Application of Precision Medicine Concepts in Ambulatory Antibiotic Management of Acute Pyelonephritis.

Acute pyelonephritis (APN) is a relatively common community-acquired infection, particularly in women. The early appropriate antibiotic treatment of this potentially life-threatening infection is associated with improved outcomes. The international management guidelines for complicated urinary tract infections and APN recommend using oral antibiotics with <10% resistance among urinary pathogens. However, increasing antibiotic resistance rates among Escherichia coli and other Enterobacterales to fluoroquinolones, trimethoprim-sulfamethoxazole (TMP-SMX), and beta-lactams has left patients without reliable oral antibiotic treatment options for APN. This narrative review proposes using precision medicine concepts to improve empirical antibiotic therapy for APN in ambulatory settings. Whereas resistance rates to a particular antibiotic class may exceed 10% at the population-based level, the predicted antibiotic resistance rates based on patient-specific risk factors fall under 10% in many patients with APN on the individual level. The utilization of clinical tools for the prediction of fluoroquinolones, TMP-SMX, and third-generation cephalosporin resistance improves the ambulatory antibiotic management of APN. It may also reduce the need to switch antibiotic therapy later based on the in vitro antibiotic susceptibility testing results of bacterial isolates in urinary cultures. This approach may mitigate the burden of increasing antibiotic resistance in the community by ensuring that the initial antibiotic prescribed has the highest likelihood of treating APN appropriately.

Magnetic Targeting of Gadolinium Contrast to Enhance MRI of the Inner Ear in Endolymphatic Hydrops.

OBJECTIVES: 1. Determine the feasibility and efficiency of local magnetic targeting delivery of gadolinium (Gad) contrast to the inner ear in rodents. 2. Assess any potential ototoxicity of magnetic targeting delivery of Gad in the inner ear. 3. Study the utility of magnetic targeting delivery of Gad to visualize and quantify endolymphatic hydrops (EH) in a transgenic mouse model. STUDY DESIGN: Controlled in vivo animal model study. METHODS: Paramagnetic Gad was locally delivered to the inner ear using the magnetic targeting technique in both rat and mouse models. Efficiency of contrast delivery was assessed using magnetic resonance imaging (MRI). Ototoxicity of Gad was examined with histology of the cochlea and functional audiological tests. The Phex mouse model was used to study EH, hearing loss, and balance dysfunction. Magnetic targeting delivery of Gad contrast was used in the Phex mouse model to visualize the effects of EH using MRI. RESULTS: Magnetic targeting improved the delivery of Gad to the inner ear and the technique was reproducible in both rat and mouse models. The delivery method did not result in microstructural damage or any significant hearing loss in a normal animal. Magnetic targeting of Gad in the Phex mouse model allowed detailed visualization and quantification of EH. CONCLUSION: This study provided the first evidence of the effectiveness and efficiency of the local magnetic targeting delivery of gadolinium contrast to the inner ear and its application to the visualization and quantification of EH. Laryngoscope, 133:914-923, 2023.

Epidemiology, Outcomes and Tolerability of Protracted Treatment of Nontuberculous Mycobacterial Infections at a Community Teaching Hospital in the Southeastern United States.

Nontuberculous mycobacterial (NTM) infections present a treatment challenge for clinicians and patients. There are limited data about current susceptibility patterns and treatment outcomes in U.S. adults. This was a 10-year, single-center, retrospective, observational cohort study of adults with a positive NTM culture and clinical suspicion of infection between 1 January 2010 and 30 June 2020. The primary objective was to identify predictors for favorable treatment outcomes. Key secondary objectives were characterization of NTM epidemiology, susceptibility profiles, and safety and tolerability of treatment, including the proportion of subjects with an antimicrobial change and the reasons for the change. Of 250 subjects diagnosed with NTM infection, the most prevalent NTM isolates were Mycobacterium avium intracellulare complex (66.8%) followed by Mycobacterium abscessus (17.6%). Antimicrobial susceptibility data were available for 52.4% of the cohort (45.8% slow growers; 54.2% rapid growers). Only 88 (35%) subjects received treatment with evaluable clinical outcomes. The proportion of subjects with a favorable outcome was 61.4%. More subjects in the unfavorable outcome group experienced a change in antimicrobial therapy (73.5% vs. 51.9%, p = 0.043). The most common reason for antimicrobial change was adverse drug events (n = 36, 67.9%). In the regression model, private insurance was associated with a favorable outcome, whereas having multiple antimicrobial changes was associated with an unfavorable outcome. The complexity of NTM treatment and high incidence of medication-related issues suggest the necessity of interdisciplinary collaboration to improve overall treatment outcomes in NTM infections.

Neural responses to naturalistic audiovisual speech are related to listening demand in cochlear implant users.

There is a weak relationship between clinical and self-reported speech perception outcomes in cochlear implant (CI) listeners. Such poor correspondence may be due to differences in clinical and "real-world" listening environments and stimuli. Speech in the real world is often accompanied by visual cues, background environmental noise, and is generally in a conversational context, all factors that could affect listening demand. Thus, our objectives were to determine if brain responses to naturalistic speech could index speech perception and listening demand in CI users. Accordingly, we recorded high-density electroencephalogram (EEG) while CI users listened/watched a naturalistic stimulus (i.e., the television show, "The Office"). We used continuous EEG to quantify "speech neural tracking" (i.e., TRFs, temporal response functions) to the show's soundtrack and 8-12 Hz (alpha) brain rhythms commonly related to listening effort. Background noise at three different signal-to-noise ratios (SNRs), +5, +10, and +15 dB were presented to vary the difficulty of following the television show, mimicking a natural noisy environment. The task also included an audio-only (no video) condition. After each condition, participants subjectively rated listening demand and the degree of words and conversations they felt they understood. Fifteen CI users reported progressively higher degrees of listening demand and less words and conversation with increasing background noise. Listening demand and conversation understanding in the audio-only condition was comparable to that of the highest noise condition (+5 dB). Increasing background noise affected speech neural tracking at a group level, in addition to eliciting strong individual differences. Mixed effect modeling showed that listening demand and conversation understanding were correlated to early cortical speech tracking, such that high demand and low conversation understanding occurred with lower amplitude TRFs. In the high noise condition, greater listening demand was negatively correlated to parietal alpha power, where higher demand was related to lower alpha power. No significant correlations were observed between TRF/alpha and clinical speech perception scores. These results are similar to previous findings showing little relationship between clinical speech perception and quality-of-life in CI users. However, physiological responses to complex natural speech may provide an objective measure of aspects of quality-of-life measures like self-perceived listening demand.

Evidence of visual crossmodal reorganization positively relates to speech outcomes in cochlear implant users.

Deaf individuals who use a cochlear implant (CI) have remarkably different outcomes for auditory speech communication ability. One factor assumed to affect CI outcomes is visual crossmodal plasticity in auditory cortex, where deprived auditory regions begin to support non-auditory functions such as vision. Previous research has viewed crossmodal plasticity as harmful for speech outcomes for CI users if it interferes with sound processing, while others have demonstrated that plasticity related to visual language may be beneficial for speech recovery. To clarify, we used electroencephalography (EEG) to measure brain responses to a partial face speaking a silent single-syllable word (visual language) in 15 CI users and 13 age-matched typical-hearing controls. We used source analysis on EEG activity to measure crossmodal visual responses in auditory cortex and then compared them to CI users' speech-in-noise listening ability. CI users' brain response to the onset of the video stimulus (face) was larger than controls in left auditory cortex, consistent with crossmodal activation after deafness. CI users also produced a mixture of alpha (8-12 Hz) synchronization and desynchronization in auditory cortex while watching lip movement while controls instead showed desynchronization. CI users with higher speech scores had stronger crossmodal responses in auditory cortex to the onset of the video, but those with lower speech scores had increases in alpha power during lip movement in auditory areas. Therefore, evidence of crossmodal reorganization in CI users does not necessarily predict poor speech outcomes, and differences in crossmodal activation during lip reading may instead relate to strategies or differences that CI users use in audiovisual speech communication.

Local magnetic delivery of adeno-associated virus AAV2(quad Y-F)-mediated BDNF gene therapy restores hearing after noise injury.

Moderate noise exposure may cause acute loss of cochlear synapses without affecting the cochlear hair cells and hearing threshold; thus, it remains "hidden" to standard clinical tests. This cochlear synaptopathy is one of the main pathologies of noise-induced hearing loss (NIHL). There is no effective treatment for NIHL, mainly because of the lack of a proper drug-delivery technique. We hypothesized that local magnetic delivery of gene therapy into the inner ear could be beneficial for NIHL. In this study, we used superparamagnetic iron oxide nanoparticles (SPIONs) and a recombinant adeno-associated virus (AAV) vector (AAV2(quad Y-F)) to deliver brain-derived neurotrophic factor (BDNF) gene therapy into the rat inner ear via minimally invasive magnetic targeting. We found that the magnetic targeting effectively accumulates and distributes the SPION-tagged AAV2(quad Y-F)-BDNF vector into the inner ear. We also found that AAV2(quad Y-F) efficiently transfects cochlear hair cells and enhances BDNF gene expression. Enhanced BDNF gene expression substantially recovers noise-induced BDNF gene downregulation, auditory brainstem response (ABR) wave I amplitude reduction, and synapse loss. These results suggest that magnetic targeting of AAV2(quad Y-F)-mediated BDNF gene therapy could reverse cochlear synaptopathy after NIHL.

Cortical alpha oscillations in cochlear implant users reflect subjective listening effort during speech-in-noise perception.

Listening to speech in noise is effortful for individuals with hearing loss, even if they have received a hearing prosthesis such as a hearing aid or cochlear implant (CI). At present, little is known about the neural functions that support listening effort. One form of neural activity that has been suggested to reflect listening effort is the power of 8-12 Hz (alpha) oscillations measured by electroencephalography (EEG). Alpha power in two cortical regions has been associated with effortful listening-left inferior frontal gyrus (IFG), and parietal cortex-but these relationships have not been examined in the same listeners. Further, there are few studies available investigating neural correlates of effort in the individuals with cochlear implants. Here we tested 16 CI users in a novel effort-focused speech-in-noise listening paradigm, and confirm a relationship between alpha power and self-reported effort ratings in parietal regions, but not left IFG. The parietal relationship was not linear but quadratic, with alpha power comparatively lower when effort ratings were at the top and bottom of the effort scale, and higher when effort ratings were in the middle of the scale. Results are discussed in terms of cognitive systems that are engaged in difficult listening situations, and the implication for clinical translation.

Neural correlates of visual stimulus encoding and verbal working memory differ between cochlear implant users and normal-hearing controls.

A common concern for individuals with severe-to-profound hearing loss fitted with cochlear implants (CIs) is difficulty following conversations in noisy environments. Recent work has suggested that these difficulties are related to individual differences in brain function, including verbal working memory and the degree of cross-modal reorganization of auditory areas for visual processing. However, the neural basis for these relationships is not fully understood. Here, we investigated neural correlates of visual verbal working memory and sensory plasticity in 14 CI users and age-matched normal-hearing (NH) controls. While we recorded the high-density electroencephalogram (EEG), participants completed a modified Sternberg visual working memory task where sets of letters and numbers were presented visually and then recalled at a later time. Results suggested that CI users had comparable behavioural working memory performance compared with NH. However, CI users had more pronounced neural activity during visual stimulus encoding, including stronger visual-evoked activity in auditory and visual cortices, larger modulations of neural oscillations and increased frontotemporal connectivity. In contrast, during memory retention of the characters, CI users had descriptively weaker neural oscillations and significantly lower frontotemporal connectivity. We interpret the differences in neural correlates of visual stimulus processing in CI users through the lens of cross-modal and intramodal plasticity.

Poor early cortical differentiation of speech predicts perceptual difficulties of severely hearing-impaired listeners in multi-talker environments.

Hearing impairment disrupts processes of selective attention that help listeners attend to one sound source over competing sounds in the environment. Hearing prostheses (hearing aids and cochlear implants, CIs), do not fully remedy these issues. In normal hearing, mechanisms of selective attention arise through the facilitation and suppression of neural activity that represents sound sources. However, it is unclear how hearing impairment affects these neural processes, which is key to understanding why listening difficulty remains. Here, severely-impaired listeners treated with a CI, and age-matched normal-hearing controls, attended to one of two identical but spatially separated talkers while multichannel EEG was recorded. Whereas neural representations of attended and ignored speech were differentiated at early (~ 150 ms) cortical processing stages in controls, differentiation of talker representations only occurred later (~250 ms) in CI users. CI users, but not controls, also showed evidence for spatial suppression of the ignored talker through lateralized alpha (7-14 Hz) oscillations. However, CI users' perceptual performance was only predicted by early-stage talker differentiation. We conclude that multi-talker listening difficulty remains for impaired listeners due to deficits in early-stage separation of cortical speech representations, despite neural evidence that they use spatial information to guide selective attention.

Evaluation of Antimicrobial Utilization and Concordance with National Guidelines at a Tertiary Hospital in the Southern Highlands Zone of Tanzania.

Antimicrobial resistance is a growing concern in sub-Saharan Africa, and antimicrobial stewardship (AMS) programs have not been widely implemented in this region. We evaluated antibiotic prescribing patterns and concordance with national guidelines at Mbeya Zonal Referral Hospital (MZRH) in Tanzania. Adult inpatient medical records were chronologically reviewed from January 1, 2018 until 100 records documenting antibiotic therapy were evaluated. The primary endpoint was concordance with national guidelines for indication-based antibiotic selection and duration. Data were summarized using descriptive statistics. Overall, 155 records with sufficient data were reviewed. The 100 records which involved antibiotic therapy represented 171 unique antibiotic courses. The most common indication for antibiotics was bacterial pneumonia. Ceftriaxone and metronidazole, the most commonly used antibiotics, were administered in 40% and 24% of courses, respectively. Indication-based antibiotic selection was concordant with national guidelines in 63% of courses, but this fell to 15% when course duration was taken into account. Antibiotic courses were completed as prescribed 28% of the time among evaluable courses. A microbiologic culture of any kind was obtained in 17% of patients. In conclusion, antibiotic therapy was often incomplete, was generally guideline discordant, exhibited limited diversity of selection, and frequently lacked diagnostic confirmation. These data, combined with local susceptibility patterns, may be used to foster AMS efforts for improved compliance with guidelines at MZRH in the future.

Envelope following responses, noise exposure, and evidence of cochlear synaptopathy in humans: Correction and comment.

A correction and comment are provided for a recent article by Paul, Waheed, Bruce, and Roberts [(2017). J. Acoust. Soc. Am. 142(5), EL434-EL440].

Towards an objective test of chronic tinnitus: Properties of auditory cortical potentials evoked by silent gaps in tinnitus-like sounds.

A common method designed to identify if an animal hears tinnitus assumes that tinnitus "fills-in" silent gaps in background sound. This phenomenon has not been reliably demonstrated in humans. One test of the gap-filling hypothesis would be to determine if gap-evoked cortical potentials are absent or attenuated when measured within background sound matched to the tinnitus sensation. However the tinnitus sensation is usually of low intensity and of high frequency, and it is unknown if cortical responses can be measured with such "weak" stimulus properties. Therefore the aim of the present study was to test the plausibility of observing these responses in the EEG in humans without tinnitus. Twelve non-tinnitus participants heard narrowband noises centered at sound frequencies of 5 or 10 kHz at sensation levels of either 5, 15, or 30 dB. Silent gaps of 20 ms duration were randomly inserted into noise stimuli, and cortical potentials evoked by these gaps were measured by 64-channel EEG. Gap-evoked cortical responses were statistically identifiable in all conditions for all but one participant. Responses were not significantly different between noise frequencies or levels. Results suggest that cortical responses can be measured when evoked by gaps in sounds that mirror acoustic properties of tinnitus. This design can validate the animal model and be used as a tinnitus diagnosis test in humans.

Impact of Penicillin Allergy on Empirical Carbapenem Use in Gram-Negative Bloodstream Infections: An Antimicrobial Stewardship Opportunity.

OBJECTIVES: Retrospective matched-cohort study evaluating association between penicillin allergy and empirical carbapenem use in gram-negative bloodstream infections (BSIs) and utility of antimicrobial stewardship interventions in reducing carbapenem utilization. METHODS: Hospitalized adults with community-onset gram-negative BSI from January 1, 2010, to June 30, 2015, at two large community hospitals in Columbia, SC, were identified. Antimicrobial stewardship interventions targeting penicillin allergy and carbapenem utilization were fully implemented January 1, 2014. Multivariate logistic regression was used to examine impact of penicillin allergy and antimicrobial stewardship interventions on empirical carbapenem use. Kaplan-Meier analysis was used to evaluate time to carbapenem deescalation in patients with penicillin allergy before and after interventions. RESULTS: Patients with penicillin allergy (n=140) were more likely to receive empirical carbapenem therapy for community-onset gram-negative BSI compared to those without penicillin allergy (n=140) (27% vs 12%, p=0.002). After adjustments in the multivariate model, penicillin allergy (odds ratio [OR] 3.98, 95% confidence interval [CI] 1.98-8.45) and prior ß-lactam use (OR 2.72, 95% CI 1.07-6.64) were independently associated with empirical carbapenem use, whereas antimicrobial stewardship interventions were associated with decline in carbapenem utilization (OR 0.41, 95% CI 0.16-0.94). Among patients with penicillin allergy who were prescribed empirical carbapenems, median time to carbapenem deescalation was significantly shorter in the postintervention versus preintervention period (2.0 vs 4.2 days, p=0.004). CONCLUSION: Penicillin allergy was a significant contributor to carbapenem use in community-onset gram-negative BSI. This was subject to modification by antimicrobial stewardship interventions, which successfully reduced overall carbapenem use and duration of carbapenem therapy in patients with penicillin allergy.

Subcortical amplitude modulation encoding deficits suggest evidence of cochlear synaptopathy in normal-hearing 18-19 year olds with higher lifetime noise exposure.

Noise exposure and aging can damage cochlear synapses required for suprathreshold listening, even when cochlear structures needed for hearing at threshold remain unaffected. To control for effects of aging, behavioral amplitude modulation (AM) detection and subcortical envelope following responses (EFRs) to AM tones in 25 age-restricted (18-19 years) participants with normal thresholds, but different self-reported noise exposure histories were studied. Participants with more noise exposure had smaller EFRs and tended to have poorer AM detection than less-exposed individuals. Simulations of the EFR using a well-established cochlear model were consistent with more synaptopathy in participants reporting greater noise exposure.

Evidence that hidden hearing loss underlies amplitude modulation encoding deficits in individuals with and without tinnitus.

Damage to auditory nerve fibers that expresses with suprathreshold sounds but is hidden from the audiogram has been proposed to underlie deficits in temporal coding ability observed among individuals with otherwise normal hearing, and to be present in individuals experiencing chronic tinnitus with clinically normal audiograms. We tested whether these individuals may have hidden synaptic losses on auditory nerve fibers with low spontaneous rates of firing (low-SR fibers) that are important for coding suprathreshold sounds in noise while high-SR fibers determining threshold responses in quiet remain relatively unaffected. Tinnitus and control subjects were required to detect the presence of amplitude modulation (AM) in a 5 kHz, suprathreshold tone (a frequency in the tinnitus frequency region of the tinnitus subjects, whose audiometric thresholds were normal to 12 kHz). The AM tone was embedded within background noise intended to degrade the contribution of high-SR fibers, such that AM coding was preferentially reliant on low-SR fibers. We also recorded by electroencephalography the "envelope following response" (EFR, generated in the auditory midbrain) to a 5 kHz, 85 Hz AM tone presented in the same background noise, and also in quiet (both low-SR and high-SR fibers contributing to AM coding in the latter condition). Control subjects with EFRs that were comparatively resistant to the addition of background noise had better AM detection thresholds than controls whose EFRs were more affected by noise. Simulated auditory nerve responses to our stimulus conditions using a well-established peripheral model suggested that low-SR fibers were better preserved in the former cases. Tinnitus subjects had worse AM detection thresholds and reduced EFRs overall compared to controls. Simulated auditory nerve responses found that in addition to severe low-SR fiber loss, a degree of high-SR fiber loss that would not be expected to affect audiometric thresholds was needed to explain the results in tinnitus subjects. The results indicate that hidden hearing loss could be sufficient to account for impaired temporal coding in individuals with normal audiograms as well as for cases of tinnitus without audiometric hearing loss.

Safety and Tolerability of Stribild in the Southeast United States.

PURPOSE: The purpose of this study is to assess postmarketing safety and tolerability of Stribild (elvitegravir [EVG]/cobicistat [COBI]/tenofovir disoproxil fumarate [TDF]/emtricitabine [FTC]). METHODS: A retrospective, pharmacoepidemiologic study in 2 outpatient HIV clinics in the Southeast United States was conducted among adults receiving EVG/COBI/TDF/FTC. We evaluated incidence and treatment-related adverse events, including change in serum creatinine (SCr). RESULTS: Patients were primarily treatment experienced (n = 173, 60%), African American (n = 210, 73%), and males (n = 187, 65%). One hundred ninety-five (68%) patients had any increase in SCr, and 65 (23%) had an increase of ≥0.3 mg/dL. Mean SCr change from baseline to peak was 0.2 mg/dL. Being treatment experienced (odds ratio [OR] = 2.21, 95% confidence interval [CI]: 1.12-4.38) was associated with SCr ≥0.3 mg/dL, while body mass index ≥30 kg/m(2) (OR = 0.41, 95% CI: 0.18-0.93) was protective. Twenty (7%) patients discontinued therapy, 3 due to acute kidney injury. CONCLUSION: Our results demonstrate limited adverse events and low discontinuation rates associated with EVG/COBI/TDF/FTC.

Evidence for differential modulation of primary and nonprimary auditory cortex by forward masking in tinnitus.

It has been proposed that tinnitus is generated by aberrant neural activity that develops among neurons in tonotopic of regions of primary auditory cortex (A1) affected by hearing loss, which is also the frequency region where tinnitus percepts localize (Eggermont and Roberts 2004; Roberts et al., 2010, 2013). These models suggest (1) that differences between tinnitus and control groups of similar age and audiometric function should depend on whether A1 is probed in tinnitus frequency region (TFR) or below it, and (2) that brain responses evoked from A1 should track changes in the tinnitus percept when residual inhibition (RI) is induced by forward masking. We tested these predictions by measuring (128-channel EEG) the sound-evoked 40-Hz auditory steady-state response (ASSR) known to localize tonotopically to neural sources in A1. For comparison the N1 transient response localizing to distributed neural sources in nonprimary cortex (A2) was also studied. When tested under baseline conditions where tinnitus subjects would have heard their tinnitus, ASSR responses were larger in a tinnitus group than in controls when evoked by 500 Hz probes while the reverse was true for tinnitus and control groups tested with 5 kHz probes, confirming frequency-dependent group differences in this measure. On subsequent trials where RI was induced by masking (narrow band noise centered at 5 kHz), ASSR amplitude increased in the tinnitus group probed at 5 kHz but not in the tinnitus group probed at 500 Hz. When collapsed into a single sample tinnitus subjects reporting comparatively greater RI depth and duration showed comparatively larger ASSR increases after masking regardless of probe frequency. Effects of masking on ASSR amplitude in the control groups were completely reversed from those in the tinnitus groups, with no change seen to 5 kHz probes but ASSR increases to 500 Hz probes even though the masking sound contained no energy at 500 Hz (an "off-frequency" masking effect). In contrast to these findings for the ASSR, N1 amplitude was larger in tinnitus than control groups at both probe frequencies under baseline conditions, decreased after masking in all conditions, and did not relate to RI. These results suggest that aberrant neural activity occurring in the TFR of A1 underlies tinnitus and its modulation during RI. They indicate further that while neural changes occur in A2 in tinnitus, these changes do not reflect the tinnitus percept. Models for tinnitus and forward masking are described that integrate these findings within a common framework.

Modulation of electrocortical brain activity by attention in individuals with and without tinnitus.

Age and hearing-level matched tinnitus and control groups were presented with a 40 Hz AM sound using a carrier frequency of either 5 kHz (in the tinnitus frequency region of the tinnitus subjects) or 500 Hz (below this region). On attended blocks subjects pressed a button after each sound indicating whether a single 40 Hz AM pulse of variable increased amplitude (target, probability 0.67) had or had not occurred. On passive blocks subjects rested and ignored the sounds. The amplitude of the 40 Hz auditory steady-state response (ASSR) localizing to primary auditory cortex (A1) increased with attention in control groups probed at 500 Hz and 5 kHz and in the tinnitus group probed at 500 Hz, but not in the tinnitus group probed at 5 kHz (128 channel EEG). N1 amplitude (this response localizing to nonprimary cortex, A2) increased with attention at both sound frequencies in controls but at neither frequency in tinnitus. We suggest that tinnitus-related neural activity occurring in the 5 kHz but not the 500 Hz region of tonotopic A1 disrupted attentional modulation of the 5 kHz ASSR in tinnitus subjects, while tinnitus-related activity in A1 distributing nontonotopically in A2 impaired modulation of N1 at both sound frequencies.

Update on raltegravir and the development of new integrase strand transfer inhibitors.

Raltegravir (RAL) is the first antiretroviral in the integrase strand transfer inhibitors (INSTI) class. The use of RAL has expanded since its approval in October 2007 for multidrug-resistant human immunodeficiency virus type 1 infection in adults. RAL is now a guideline-preferred treatment option for antiretroviral-naïve patients, indicated for treatment in adolescents, and is being studied as an integral part of nucleoside sparing regimens. The development of resistance and the need for a once-daily dosing option has led to the development of new INSTIs, including elvitegravir and dolutegravir. Elvitegravir is being studied in a promising once-daily single-tablet regimen with tenofovir, emtricitabine, and the investigational pharmacoenhancer cobicistat. The development of cobicistat and the new once-daily INSTIs may revolutionize the treatment of human immunodeficiency virus type 1 infection. This article reviews the current literature on raltegravir and new developments in the INSTI class.