The radiation of New Zealand's skinks and geckos is associated with distinct viromes.

BACKGROUND: New Zealand is home to over 120 native endemic species of skinks and geckos that radiated over the last 20-40 million years, likely driven by the exploitation of diverse habitats formed during the Miocene. The recent radiation of animal hosts may facilitate cross-species virus transmission, likely reflecting their close genetic relationships and therefore relatively low barriers for viruses to emerge in new hosts. Conversely, as animal hosts adapt to new niches, even within specific geographic locations, so too could their viruses. Consequently, animals that have niche-specialised following radiations may be expected to harbour genetically distinct viruses. Through a metatranscriptomic analysis of eight of New Zealand's native skink and gecko species, as well as the only introduced lizard species, the rainbow skink (Lampropholis delicata), we aimed to reveal the diversity of viruses in these hosts and determine whether and how the radiation of skinks and geckos in New Zealand has impacted virus diversity and evolution. RESULTS: We identified a total of 15 novel reptilian viruses spanning 11 different viral families, across seven of the nine species sampled. Notably, we detected no viral host-switching among the native animals analysed, even between those sampled from the same geographic location. This is compatible with the idea that host speciation has likely resulted in isolated, niche-constrained viral populations that have prevented cross-species transmission. Using a protein structural similarity-based approach, we further identified a highly divergent bunya-like virus that potentially formed a new family within the Bunyavirales. CONCLUSIONS: This study has broadened our understanding of reptilian viruses within New Zealand and illustrates how niche adaptation may limit viral-host interactions.

Risks and benefits of sentinel lymph node evaluation in the management of endometrial intraepithelial neoplasia.

INTRODUCTION: Endometroid intraepithelial neoplasia (EIN) is a premalignant lesion to endometrial cancer. Increasing number of gynecologic oncologists are performing sentinel lymph node (SLN) evaluation during hysterectomy for EIN to ensure complete staging if there is cancer on the final specimen. However, there are no clear guidelines and the benefits and risks to performing SLN evaluation for EIN patients are unclear. AREAS COVERED: This narrative review examines the advantages and disadvantages of SLN evaluation for EIN patients and provides an algorithm to assist clinicians in selectively applying the procedure for maximal patient benefit. Relevant articles up to March 2024 were obtained from a PubMed search on SLN use with endometrial pathology. EXPERT OPINION: Sentinel lymph node evaluation for patients with EIN is safe, feasible and particularly important for the approximately 10% of patients with high-risk endometrial carcinoma on final pathology. However, as most diagnosed carcinomas are low-risk, SLN evaluation would have limited oncologic benefit. While SLN assessment may overtreat most patients with EIN, a significant minority of patients will be improperly staged. We propose an algorithm highlighting the importance of maximal preoperative endometrial sampling and stratifying patients via risk factors to selectively identify those who would benefit most from SLN evaluation.

Endometroid intraepithelial neoplasia (EIN) is a premalignant lesion to endometrial cancer, the most common gynecologic cancer in the United States. The definitive treatment for EIN is hysterectomy. An increasing number of gynecologic oncologists are performing sentinel lymph node (SLN) assessment during surgery for EIN since 30-40% of patients with EIN will have underlying carcinoma. For those patients, lymph node evaluation is important for cancer staging, especially if high-risk or advanced stage disease is found on the pathologic specimen. The SLN procedure cannot be performed post-hysterectomy, so an improperly staged patient may require a second operation for lymphadenectomy; this has a greater chance of morbidity compared to a SLN biopsy. However, a SLN evaluation still confers perioperative risk and comes at an additional monetary cost, especially when most patients diagnosed with endometrial cancer after EIN will ultimately have low-risk, stage IA disease. We propose an algorithm for clinicians to help determine which patients with EIN would best benefit from the SLN procedure; this includes maximizing preoperative endometrial sampling and considering selective criterion with risk factors for concurrent endometrial carcinoma including age, endometrial thickness, obesity, and molecular classification.

Spontaneous intrauterine pregnancy after tubal sterilization: A case report.

The sterilization failure rate of a total bilateral salpingectomy is unknown. After a total bilateral salpingectomy, spontaneous intrauterine pregnancy is extremely rare; only four cases have been documented. This case report describes a 34-year-old G4P1213 with a history of bilateral salpingectomy who was found to have a viable intrauterine pregnancy. The pregnancy was continued and ended in a repeat cesarean section. At the time of surgery, a left tubal remnant was noted. While the patient was originally reported to have a complete salpingectomy, the evidence of a tubal stump makes this an unintended partial salpingectomy. It is theorized that dense pelvic adhesions at the time of the left salpingectomy increased the likelihood of sterilization failure. This is the first case report to evaluate the pelvic cavity after an intrauterine pregnancy following a reported complete bilateral salpingectomy. Patients should be counseled on the risk of ectopic and intrauterine pregnancy following a bilateral salpingectomy.

Total infectome investigation of diphtheritic stomatitis in yellow-eyed penguins (Megadyptes antipodes) reveals a novel and abundant megrivirus.

First identified in 2002, diphtheritic stomatitis (DS) is a devastating disease affecting yellow-eyed penguins (Megadyptes antipodes, or hoiho in te reo Maori). The disease is associated with oral lesions in chicks and has caused significant morbidity and mortality. DS is widespread among yellow-eyed penguin chicks on mainland New Zealand yet appears to be absent from the subantarctic population. Corynebacterium spp. have previously been suspected as causative agents yet, due to inconsistent cultures and inconclusive pathogenicity, their role in DS is unclear. Herein, we used a metatranscriptomic approach to identify potential causative agents of DS by revealing the presence and abundance of all viruses, bacteria, fungi and protozoa - together, the infectome. Oral and cloacal swab samples were collected from presymptomatic, symptomatic and recovered chicks along with a control group of healthy adults. Two novel viruses from the Picornaviridae were identified, one of which - yellow-eyed penguin megrivirus - was highly abundant in chicks irrespective of health status but not detected in healthy adults. Tissue from biopsied oral lesions also tested positive for the novel megrivirus upon PCR. We found no overall clustering among bacteria, protozoa and fungi communities at the genus level across samples, although Paraclostridium bifermentans was significantly more abundant in oral microbiota of symptomatic chicks compared to other groups. The detection of a novel and highly abundant megrivirus has sparked a new line of inquiry to investigate its potential association with DS.

Intranasal Olopatadine-Mometasone in the Treatment of Seasonal Allergic Rhinitis.

OBJECTIVE: To review the pharmacology, efficacy, and safety of intranasal olopatadine hydrochloride-mometasone furoate (OM) combination in the treatment of seasonal allergic rhinitis (SAR). DATA SOURCES: The PubMed database and ClinicalTrials.gov were searched using the following terms: mometasone + olopatadine, GSP301, mometasone furoate, and olopatadine hydrochloride. STUDY SELECTION AND DATA EXTRACTION: Articles published in English between January 1987 and August 2022 related to pharmacology, safety, and clinical trials were assessed. DATA SYNTHESIS: In 2 phase II clinical trials, twice-daily (BID) and once-daily (QDay) intranasal OM demonstrated significant improvements in reflective total nasal symptom score (rTNSS) (BID P < 0.001 and QDay P < 0.001) and instantaneous total nasal symptom score (iTNSS) (BID P < 0.001 and P < 0.0001; QDay P < 0.001 and P < 0.0001). In 2 phase III clinical trials, BID OM showed significant improvements in rTNSS vs. placebo (P < 0.001), olopatadine monotherapy (P = 0.03 and P = 0.003), and mometasone monotherapy (P = 0.02 and P = 0.059). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: OM is indicated for treatment of SAR symptoms. Caution with use must be considered for certain high-risk patients, existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. Due to its quick and sustained onset of action, OM may be an ideal agent for initial treatment of moderate-severe SAR for patients 12 years and older. CONCLUSION: OM significantly improves SAR symptoms and is a viable treatment option in short-term SAR.

Meta-analysis and systematic review of the association between adverse childhood events and irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction characterized by abdominal pain, bowel habits alterations, constipation, and/or diarrhea. Adverse childhood experiences (ACEs) are events such as abuse and mental illness causing childhood trauma. Studies report higher prevalence of ACEs in patients with IBS with varied effect consistency and association strength. A systematic review and meta-analysis were conducted to evaluate current literature, assess heterogeneity and research gaps in this relationship. A search across PubMed, Embase, PsycINFO, and Google Scholar with keywords ('childhood adversity' OR 'childhood trauma' OR 'adverse childhood events') AND ('irritable colon' OR 'irritable bowel syndrome') yielded 106 studies. A restricted maximum likelihood model of 15 chosen studies with 272,686 participants found the association between ACEs and IBS to be uncertain given the considerable heterogeneity (I2=93.58%, p<0.001). Objective reporting methods for ACE and IBS, study size, and study quality explained some heterogeneity. Twelve studies showed publication bias (Egger's test, p<0.001), which further weakened interpretation. Gender-stratified subanalysis of three studies found ACEs associated with IBS in females (pOR=2.20, 95% CI (1.13 to 4.29), I2=66.90%) with substantial heterogeneity, but no association in males (pOR=1.30, 95% CI (0.62 to 2.78)). This meta-analysis explores the current literature to understand the biopsychosocial perspective of IBS and ACEs' role as risk factors. However, the risk of publication and design/study quality biases substantiates the need for further research. If an association is confirmed, further mechanistic research and development of targeted psychological therapies may be warranted.

Transvenous embolization of bilateral indirect carotid-cavernous fistulas via a unilateral transorbital approach.

A 73-year-old man with a complex ophthalmologic history presented with several weeks of worsening diplopia, visual acuity, and proptosis bilaterally. Cerebral angiography demonstrated bilateral indirect Barrow type B carotid-cavernous fistulas (CCFs). Transarterial embolization was not attempted due to small arterial diameter and risk of stroke. Multiple attempts were made to access the fistula via a transfemoral venous approach and were unsuccessful. A transorbital puncture was performed, which allowed access to both cavernous sinuses via a unilateral approach. After embolization with Onyx, there was no residual fistula. The patient had a left-sided retrobulbar hematoma from the access. Right eye vision improved postoperatively.

Structural Insights into Endobiotic Reactivation by Human Gut Microbiome-Encoded Sulfatases.

Phase II drug metabolism inactivates xenobiotics and endobiotics through the addition of either a glucuronic acid or sulfate moiety prior to excretion, often via the gastrointestinal tract. While the human gut microbial ß-glucuronidase enzymes that reactivate glucuronide conjugates in the intestines are becoming well characterized and even controlled by targeted inhibitors, the sulfatases encoded by the human gut microbiome have not been comprehensively examined. Gut microbial sulfatases are poised to reactivate xenobiotics and endobiotics, which are then capable of undergoing enterohepatic recirculation or exerting local effects on the gut epithelium. Here, using protein structure-guided methods, we identify 728 distinct microbiome-encoded sulfatase proteins from the 4.8 million unique proteins present in the Human Microbiome Project Stool Sample database and 1766 gut microbial sulfatases from the 9.9 million sequences in the Integrated Gene Catalogue. We purify a representative set of these sulfatases, elucidate crystal structures, and pinpoint unique structural motifs essential to endobiotic sulfate processing. Gut microbial sulfatases differentially process sulfated forms of the neurotransmitters serotonin and dopamine, and the hormones melatonin, estrone, dehydroepiandrosterone, and thyroxine in a manner dependent both on variabilities in active site architecture and on markedly distinct oligomeric states. Taken together, these data provide initial insights into the structural and functional diversity of gut microbial sulfatases, providing a path toward defining the roles these enzymes play in health and disease.

Gut microbial ß-glucuronidases reactivate estrogens as components of the estrobolome that reactivate estrogens.

Gut microbial ß-glucuronidase (GUS) enzymes have been suggested to be involved in the estrobolome, the collection of microbial reactions involving estrogens. Furthermore, bacterial GUS enzymes within the gastrointestinal tract have been postulated to be a contributing factor in hormone-driven cancers. However, to date, there has been no experimental evidence to support these hypotheses. Here we provide the first in vitro analysis of the ability of 35 human gut microbial GUS enzymes to reactivate two distinct estrogen glucuronides, estrone-3-glucuronide and estradiol-17-glucuronide, to estrone and estradiol, respectively. We show that certain members within the Loop 1, mini-Loop 1, and FMN-binding classes of gut microbial GUS enzymes can reactivate estrogens from their inactive glucuronides. We provide molecular details of key interactions that facilitate these catalytic processes and present the structures of two novel human gut microbial GUS enzymes related to the estrobolome. Further, we demonstrate that estrogen reactivation by Loop 1 bacterial GUS enzymes can be inhibited both in purified enzymes and in fecal preparations of mixed murine fecal microbiota. Finally, however, despite these in vitro and ex vivo data, we show that a Loop 1 GUS-specific inhibitor is not capable of reducing the development of tumors in the PyMT mouse model of breast cancer. These findings validate that gut microbial GUS enzymes participate in the estrobolome but also suggest that the estrobolome is a multidimensional set of processes on-going within the mammalian gastrointestinal tract that likely involves many enzymes, including several distinct types of GUS proteins.

Targeting Regorafenib-Induced Toxicity through Inhibition of Gut Microbial ß-Glucuronidases.

Regorafenib (Stivarga) is an oral small molecule kinase inhibitor used to treat metastatic colorectal cancer, hepatocellular carcinomas, and gastrointestinal stromal tumors. Diarrhea is one of the most frequently observed adverse reactions associated with regorafenib. This toxicity may arise from the reactivation of the inactive regorafenib-glucuronide to regorafenib by gut microbial ß-glucuronidase (GUS) enzymes in the gastrointestinal tract. We sought to unravel the molecular basis of regorafenib-glucuronide processing by human intestinal GUS enzymes and to examine the potential inhibition of these enzymes. Using a panel of 31 unique gut microbial GUS enzymes derived from the 279 mapped from the human gut microbiome, we found that only four were capable of regorafenib-glucuronide processing. Using crystal structures as a guide, we pinpointed the molecular features unique to these enzymes that confer regorafenib-glucuronide processing activity. Furthermore, a pilot screen identified the FDA-approved drug raloxifene as an inhibitor of regorafenib reactivation by the GUS proteins discovered. Novel synthetic raloxifene analogs exhibited improved potency in both in vitro and ex vivo studies. Taken together, these data establish that regorafenib reactivation is exclusively catalyzed by gut microbial enzymes and that these enzymes are amenable to targeted inhibition. Our results unravel key molecular details of regorafenib reactivation in the GI tract and provide a potential pathway to improve clinical outcomes with regorafenib.

Prolonged Prepregnant Maternal High-Fat Feeding Reduces Fetal and Neonatal Blood Glucose Concentrations by Enhancing Fetal ß-Cell Development in C57BL/6 Mice.

The main objective of this study was to investigate the effect of maternal obesity on offspring's glucose metabolism during the perinatal period. Maternal obesity was established by feeding C57BL/6 mice with a high-fat (HF) diet before or during pregnancy. Our results showed that prolonged prepregnant HF feeding but not HF feeding during pregnancy significantly reduced fetal and neonatal blood glucose concentrations. Remarkably, elevated blood insulin concentrations and increased activation of insulin signaling were observed in fetuses and neonates from prepregnant HF-fed dams. In addition, significantly larger ß-cell areas were observed in pancreases of fetuses and neonates from prepregnant HF-fed dams. Although there was no significant change in placental cross-sectional area or GLUT 1 expression, prepregnant HF feeding significantly enhanced the expression of genes that control placental fatty acid supply. Interestingly, reducing fatty acid supply to the placenta and fetus by placental-specific knockout of adipose triglyceride lipase not only reduced fetal ß-cell area and blood insulin concentration but also attenuated prepregnant HF feeding-induced reduction in offspring blood glucose concentrations during the perinatal period. Together, these results indicate that placental and fetal fatty acid supply plays an important role in fetal ß-cell development, insulin secretion, and glucose metabolism. Prolonged prepregnant maternal HF feeding resembles pregravid maternal obesity in mice, which reduces fetal and neonatal blood glucose concentrations by enhancing fetal ß-cell development and insulin secretion.

Use of a three-tiered clinical decision rule to quantify unnecessary radiological investigation of suspected pulmonary embolism.

BACKGROUND: Clinical decision rules for suspected pulmonary embolism are proposed to identify patients suitable for discharge without radiological investigation. Their use varies between institutions. AIMS: To quantify unnecessary radiological investigations for suspected pulmonary embolism (PE) as defined by a newly proposed three-tiered clinical decision rule incorporating the revised Geneva score, Pulmonary Embolism Rule-Out Criteria and D-dimer. To quantify missed diagnosis of PE if the proposed clinical decision rule were followed. METHODS: A retrospective audit was conducted; applying the proposed clinical decision rule to 584 emergency department (ED)-based encounters at the Royal Adelaide Hospital from May to November 2015. Encounters were confined to emergency presentations where suspected acute PE was investigated with computed tomography pulmonary angiography or ventilation-perfusion scanning; inpatient and follow-up studies were excluded. Sensitivity, specificity, positive predictive value and negative predictive value of the proposed clinical decision rule within the studied population were calculated. RESULTS: Data were obtained for 584 patient encounters where suspected PE was investigated radiologically. Applied retrospectively, the proposed clinical decision rule had a negative predictive value of 97.7% and a sensitivity of 98.5% for radiologically proven PE; 9.2% of scans could have been avoided. One case of PE would have been missed; a false-negative rate of 1.5%. CONCLUSION: Retrospective application of the proposed clinical decision rule to the studied cohort indicates at least 9% of radiological investigations were unnecessary. A prospective study is needed to assess the safety and cost-effectiveness of applying such a pathway to all patients presenting to ED with suspected PE.

Randomized, Double-Blind Study Comparing Patient Comfort and Safety Between Iodixanol 320 mg I/mL and Iopamidol 370 mg I/mL in Patients Undergoing Peripheral Arteriography - The COMFORT II Trial.

BACKGROUND: Numerous clinical trials conducted 10-20 years ago evaluated contrast-induced discomfort. It is unknown whether those data are applicable to current-day clinical practice. This study was performed to provide contemporary contrast-induced patient discomfort data obtained during peripheral arteriography procedures using iso-osmolar iodixanol 320 mg I/mL, compared to low-osmolar iopamidol 370 mg I/mL. METHODS AND RESULTS: Patients receiving iodixanol or iopamidol reported discomfort (heat, coldness, or pain) using a 10-point scale, which was converted to intensity categories: 0 = none; 1-3 = mild; 4-7 = moderate; and 8-10 = severe. Image diagnostic quality was assessed. Patients receiving iodixanol (n = 127; 61% male; mean age, 64 years) had less moderate/severe discomfort (67.7% vs 84.0%; P=.01) than those receiving iopamidol (n = 126; 64% male; mean age, 62 years), with pain contributing predominantly (7.3% vs 44.0%; P<.001) for all injection scores. Patients receiving iodixanol experienced less severe discomfort (16.9% vs 46.4%; P<.001), heat (15.3% vs 36.8%; P<.001), and pain (2.4% vs 23.2%; P<.001) for all injections, compared with patients receiving iopamidol. Image quality was rated as excellent in most patients (iodixanol 86.5% vs iopamidol 82.4%; P=.57). Treatment-emergent adverse events were similar between groups (iodixanol 18.9% vs iopamidol 11.9%; P=.16). CONCLUSIONS: Iodixanol injections induced significantly less moderate/severe and severe patient discomfort, heat, or pain than iopamidol, with pain contributing the most. Discomfort did not affect image quality.

Comparison of patient comfort between iodixanol and iopamidol in contrast-enhanced computed tomography of the abdomen and pelvis: a randomized trial.

BACKGROUND: Previous clinical studies have shown that iso-osmolar iodixanol (Visipaque®) causes less patient discomfort than low-osmolar contrast media (LOCM) when administered via intra-arterial injection. No data are available comparing these agents for patient discomfort when administered intravenously (i.v.) using power injectors. PURPOSE: To compare the frequency and intensity of patient discomfort between iodixanol and iopamidol (Isovue®) administered i.v. using a power injector in contrast-enhanced computed tomography (CECT) of the abdomen and pelvis. MATERIAL AND METHODS: This was a prospective, randomized, double-blind, multicenter study of iodixanol 320 mg I/mL or iopamidol 370 mg I/mL on patient discomfort. The presence of discomfort (heat, pain, coldness) and intensity was verbally rated by patients on a 0-10 scale and converted into four categories (0, none; 1-3, mild; 4-7, moderate; 8-10, severe). Image quality was evaluated. RESULTS: Of the 299 evaluable patients enrolled at nine centers, 151 received iodixanol and 148 received iopamidol. The average age was 58 years. Iodixanol patients experienced significantly less moderate/severe discomfort (35.1% vs. 67.3%; P < 0.0001) or heat (29.8% vs. 63.9%; P < 0.0001), and severe discomfort (2.6% vs. 16.3%; P = 0.0004) or heat (2.6% vs. 15%; P = 0.0008), but three times more no discomfort (21.2% vs. 7.5%; P = 0.0008) than iopamidol patients. Excellent image quality was in 95.4% of iodixanol vs. 89.9% of iopamidol patients (P = 0.0508). Overall, adverse event (AE) rate excluding patient discomfort was 19.9% in the iodixanol group and 14.9% in the iopamidol group (P = 0.2870), but contrast-related AEs were comparable: 11.3% vs. 10.1% (P = 0.8522). Delayed skin reactions occurred in 2.6% of patients in the iodixanol group and in no patient in the iopamidol group (P = 0.1226). CONCLUSION: Patients receiving iodixanol had significantly lower moderate-to-severe or severe discomfort than patients receiving iopamidol, with heat being the major contributor. Iodixanol use trended towards better image quality but the difference was not statistically significant. No significant differences in incidences of overall or contrast-related AEs or delayed skin reactions were seen between the two groups. These data support that CM osmolality may be a key determinant of patient discomfort.

Ceftaroline: a new broad-spectrum cephalosporin.

PURPOSE: The pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of ceftaroline are reviewed. SUMMARY: Ceftaroline, a new broad- spectrum antibiotic, is approved for the treatment of complicated skin and skin structure infections (cSSSIs) and community- acquired pneumonia (CAP). This ß-lactam antibiotic has extended activity against gram-positive organisms and has activity against common gram-negative organisms. The drug's spectrum of activity includes both methicillin-resistant Staphylococcus aureus and multidrug-resistant Streptococcus pneumoniae. However, its activity against extended-spectrum ß-lactamase-producing bacteria is limited. These bacteria, particularly those that express AmpC ß-lactamase, greatly reduce the activity of ceftaroline. The prodrug of ceftaroline (ceftaroline fosamil) is rapidly converted to its active form (ceftaroline) in plasma. This dose-linear drug has been found to be pharmacodynamically best correlated with the percentage of time that free drug concentrations remain above the minimum inhibitory concentration. Ceftaroline's safety profile is similar to that of the other cephalosporins, with minimal adverse drug reactions, most of which are considered mild. Currently available pharmacokinetic, animal, and clinical studies have found that ceftaroline has reasonable efficacy and tolerability but have also revealed that dosing regimen modifications may be needed in patients with moderate-to-severe renal impairment. The recommended dosage of ceftaroline for the treatment of cSSSIs and CAP is 600 mg infused intravenously over 60 minutes every 12 hours. The recommended duration of therapy is 5-14 and 5-7 days for cSSSIs and CAP, respectively. Additional Phase III studies are currently underway. CONCLUSION: Ceftaroline is a new broad-spectrum cephalosporin indicated for the treatment of cSSSIs and CAP caused by susceptible gram-positive and gram-negative organisms.

Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing.

Colistin is a polymyxin antibiotic that was discovered in the late 1940s for the treatment of gram-negative infections. After several years of clinical use, its popularity diminished because of reports of significant nephrotoxicity and neurotoxicity. Recently, the antibiotic has resurfaced as a last-line treatment option for multidrug-resistant organisms such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. The need for antibiotics with coverage of these gram-negative pathogens is critical because of their high morbidity and mortality, making colistin a very important treatment option. Unfortunately, however, resistance to colistin has been documented among all three of these organisms in case reports. Although the exact mechanism causing colistin resistance has not been defined, it is hypothesized that the PmrA-PmrB and PhoP-PhoQ genetic regulatory systems may play a role. Colistin dosages must be optimized, as colistin is a last-line treatment option; in addition, suboptimal doses have been linked to the development of resistance. The lack of pharmacokinetic and pharmacodynamic studies and no universal harmonization of dose units, however, have made it difficult to derive optimal dosing regimens and specific dosing guidelines for colistin. In critically ill patients who may have multiorgan failure, renal insufficiency may alter colistin pharmacokinetics. Therefore, dosage alterations in this patient population are imperative to achieve maximal efficacy and minimal toxicity. With regard to colistin toxicity, most studies show that nephrotoxicity is reversible and less frequent than once thought, and neurotoxicity is rare. Further research is needed to fully understand the impact that the two regulatory systems have on resistance, as well as the dosages of colistin needed to inhibit and overcome these developing patterns.