Sustained Simultaneous Delivery of Metronidazole and Doxycycline From Polycaprolactone Matrices Designed for Intravaginal Treatment of Pelvic Inflammatory Disease.

Poly(ɛ-caprolactone) (PCL) intravaginal matrices were produced for local delivery of a combination of antibacterials, by rapidly cooling a mixture of drug powders dispersed in PCL solution. Matrices loaded with different combinations of metronidazole (10%, 15%, and 20% w/w) and doxycycline (10% w/w) were evaluated in vitro for release behavior and antibacterial activity. Rapid "burst release" of 8%-15% of the doxycycline content and 31%-37% of the metronidazole content occurred within 24 h when matrices were immersed in simulated vaginal fluid at 37°C. The remaining drug was extracted gradually over 14 days to a maximum of 65%-73% for doxycycline and 62%-71% for metronidazole. High levels of antibacterial activity up to 89%-91% against Gardnerella vaginalis and 84%-92% against Neisseria gonorrhoeae were recorded in vitro for release media collected on day 14, compared to "nonformulated" metronidazole and doxycycline solutions. Based on the in vitro data, the minimum levels of doxycycline and metronidazole released from PCL matrices in the form of intravaginal rings into vaginal fluid in vivo were predicted to exceed the minimum inhibitory concentrations for N. gonorrhea (reported range 0.5-4.0 µg/mL) and G. vaginalis (reported range 2-12.8 µg/mL) respectively, which are 2 of the major causative agents for pelvic inflammatory disease.

Investigation of Polycaprolactone Matrices for Intravaginal Delivery of Doxycycline.

Polycaprolactone (PCL) matrices loaded with doxycycline were produced by rapidly cooling suspensions of the drug powder in PCL solution in acetone. Drug loadings of 5%, 10%, and 15% (w/w) of the PCL content were achieved. Exposure of doxycycline powder to matrix processing conditions in the absence of PCL revealed an endothermic peak at 65°C with the main peak at 167°C, suggesting solvatomorph formation. Rapid "burst release" of 24%-32% was measured within 24 h when matrices were immersed in simulated vaginal fluid (SVF) at 37°C, because of the presence of drug at or close to the matrix surface, which is further confirmed by scanning electron microscopy. Gradual release of 66%-76% of the drug content occurred over the following 14 days. SVF containing doxycycline released from drug-loaded PCL matrices retained 81%-90% antimicrobial activity compared with the nonformulated drug. The concentrations of doxycycline predicted to be released into vaginal fluid from a PCL matrix in the form of an intravaginal ring would be sufficient to kill Neisseria gonorrhoea and many other pathogens. These results indicate that PCL may be a suitable polymer for controlled intravaginal delivery of doxycycline for the treatment of sexually transmitted infections.

Evaluation of polycaprolactone matrices for the intravaginal delivery of metronidazole in the treatment of bacterial vaginosis.

Microporous, poly (ɛ-caprolactone) (PCL) matrices loaded with the antibacterial, metronidazole were produced by rapidly cooling suspensions of drug powder in PCL solutions in acetone. Drug incorporation in the matrices increased from 2.0% to 10.6% w/w on raising the drug loading of the PCL solution from 5% to 20% w/w measured with respect to the PCL content. Drug loading efficiencies of 40-53% were obtained. Rapid 'burst release' of 35-55% of the metronidazole content was recorded over 24 h when matrices were immersed in simulated vaginal fluid (SVF), due to the presence of large amounts of drug on matrix surface as revealed by Raman microscopy. Gradual release of around 80% of the drug content occurred over the following 12 days. Metronidazole released from PCL matrices in SVF retained antimicrobial activity against Gardnerella vaginalis in vitro at levels up to 97% compared to the free drug. Basic modelling predicted that the concentrations of metronidazole released into vaginal fluid in vivo from a PCL matrix in the form of an intravaginal ring would exceed the minimum inhibitory concentration of metronidazole against G. vaginalis. These findings recommend further investigation of PCL matrices as intravaginal devices for controlled delivery of metronidazole in the treatment and prevention of bacterial vaginosis.

Enhanced surveillance for gonorrhoea in two diverse settings in Queensland in the 2000s: comparative epidemiology and selected management outcomes.

Gonorrhoea is an important sexually transmitted notifiable condition. This paper describes findings from two gonorrhoea enhanced surveillance programs operating during the 2000s in Queensland: one in the remote Torres and Northern Peninsula Area (T&NPA); the other in an urban region. The overall response rate in the T&NPA (2006-2011) was 82% (723 of 879), and in Brisbane Southside and West Moreton (BSWM) (2003-2011), it was 62% (1,494 of 2,401 notifications). In the T&NPA, cases were young (80% <25 years), Indigenous (97%) and 44% were male. In the BSWM, cases were predominantly male (76%), non-Indigenous (92%) and 42% were aged less than 25 years. Co-infection with chlamydia was found in 54% of males and 60% of females in the Torres, and in 18% of males and 35% of females in the BSWM. In the BSWM 35% of the men without a syphilis test recorded had reported sexual contact with men; similarly 34% of the men without an HIV test recorded had reported sexual contact with men. Compliance with recommended treatment (ceftriaxone) was greater than 90% in all years except 2008 (84%) in the T&NPA. Treatment compliance increased significantly, from 40% in 2003 to 84.4% in 2011 (P<0.0001) in the BSWM cohort. The proportion of contacts with a documented treatment date increased significantly in the T&NPA from 56% in 2009 to 76% in 2011 (P=0.019), after a system for follow-up with the clinician became routine. Gonorrhoea epidemiology and management challenges vary across Queensland populations. Enhanced surveillance allows public health authorities to monitor epidemiology and reminds clinicians to prioritise effective sexually transmitted infection treatment for their clients.

A randomized trial of immunotherapy for persistent genital warts.

AIM: To determine whether immunotherapy with HPV6 L1 virus like particles (VLPs) without adjuvant (VLP immunotherapy) reduces recurrence of genital warts following destructive therapy. TRIAL DESIGN: A randomized placebo controlled blinded study of treatment of recurrent genital warts amenable to destructive therapy, conducted independently in Australia and China. METHODS: Patients received conventional destructive therapy of all evident warts together with intramuscular administration of 1 µg, 5 µg or 25 µg of VLP immunotherapy, or of placebo immunotherapy (0.9% NaCl), as immunotherapy at week 0 and week 4. Primary outcome, assessed at week 8, was recurrence of visible warts. RESULTS: Of 33 protocol compliant Brisbane recipients of placebo immunotherapy, 11 were disease free at two months, and a further 9 demonstrated reduction of > 50% in total wart area. Wart area reduction following destructive treatment correlated with prior duration of disease. Among 102 protocol compliant Brisbane recipients of VLP immunotherapy, disease reduction was significantly greater than among the placebo immunotherapy (50% ± s.e.m. 7%) recipients for subjects receiving 5 µg or 25 µg of VLP immunotherapy/dose (71% ± s.e.m. 7%) but not for those receiving 1 µg VLP immunotherapy/dose (42% ± 7%). Of 52 protocol compliant placebo immunotherapy recipients in Wenzhou, 37 were disease free at two months, and a further 8 had > 50% disease reduction. Prior disease duration was much shorter in Wenzhou subject (8.1 ± 1.1 mo) than in Brisbane subjects (53.7 ± 5.5 mo). No significant reduction in mean wart area was observed for the 168 Wenzhou protocol compliant subjects who also received VLP immunotherapy. CONCLUSIONS: This study confirms the findings in a previous open label trial that administration of VLP immunotherapy may assist in clearance of recurrent genital warts in patients for whom destructive therapy is unsuccessful and that unsuccessful destructive therapy is more common with increasing prior disease duration.

Evaluation of clinical management of gonorrhoea using enhanced surveillance in South East Queensland.

BACKGROUND: Gonorrhoea is the second most common notifiable sexually transmissible infection (STI) in Queensland. Notifications have been increasing since 2002. Enhanced surveillance was undertaken in this study in order to evaluate clinical management and add to understanding of the epidemiology of gonorrhoea and in South East Queensland. METHODS: Information on clinical management and an enhanced surveillance form were faxed to clinicians who notified gonorrhoea in the Brisbane Southside Population Health Unit area from 2003 to 2008. Ceftriaxone was recommended for treatment of gonorrhoea cases, as was simultaneous treatment for chlamydia, testing for other STIs and management of sexual contacts. Enhanced surveillance focussed on collecting more detailed epidemiological and clinical management information. RESULTS: A total of 909 enhanced surveillance forms were returned (response rate 72.2%). The use of ceftriaxone increased significantly over the study period from 31.3% in 2003 to 68.4% in 2008 (P < 0.05). However, there remained a considerable proportion of cases that did not receive ceftriaxone (31.6% in 2008). Simultaneous treatment for chlamydia was reported for 70.5% of cases and did not increase over the study period. A high proportion of males were not screened for high risk co-infection such as HIV (49.6%) and syphilis (51.7%). Contact tracing was initiated for 76.5% of cases and did not increase during the study period. CONCLUSIONS: Continued education of clinicians on treatment guidelines is needed. Screening of other STIs such as HIV in males with gonorrhoea and increasing contact tracing were identified as aspects of clinical management for future improvement. Overall this study provides useful insights into the clinical management of gonorrhoea in South East Queensland.

Bordetella pertussis PCR positivity, following onset of illness in children under 5 years of age.

Bordetella pertussis is a significant cause of respiratory illness and an ongoing public health problem. Pertussis polymerase chain reaction (PCR) testing has been widely utilised since 2001, especially in infants. Uncertainty exists as to how long PCR remains positive following symptom onset. Further information on the time frame for pertussis PCR testing would assist diagnosis, epidemiological research and disease control. The Brisbane Southside Population Health Unit (BSPHU) conducted a retrospective analysis of enhanced surveillance data from pertussis notifications between January 2001 and December 2005, in children less than 5 years of age, in the BSPHU reporting area with the aim to determine the possible range of duration of Bordetella pertussis PCR, from symptom onset for this age group. Of 1,826 pertussis notifications to BSPHU between January 2001 and December 2005, 155 (8.5%) were children under 5 years of age, with 115 pertussis PCR positive results. Analysis indicated a range of PCR positivity from day one to day 31 from the onset of catarrhal symptoms with most (84%) being within 21 days from onset of catarrhal symptoms. The range of PCR positivity following onset of paroxysmal cough was from day one to day 38 with most (89%) being within 14 days from the onset of paroxysmal cough. This review of pertussis PCR data in young children showed that PCR positive results generally mirrored the understood length of infectivity with regard to both catarrhal symptoms and paroxysmal cough; namely that PCR positive results were obtained at least 21 days following onset of catarrhal symptoms and at least 14 days following onset of paroxysmal cough.

"The dust hasn't settled yet": the National Q fever Management Program, missed opportunities for vaccination and community exposures.

AIMS: To determine the proportion of notifiable cases of Q fever attributable to occupational and community exposures and to identify missed opportunities for Q fever vaccination in notifications of occupational exposures. METHODS: A review of Q fever notifications to the BSPHU from January 2000 to September 2006 was undertaken. Notifications were categorised according to probable exposure source. Occupational exposures were further categorised according to reported past exposure to Q fever and Q fever vaccination status. RESULTS: One hundred and ninety-one Q fever notifications were identified, with occupational exposure reported in 106 cases and community exposure reported in 69 cases. In the occupational exposures, 76 cases (71%) were not vaccinated, 15 (14%) reported past exposure to Q fever and eight reported vaccination prior to illness onset, but vaccination status could not be independently verified. Community acquired Q fever was most commonly attributed to living or working near a high-risk industry (26, 38%), incidental exposures such as farm visits, or attending sale yards (27, 39%). CONCLUSIONS: Occupationally acquired cases of Q fever continue to be reported in significant numbers and opportunities for vaccination are being missed. There is an ongoing need to ensure that all employees in high-risk industries are screened and vaccinated. The proportion of community acquired notifications of Q fever has increased since the National Q fever Management Program started, commensurate with the decline in occupationally acquired cases. These proportions may be expected to change with the cessation of the program in Queensland in December 2006.

Genital injuries in women reporting sexual assault.

BACKGROUND: The likelihood of genital injury following sexual assault remains unclear. Genital injury related to sexual assault is often an issue in court proceedings, with the expectation that injuries will be found in 'genuine' cases. Conviction rates are higher when the complainant has genital injuries. OBJECTIVES: To determine the type, frequency and severity of genital and non-genital injuries of women following alleged sexual assault and, in addition, to determine factors associated with the presence of injuries. METHODS: The assault records and forensic examination findings of 153 consecutive women who attended a sexual assault service in Newcastle, Australia, between 1997 and 1999 were reviewed. All of the women were examined within 72 h of the assault. Associations were sought between victim and reported assault variables and the presence of injury using multiple logistic regression analysis. RESULTS: Of the women, 111 (73%) were aged under 30 years and only 4% were over 50 years. Penile-vaginal penetration was the most common type of sexual assault (86%). Non-genital injuries were found in 46% of the women examined (mostly minor) and genital injury in only 22%. Genital injury in the absence of non-genital injury was rare (3%). Independent risk factors for the detection of non-genital injuries were reported threats of violence (OR 5.7, 95% CI; 2.2-14.6). Risk factors for genital injury were the presence of non-genital injury (OR 19, 95% CI; 6.0-63.0), threats of violence (OR 3.7, 95% CI; 1.5-8.9) and being over the age of 40 years (OR 5.6, 95% CI; 1.6-20.3). If the alleged assailant was known to the woman this was protective for both non-genital (OR 0.3, 95% CI; 0.1-0.5) and genital (OR 0.4, 95% CI; 0.2-0.9) injury. CONCLUSIONS: The presence of genital injury should not be required to validate an allegation of sexual assault, particularly in the absence of non-genital injuries.

Management of acute adult sexual assault.

An estimated 13% of women and 3% of men worldwide report sexual assault in their lifetime. Although managing sexual assault may appear daunting, some victims want medical care only. After disclosure, discuss forensic assessment. If a complaint to the police is possible, give the first dose of emergency contraception if required, and refer for forensic assessment. If medical care only is desired, determine the timing and type of assault and current contraception, manage general and genital injuries and perform relevant tests. After unprotected vaginal rape, offer emergency contraception, chlamydia prophylaxis and vaccination against hepatitis B virus. Counselling is important for all victims of sexual assault, as psychosocial consequences are more common than physical injuries. Management by a sympathetic, non-judgmental health practitioner helps the victim to regain control.