentrations were 20x, 5x, and 1x the MIC. At the time point during therapy when the tobramycin concentrations had declined to 1x the MIC, at a tobramycin half-life of 0.5 h, the times of the PAEs were approximately 0.7 and 1.7 h for P. aeruginosa and S. aureus, respectively, and the PAE disappeared completely at half-lives corresponding to those found in humans (i.e., 2 to 2.5 h). The PAE itself cannot be fully explained by the presence of free intrabacterial tobramycin or the emergence of resistant subpopulations. The explanation for the disappearance of the PAE during the dosing interval may therefore be explained by the repair of sublethal damage. Since the standard method of determining the PAE in animal models is somewhat different from the method used for measurement of the PAE in vitro, the conditions under which the PAE is measured in vivo were also simulated in the in vitro model. This resulted in PAEs longer than those found by the standard method of obtaining in vitro PAE measurements. We conclude that the PAE of tobramycin, as determined by conventional in vitro methods, has virtually no clinical importance. PAEs determined in vivo may have some clinical relevance, but they are probably primarily caused by sub-MIC effects.

Alteration of postantibiotic effect during one dosing interval of tobramycin, simulated in an in vitro pharmacokinetic model.

The kinetics of the postantibiotic effect (PAE) during one dosing interval of tobramycin against Staphylococcus aureus and Pseudomonas aeruginosa was investigated. We determined the PAE at different time points during this dosing interval of 12 h in an in vitro pharmacokinetic model simulating human pharmacokinetics in which the half-life of tobramycin was adjusted to 2.4 +/- 0.2 h. Using an enzymatic method to inactivate tobramycin, we determined PAEs in samples extracted from the model at 1, 5, 8, and 12 h, corresponding with tobramycin concentrations of 20, 5, 2, and 1 times the MIC for the test organism. The PAE decreased significantly from 2.5 h at 1 h to 0 h at 12 h. No change in MIC was observed for the strains during the experiments. We conclude that the PAE decreases with decreasing tobramycin concentrations during a 12-h dosing interval and completely disappears after the concentration has reached the MIC for the test organism. On the basis of these observations, the emphasis that is placed on the PAE in discussions about the optimal dosing interval in aminoglycoside therapy is questionable.

Synergism between tobramycin and ceftazidime against a resistant Pseudomonas aeruginosa strain, tested in an in vitro pharmacokinetic model.

Synergism between two antibiotics is usually tested by a checkerboard titration technique, or by time-kill methods. Both methods have the disadvantage that synergism is determined at constant concentrations of the antibiotics, which do not reflect reality in vivo. In the present study we determined whether synergism between tobramycin and ceftazidime can be found at declining concentrations below the MIC, and whether change in dosing sequence of the antibiotics would result in differences in killing. Three monotherapy and six combination therapy schedules were tested in an in vitro pharmacokinetic model, using a Pseudomonas aeruginosa resistant to both antibiotics. During all q8h dosing schedules the peak concentration (Cmax) was adjusted to the MIC for the strain of both antibiotics. During all monotherapy regimens bacterial growth was present, while all six combination therapy schedules showed significant killing. At t = 24 h there were no differences between all combination therapy schedules, but at t = 8 h the two combination therapy schedules with administration of tobramycin once daily showed a significantly faster killing. By using the area under the killing curve (AUKC) as a parameter for synergistic killing, simultaneous combination therapy starting with tobramycin once daily was significantly better than all other regimens. We conclude that there is synergism between tobramycin and ceftazidime at declining antibiotic concentrations below the MIC, resulting in a pronounced killing of a resistant Pseudomonas strain. Infections due to resistant Pseudomonas strains could possibly be treated by a synergistic combination of these drugs.

Comparative in vitro activities of trovafloxacin (CP-99,219) against 445 gram-positive isolates from patients with endocarditis and those with other bloodstream infections.

The in vitro activity of trovafloxacin (CP-99,219), a new fluoroquinolone, was compared with the in vitro activities of other commonly used quinolones and other antimicrobial agents against 445 gram-positive microorganisms isolated between 1986 and 1995 from patients with endocarditis and those with other bloodstream infections. The MICs at which 90% of the isolates are inhibited (MIC90) of trovafloxacin for methicillin-susceptible staphylococci, viridans group streptococci, and enterococci were 0.06, 0.25, and 0.5 mg/liter, respectively. The MIC90 of trovafloxacin for vancomycin-resistant enterococci as well as for methicillin-resistant Staphylococcus aureus and methicillin-susceptible and ciprofloxacin-resistant S. aureus, isolated from sources other than blood, was 1 mg/liter. For the quinolones the rank order of activity was trovafloxacin > sparfloxacin > ciprofloxacin = ofloxacin > pefloxacin. Depending on the species tested, trovafloxacin was 4- to 64-fold more active than ciprofloxacin. Further experimental and in vivo studies are warranted to evaluate the efficacy of trovafloxacin in the treatment of bacterial endocarditis and other infections caused by gram-positive organisms.

In-vitro activity of quinupristin/dalfopristin compared with other widely used antibiotics against strains isolated from patients with endocarditis.

The activity of quinupristin/dalfopristin was compared with that of other widely used antibiotics against 355 strains isolated from patients with endocarditis. MICs were determined by a standard agar dilution method. Quinupristin/dalfopristin was inhibitory at 1 mg/L for all coagulase-negative staphylococci (n = 36) and for the majority of Staphylococcus aureus strains (n = 87). The activity of quinupristin/dalfopristin against 186 viridans streptococci was somewhat dependent on the species, with MIC50s ranging from 0.5 to 2 mg/L, being least active against Streptococcus bovis and most active against Streptococcus gordonii and Streptococcus mitis. For the staphylococci, quinupristin/dalfopristin was as active against erythromycin-susceptible as erythromycin-resistant strains. Viridans streptococci showed a slight but significant correlation between sensitivity to erythromycin and quinupristin/dalfopristin. It is concluded that quinupristin/dalfopristin has the potential to treat serious infections such as endocarditis caused by Gram-positive cocci.

Enzymatic method for inactivation of aminoglycosides during measurement of postantibiotic effect.

To determine the postantibiotic effect of aminoglycosides, two methods are currently being used to remove the test drug: repeated washing and dilution. An enzymatic inactivation method of removing gentamicin and tobramycin was developed and compared with the dilution method. This enzymatic method provides a rapid and simple alternative method of removing aminoglycosides which results in reliable postantibiotic-effect values.

Comparison of pharmacodynamics of azithromycin and erythromycin in vitro and in vivo.

In this study, we determined the efficacy of various dosing regimens for erythromycin and azithromycin against four pneumococci with different susceptibilities to penicillin in an in vitro pharmacokinetic model and in a mouse peritonitis model. The MIC was 0.03 microg/ml, and the 50% effective doses (determined after one dose) of both drugs were comparable for the four pneumococcal strains and were in the range of 1.83 to 6.22 mg/kg. Dosing experiments with mice, using regimens for azithromycin of one to eight doses/6 h, showed the one-dose regimen to give the best result; of the pharmacodynamic parameters tested (the maximum drug concentration in serum [Cmax], the times that the drug concentration in serum remained above the MIC and above the concentration required for maximum killing, and the area under the concentration time curve), Cmax was the best predictor of outcome. The bacterial counts in mouse blood or peritoneal fluid during the first 24 h after challenge were not correlated to survival of the mice. The serum concentration profiles obtained with mice for the different dosing regimens were simulated in the in vitro pharmacokinetic model. Here as well, the one-dose regimen of azithromycin showed the best result. However, the killing curves in vivo in mouse blood and peritoneal fluid and in the vitro pharmacokinetic model were not similar. The in vitro killing curves showed a decrease of 2 log10 within 2 and 3 h for azithromycin and erythromycin, respectively whereas the in vivo killing curves showed a bacteriostatic effect for both drugs. It is concluded that the results in terms of predictive pharmacodynamic parameters are comparable for the in vitro and in vivo models and that high initial concentrations of azithromycin favor a good outcome.

In vivo synergistic interaction of liposome-coencapsulated gentamicin and ceftazidime.

Antimicrobial agents may interact synergistically. But to ensure synergy in vivo, the drugs should both be present at the site of infection at sufficiently high concentrations for an adequate period of time. Coencapsulation of the drugs in a drug carrier may ensure parallel tissue distributions. Since liposomes localize preferentially at sites of infection, this mode of drug delivery could, in addition, increase drug concentrations at the focus of infection. The therapeutic efficacy of gentamicin and ceftazidime coencapsulated into liposomes was examined by monitoring survival in a rat model of an acute unilateral pneumonia caused by antibiotic-susceptible and antibiotic-resistant Klebsiella pneumoniae strains. It is shown that administration of gentamicin in combination with ceftazidime in the free form either as single dose or as 5-day treatment resulted in an additive effect on rat survival in both models. In contrast, targeted delivery of liposome-coencapsulated gentamicin and ceftazidime resulted in a synergistic interaction of the antibiotics in both models. Consequently, liposome coencapsulation of gentamicin and ceftazidime allowed both a shorter course of treatment at lower cumulative doses compared with administration of the antibiotics in the free form to obtain complete survival of rats. Liposomal coencapsulation of synergistic antibiotics may open new perspectives in the treatment of severe infections.