Alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women: multicentre, open label, randomised, non-inferiority trial.

OBJECTIVE: To test and compare the efficacy of methenamine hippurate for prevention of recurrent urinary tract infections with the current standard prophylaxis of daily low dose antibiotics. DESIGN: Multicentre, open label, randomised, non-inferiority trial. SETTING: Eight centres in the UK, recruiting from June 2016 to June 2018. PARTICIPANTS: Women aged ≥18 years with recurrent urinary tract infections, requiring prophylactic treatment. INTERVENTIONS: Random assignment (1:1, using permuted blocks of variable length via a web based system) to receive antibiotic prophylaxis or methenamine hippurate for 12 months. Treatment allocation was not masked and crossover between arms was allowed. MAIN OUTCOME MEASURE: Absolute difference in incidence of symptomatic, antibiotic treated, urinary tract infections during treatment. A patient and public involvement group predefined the non-inferiority margin as one episode of urinary tract infection per person year. Analyses performed in a modified intention-to-treat population comprised all participants observed for at least six months. RESULTS: Participants were randomly assigned to antibiotic prophylaxis (n=120) or methenamine hippurate (n=120). The modified intention-to-treat analysis comprised 205 (85%) participants (antibiotics, n=102 (85%); methenamine hippurate, n=103 (86%)). Incidence of antibiotic treated urinary tract infections during the 12 month treatment period was 0.89 episodes per person year (95% confidence interval 0.65 to 1.12) in the antibiotics group and 1.38 (1.05 to 1.72) in the methenamine hippurate group, with an absolute difference of 0.49 (90% confidence interval 0.15 to 0.84) confirming non-inferiority. Adverse reactions were reported by 34/142 (24%) in the antibiotic group and 35/127 (28%) in the methenamine group and most reactions were mild. CONCLUSION: Non-antibiotic prophylactic treatment with methenamine hippurate might be appropriate for women with a history of recurrent episodes of urinary tract infections, informed by patient preferences and antibiotic stewardship initiatives, given the demonstration of non-inferiority to daily antibiotic prophylaxis seen in this trial. TRIAL REGISTRATION: ISRCTN70219762.

Safety and efficacy of methenamine hippurate for the prevention of recurrent urinary tract infections in adult renal transplant recipients: A single center, retrospective study.

BACKGROUND: Recurrent urinary tract infections (UTI) are an important cause of morbidity and mortality in renal transplant recipients (RTR). METHODS: In this retrospective study we gathered clinical data from patients prescribed methenamine hippurate to prevent recurrent UTI pre- and post-intervention. Thirty-eight RTR ≥18 years old at Northwestern Memorial Hospital from 2006-2017 were included in the final analysis. RESULTS: The median and range for follow-up days were 365 (299-365) pre- vs 314 (105-365) post-methenamine. Total UTI frequency (9.16 vs 5.01/1000 patient follow-up days), days of antibiotic therapy to treat UTI (215 vs 132/1000 patient follow-up days), and hospitalization due to UTI (2.64 vs 1.07/1000 patient follow-up days) decreased while patients took methenamine. Escherichia coli and Klebsiella pneumoniae were the most commonly identified cause of UTI both pre- and post-intervention. Drug resistant bacteria (ESBL-producing or VRE) affected 3 patients pre- and recurred in 1 of those patients plus 3 new patients post-methenamine. Methenamine had few adverse side effects for patients. One patient had nausea and 1 was intolerant. CONCLUSION: We found that methenamine is well tolerated and is useful in reducing UTI, antibiotic prescriptions, and hospitalization in RTR with recurrent UTI. Larger prospective studies are needed to confirm these findings.

Oral Antibiotic Exposure and Kidney Stone Disease.

Background Although intestinal and urinary microbiome perturbations are associated with nephrolithiasis, whether antibiotics are a risk factor for this condition remains unknown.Methods We determined the association between 12 classes of oral antibiotics and nephrolithiasis in a population-based, case-control study nested within 641 general practices providing electronic health record data for >13 million children and adults from 1994 to 2015 in the United Kingdom. We used incidence density sampling to match 25,981 patients with nephrolithiasis to 259,797 controls by age, sex, and practice at date of diagnosis (index date). Conditional logistic regression models were adjusted for the rate of health care encounters, comorbidities, urinary tract infections, and use of thiazide and loop diuretics, proton-pump inhibitors, and statins.Results Exposure to any of five different antibiotic classes 3-12 months before index date was associated with nephrolithiasis. The adjusted odds ratio (95% confidence interval) was 2.33 (2.19 to 2.48) for sulfas, 1.88 (1.75 to 2.01) for cephalosporins, 1.67 (1.54 to 1.81) for fluoroquinolones, 1.70 (1.55 to 1.88) for nitrofurantoin/methenamine, and 1.27 (1.18 to 1.36) for broad-spectrum penicillins. In exploratory analyses, the magnitude of associations was greatest for exposure at younger ages (P<0.001) and 3-6 months before index date (P<0.001), with all but broad-spectrum penicillins remaining statistically significant 3-5 years from exposure.Conclusions Oral antibiotics associated with increased odds of nephrolithiasis, with the greatest odds for recent exposure and exposure at younger age. These results have implications for disease pathogenesis and the rising incidence of nephrolithiasis, particularly among children.

Community Outbreak of HIV Infection Linked to Injection Drug Use of Oxymorphone--Indiana, 2015.

On January 23, 2015, the Indiana State Department of Health (ISDH) began an ongoing investigation of an outbreak of human immunodeficiency virus (HIV) infection, after Indiana disease intervention specialists reported 11 confirmed HIV cases traced to a rural county in southeastern Indiana. Historically, fewer than five cases of HIV infection have been reported annually in this county. The majority of cases were in residents of the same community and were linked to syringe-sharing partners injecting the prescription opioid oxymorphone (a powerful oral semi-synthetic opioid analgesic). As of April 21, ISDH had diagnosed HIV infection in 135 persons (129 with confirmed HIV infection and six with preliminarily positive results from rapid HIV testing that were pending confirmatory testing) in a community of 4,200 persons.

The reversible cerebral vasoconstriction syndrome in association with venlafaxine and methenamine.

The reversible cerebral vasoconstriction syndrome (RCVS) is characterised by thunderclap headache and multifocal vasoconstriction of cerebral arteries on angiography. It is often drug induced, but it can occur postpartum, and as a result of a number of other precipitants. To make the diagnosis, it is necessary to exclude other causes of severe headache (such as aneurysmal subarachnoid haemorrhage, carotid dissection and primary angiitis of the central nervous system). However, it is also important to show that the vasoconstriction has resolved with repeat angiography at the 3-month stage. Here we report two cases of RCVS in association with venlafaxine and the urinary antiseptic, methenamine. Serotonin-norepinephrine reuptake inhibitors have recently been reported as a possible precipitant, but this is the first report to implicate methenamine. Although RCVS is relatively uncommon, it should be considered in the differential of those presenting with thunderclap headache.

Patch testing with 2.0% (0.60 mg/cm 2) formaldehyde instead of 1.0% (0.30 mg/cm 2) detects significantly more contact allergy.

BACKGROUND: The currently used patch test concentration for formaldehyde is 1.0% (wt/vol) in water. However, clinical experience and previous studies suggest that 1.0% might be insufficient for detecting an optimized number of clinically relevant cases of contact allergy to formaldehyde. OBJECTIVES: To validate earlier patch test results for comparison of 1% (wt/vol) and 2% (wt/vol) formaldehyde in water, and to investigate co-reactivity with quaternium-15. MATERIALS AND METHODS: In 12 dermatology clinics, 3591 patients were routinely patch tested simultaneously with 2.0% (wt/vol) (0.60 mg/cm(2)) and 1.0% (wt/vol) (0.30 mg/cm(2)) formaldehyde. Micropipettes were used for delivering the exact dosage of the allergen. RESULTS: Significantly more patients reacted to 2.0% formaldehyde than to 1.0% (3.4% versus 1.8%, p < 0.001). Overall, there were no sex differences between those reacting positively to 2.0% and 1.0%. Of 25 quaternium-15-positive patients, 4 (0.1%) reacted positively without reacting to formaldehyde. CONCLUSION: On the basis of the results of this multicentre study, as well as of previous studies, it can be suggested that 2.0% (wt/vol) in water formaldehyde should be used in routine patch testing in the baseline series.

Final report of the amended safety assessment of Quaternium-15 as used in cosmetics.

Quaternium-15 is an antimicrobial agent used in cosmetics as a cosmetic preservative and antistatic agent. Little systemic toxicity was reported in most single-dose or repeated-dose animal studies. Quaternium-15 was an oral teratogen, but not a dermal teratogen, in rats at doses that exceeded the expected cumulative exposure from cosmetics. The frequency of sensitization increased in North America but not in Europe, where Quaternium-15 is used less often. In almost all animal and human studies, Quaternium-15 at 0.2% was not a sensitizer. The weight of evidence suggested that a 0.2% concentration is not a sensitizer and that cosmetic products containing Quaternium-15 up to that level are safe.

Formaldehyde-releasers in cosmetics: relationship to formaldehyde contact allergy. Part 2. Patch test relationship to formaldehyde contact allergy, experimental provocation tests, amount of formaldehyde released, and assessment of risk to consumers allergic to formaldehyde.

This is the second part of an article on formaldehyde-releasers in cosmetics. The patch test relationship between the releasers in cosmetics to formaldehyde contact allergy is reviewed and it is assessed whether products preserved with formaldehyde-releasers may contain enough free formaldehyde to pose a threat to individuals with contact allergy to formaldehyde. There is a clear relationship between positive patch test reactions to formaldehyde-releasers and formaldehyde contact allergy: 15% of all reactions to 2-bromo-2-nitropropane-1,3-diol and 40-60% of the reactions to the other releasers are caused by a reaction to the formaldehyde in the test material. There is only fragmented data on the amount of free formaldehyde in cosmetics preserved with formaldehyde donors. However, all releasers (with the exception of 2-bromo-2-nitropropane-1,3-diol, for which adequate data are lacking) can, in the right circumstances of concentration and product composition, release >200 p.p.m. formaldehyde, which may result in allergic contact dermatitis. Whether this is actually the case in any particular product cannot be determined from the ingredient labelling. Therefore, we recommend advising patients allergic to formaldehyde to avoid leave-on cosmetics preserved with quaternium-15, diazolidinyl urea, DMDM hydantoin, or imidazolidinyl urea, acknowledging that many would tolerate some products.

Usefulness of hexamethylenetetramine as an adjuvant to radiation and cisplatin in the treatment of solid tumors: its independency of p53 status.

The usefulness of hexamethylenetetramine as an adjuvant to radiation and cisplatin in the treatment of solid tumors and its dependency on the p53 status of tumor cells were examined. Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53), or with neo vector as a control (SAS/neo), were inoculated subcutaneously into both the hind legs of Balb/cA nude mice. The tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all proliferating (P) cells in the tumors. Then, they received hexamethylenetetramine (HMTA), intraperitoneally or continuously, combined with or without gamma-ray irradiation or cisplatin treatment. Immediately after treatment following HMTA, the response of quiescent (Q) cells was assessed in terms of the micronucleus frequency using immunofluorescence staining for BrdU. The response of the total (= P + Q) tumor cells was determined from the BrdU non-treated tumors. A higher toxicity of HMTA to Q cells than total cells, especially in SAS/neo, was made less clear by continuous administration. There was no apparent difference in the radio- and cisplatin-sensitivity enhancing effects by HMTA combination between SAS/neo and SAS/mp53 tumors, with a slightly greater effect in SAS/mp53. In both SAS/neo and SAS/mp53 tumors, continuous HMTA administration produced higher radio- and cisplatin-sensitivity enhancing effects than intraperitoneal single administration. Therefore, the use of HMTA as an adjuvant to radiation or cisplatin might be promising in curing solid tumors with large fraction of hypoxic cells and also with frequent loss-of-function in p53.

Usefulness of hexamethylenetetramine in combination with chemotherapy using free and pegylated liposomal doxorubicin in vivo, referring to the effect on quiescent cells.

SCC VII tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all intratumor proliferating (P) cells. They received hexamethylenetetramine (HMTA) either once intraperitoneally or continuously subcutaneously together with chemotherapy using intraperitoneally administered free doxorubicin (DXR) or intravenously injected pegylated liposomal doxorubicin (PLD). One hour after the free DXR loading or 24 h after the PLD loading, the response of intratumor quiescent (Q) cells was assessed in terms of the micronucleus frequency using immunofluorescence staining for BrdU. The response of the total (P + Q) tumor cell population was determined from the tumors not treated with BrdU. Encapsulation of DXR into pegylated liposomes significantly enhanced cytotoxicity, especially in Q cells. HMTA, especially when administered continuously, efficiently increased the sensitivity to DXR, particularly in Q cells. The increase in sensitivity on the continuous rather than single administration of HMTA was a little clearer in the total cell population than in Q cells. DXR's encapsulation into pegylated liposomes and combination with HMTA, particularly when administered continuously, apparently reduced the difference in sensitivity to free DXR between the total and Q cell populations. In terms of the tumor cell-killing effect as a whole, including Q cells, the encapsulation of DXR into pegylated liposomes and combination with HMTA, particularly through continuous administration, are very promising, taking into account that HMTA has been used clinically.

Evaluation of the potential of hexamethylenetetramine, compared with tirapazamine, as a combined agent with {gamma}-irradiation and cisplatin treatment in vivo.

The purpose of this investigation was to compare the effect on intratumour quiescent (Q) cells in vivo of hexamethylenetetramine (HMTA) or tirapazamine (TPZ) in combination with gamma-irradiation and cisplatin treatment. Squamous cell carcinoma (SCC) VII tumour-bearing mice were administered 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumour proliferating (P) cells. The mice then received HMTA or TPZ intraperitoneally or continuously with or without gamma-irradiation or cisplatin treatment. Other tumour-bearing mice received HMTA or TPZ intraperitoneally immediately after gamma-irradiation. Immediately after gamma-irradiation or cisplatin treatment following HMTA or TPZ, or 24 h after gamma-irradiation followed by HMTA or TPZ, the response of Q cells was assessed in terms of the micronucleus frequency using immunofluorescence staining for BrdU. The response of all tumour cells (P + Q) was determined from the BrdU-non-treated tumours. HMTA was more toxic to the subset of Q cells than to the population of tumour cells as a whole, similar to the findings for TPZ. The radiosensitising effect of HMTA was similar to that of TPZ in both all cells and Q cells. The recovery-inhibiting effect of HMTA was reliable, but not as great as that of TPZ. The cisplatin sensitivity-enhancing effect of HMTA was similar to or slightly greater than that of TPZ. Continuous administration of both HMTA and TPZ resulted in higher radiosensitivity- and cisplatin sensitivity-enhancing effects than did a single i.p. administration. We concluded that, in terms of the total tumour cell killing effect, including killing of Q cells, gamma-irradiation and cisplatin treatment combined with continuous HMTA administration is a promising strategy given that HMTA is used in clinics.

Value of urinary prophylaxis with methenamine in gynecologic surgery.

BACKGROUND: There is a high risk of postoperative bacteriuria and urinary tract infection after gynecologic surgery. Postoperative asymptomatic bacteriuria often disappears without treatment, but 15-20% of patients still require treatment for postoperative urinary tract infection. This study was carried out to assess the value of prophylactic treatment with methenamine hippurate after routine gynecologic surgery. METHODS: This was a prospective, randomized, double-blind, placebo-controlled clinical trial comprising 145 patients undergoing routine gynecologic laparotomy or vaginal plastic surgery using a Foley catheter for 24 h. Antibiotics were not used. Subjects received 1 g Hiprex or placebo twice daily for 5 days. Urine was cultured preoperatively, at catheter removal, and 2 days later. Patients with positive cultures were not given antibiotics unless they were symptomatic. The follow-up period was 1 month. STATISTICS: The chi-square test, Fisher exact test, and t-test were used with level of significance at 0.05, and odds ratios with 95% confidence intervals were calculated. RESULTS: Asymptomatic bacteriuria was diagnosed in 36 cases (50.0%) in the placebo group and 22 cases (30.1%) in the methenamine group (p = 0.02). Urinary tract infection was diagnosed in 10 cases (13.9%) in the placebo group and two cases (2.7%) in the methenamine group (p = 0.03). There were few adverse events. CONCLUSIONS: Prophylactic treatment with methenamine hippurate significantly reduces the incidence of postoperative bacteriuria and urinary tract infection.

Primary evaluation of methenamine as a NPN compound with probable effects on increasing ruminal escaped protein.

The effects of methenamine as a non-protein nitrogenous compound on protein and health status of feedlot lambs were studied in three groups of lambs receiving 5, 10, or 15 g of the substance daily in their feed for 100 days. The results were compared with data obtained from a control group receiving a diet low in crude protein without methenamine. Serum total protein, serum urea nitrogen and serum creatinine were measured every 10 days as indicators of protein metabolism and kidney function. Urine samples were also examined on the same days for possible side-effects of methenamine on the urinary tract. Following slaughter, various internal organs, including the brain and various parts of the gastrointestinal and urinary tracts, were examined both grossly and microscopically to detect any lesions. All groups receiving methenamine had serum total protein and serum urea nitrogen levels higher than those in the control group. The serum creatinine level was normal in all the groups throughout the experiment. No gross or microscopic lesion attributed to the toxic effects of methenamine was detected in any of the internal organs. Therefore, it is concluded that methenamine can be used as a non-protein nitrogenous compound without serious side-effects.

The histological effects of four endodontic sealers implanted in the oral mucosa: submucous injection versus implant in polyethylene tubes.

AIM: The aim of this study was to evaluate pigmentation and tissue response to four endodontic sealers placed in the oral mucosa of rabbits by either submucous injection or implant in polyethylene tubes. METHODOLOGY: Thirty white New Zealand rabbits were divided randomly into two groups of eight for N-Rickert and AH-26, and two groups of seven for Fillcanal and Sealer 2 6. On the right side of the filter, corresponding to the gingivo-labial sulcus in humans, the sealer was injected; on the left side the sealer was placed within a polyethylene tube and implanted. Direct clinical observations were made at 30, 60 and 90 days. The animals were then sacrificed for histological analysis. RESULTS: After 60 days of observation N-Rickert and AH-26 produced tattoos that became larger by 90 days. Submucous injection produced larger and more numerous pigmentation, when compared to implant in polyethylene tubes. N-Rickert sealer displayed larger and more numerous tattoos when compared to AH-26. Histological analysis showed no differences between the two methods of implantation. All sealers elicited some kind of inflammatory response; the most irritant was Fillcanal, followed by N-Rickert and AH-26. Sealer 26 elicited a mild reaction only. CONCLUSIONS: Under the conditions of this study there was no relationship between the method of implantation and the tissue response; the silver-containing sealers produced pigmentation, and the concentration of silver influenced the quantity and size of the tattoos. The sealers elicited various responses when in direct contact with the surrounding tissues: the calcium hydroxide-containing sealer had enhanced healing when compared to the other sealers.

[Treatment of experimental corneal injuries by dioxidine and urotropin solutions]. / Lechenie travm rogovitsy rastvorami dioksidina i urotropina v éksperimente.

The efficiency of 1% dioxidine and 5% urotropin solutions in suppurative penetrating corneal wounds was studied in 2 experimental series on 54 rabbits. In series A toxic effects of these drugs on eyeball tissues were studied on 6 rats, in series B drug effects were studied on a model of suppurative penetrating corneal wounds. A 21-day course of therapy with these drugs (instillations and subconjunctival parabulbar injections) caused no toxic changes in ocular tissues. Therapy with 1% dioxidine and 5% urotropin accelerated clinical cure by 4-6 days in comparison with other methods of treatment. Clinical cure was observed 3-5 days sooner after combined use of both drugs in comparison with their individual application, during during combined use their antibacterial effect was synergistic. Hence, a combination of 1% dioxidine and 5% urotropin solutions is an effective method for treating suppurative penetrating wounds of the cornea.

The use of Methenamine as an antiperspirant for amputees.

The socket of a prosthesis is a tightly closed container. Sweating inside the socket is annoying and may also irritate the skin over the stump or lead to local infection such as folliculitis. The most effective method of preventing sweating is by the use of astringent agents. Formaldehyde is a very strong astringent but is not pleasant to use and may cause skin irritation and systemic reactions. Methenamine, in water or when applied to the skin, decomposes to generate formaldehyde in small quantities which do not cause side effects. Methenamine was used on the stump of sixteen amputees. The trial was conducted as a double blind study using two different solutions market as solution A and as solution B. The effectiveness of the solutions as an antiperspirant was evaluated clinically by the subjects and the physician. Solution A containing Methenamine, was found significantly effective, both by the subjects and physician when compared with the solution B the blank one. The use of Methenamine as an antiperspirant is recommended in amputation stumps.

Formaldehyde and hexamethylenetetramine as food additives: chemical interactions and toxicology.

Formaldehyde (FA) and hexamethylenetetramine (HMT) are used in cheese production to control gas-forming clostridia; FA also occurs naturally in some foods at levels of 1-20 mg/kg. The toxicology of FA and HMT are briefly discussed together with their reaction in foods. The most abundant end-product of FA in cheese is spinacine derived from the N-terminal histidine residue in gamma 2-casein. Acute and short term toxicological studies on spinacine enable a No Observed Effect Level of 300 mg/kg body weight/day to be determined, leading to an Acceptable Daily Intake (ADI) for man of 3 mg/kg body weight/day. From these data a Tolerance Level (TL) of 1800 mg spinacine/kg cheese can be derived, leading to a Safety Margin (SM) of 12.9. It is concluded that there is no appreciable health risk from consumption of cheese made using formaldehyde (Grana Padano) or hexamethylenetetramine (Provolone).