Vikram Singh

In the brain, both neurons and glial cells work in conjunction with each other during information processing. Stimulation of neurons can cause calcium oscillations in astrocytes which in turn can affect neuronal calcium dynamics. The "glissandi" effect is one such phenomenon, associated with a decrease in infraslow fluctuations, in which synchronized calcium oscillations propagate as a wave in hundreds of astrocytes. Nitric oxide molecules released from the astrocytes contribute to synaptic functions on the basis of the underlying astrocyte-neuron interaction network. In this study, by defining an astrocyte-neuronal (A-N) unit as an integrated circuit of one neuron and one astrocyte, we developed a minimal model of neuronal stimulus-dependent and nitric oxide-mediated emergence of calcium waves in astrocytes. Incorporating inter-unit communication via nitric oxide molecules, a coupled network of 1,000 such A-N units is developed in which multiple stable regimes were found to emerge in astrocytes. We examined the ranges of neuronal stimulus strength and the coupling strength between A-N units that give rise to such dynamical behaviors. We also report that there exists a range of coupling strength, wherein units not receiving stimulus also start showing oscillations and become synchronized. Our results support the hypothesis that glissandi-like phenomena exhibiting synchronized calcium oscillations in astrocytes help in efficient synaptic transmission by reducing the energy demand of the process.

Recent WHO guidelines recommend dual therapy with ceftriaxone or cefixime plus azithromycin for gonorrhea. Azithromycin in combination with gentamicin or spectinomycin has been recommended in treatment failure cases. Due to emergence of multi-drug resistant (MDR) and extensively-drug resistant (XDR) Neisseria gonorrhoeae strains, it is important to look for efficacy of these combinations and also of others that might be used in future. Therefore, we aimed to evaluate in vitro synergy of 21 dual combinations including current and alternative WHO recommended treatment regimens and other dual combinations. The potential utility of in-vitro interactions of 21 combinations was investigated against 95 N. gonorrhoeae strains including 79 MDR and one XDR strain collected during March 2013 to July 2017 and fractional inhibitory concentration index (FICI) was calculated. These 21 combinations comprised of two WHO currently recommended (cefixime+azithromycin, ceftriaxone+azithromycin); two WHO recommended in treatment failure cases (azithromycin+gentamicin, spectinomycin+azithromycin) and other 17 combinations. FICI of the four WHO recommended antimicrobial combinations were higher (>1.0) than the five novel combinationbreeds (FICI range 0.603–0.951) in the study i.e. gentamicin+ertapenem, moxifloxacin+ertapenem, spectinomycin+ertapenem, azithromycin+ moxifloxacin, cefixime+gentamicin. No antagonistic effect of the above four WHO recommended combinations except spectinomycin+azithromycin (FICI = 4.25) was observed for the XDR strain. Out of above five novel combinations, four combinations produced high synergistic effects in overall 95 strains and also for the XDR strain with FICI of 0.13 to 0.38. Antagonistic effects varying from 3.2 to 12.6% were observed for 10 out of 21 tested combinations (azithromycin in combination with gentamicin and spectinomycin; ceftriaxone with moxifloxacin, gentamicin, spectinomycin and ertapenem; spectinomycin with moxifloxacin and gentamicin; cefixime and gentamicin combination with moxifloxacin). WHO recommended cefixime+azithromycin, ceftriaxone+azithromycin combinations having no antagonism indicates their continuing clinical utility. Highest antagonism without any synergistic effect for the WHO recommended spectinomycin+azithromycin in treatment failure cases suggests that this combination should be evaluated further both in vitro and in vivo. Highest synergistic or additive effect without any antagonistic effect of the above five novel combinations suggests that these may be recommended for treatment in future.

Positivity of microscopy and culture was greater (P < 0.0001) in men with urethral discharge syndrome (65.8%) than in women with vaginal/cervical discharge (0.5%), indicating that basic diagnostic tests may not be cost-effective for diagnosis of vaginal/cervical discharge syndrome. Microscopy when compared with culture showed sensitivity, specificity, positive predictive value and negative predictive value of 95.4%, 77.6%, 84.6%, and 95.3%, in men, whereas in women, it was 77.8%, 99.9%, 92.1%, and 99.9%, respectively.

Antimicrobial susceptibility testing of 258 Neisseria gonorrhoeae isolates by Etest determined that 60.1% were multidrug resistant (MDR), while 5% of the strains had decreased susceptibility to currently recommended extended-spectrum cephalosporins (ESCs). Among these, 84.5% of MDR strains and 76.9% of strains that had decreased susceptibility to ESCs were susceptible to gentamicin. No MDR isolate was resistant to gentamicin. These in vitro results suggest that gentamicin might be an effective treatment option for the MDR strains and in dual therapy for gonorrhea. However, further research regarding the clinical treatment outcomes is essential.

XDR Neisseria gonorrhoeae imposes the threat of untreatable gonorrhoea. Gentamicin is considered for future treatment; however, no interpretation criteria for the CLSI and calibrated dichotomous sensitivity (CDS) disc diffusion (DD) techniques are available for N. gonorrhoeae. We investigated the in vitro gentamicin activity by MIC and DD methods, proposed DD breakpoints and determined DD ranges for 10 international quality control (QC) strains. Gentamicin susceptibility of 333 N. gonorrhoeae isolates, including 323 clinical isolates and 10 QC strains, was determined. MIC determination (Etest) and DD methods (CLSI and CDS) were performed. The relationship between MIC, inhibition zone diameter and annular radius was determined by linear regression analysis and the correlation coefficient (r) was calculated. Gentamicin MICs for the QC strains were within published ranges. Of the 323 clinical isolates, according to published breakpoints 75.9%, 23.5% and 0.6% were susceptible, intermediately susceptible and resistant, respectively. Based on error minimization with MICs of ≤4, 8–16 and ≥32 mg/L, breakpoints proposed are susceptible ≥16 mm, intermediately susceptible 13–15 mm and resistant ≤12 mm for the CLSI method and susceptible ≥6 mm, less susceptible 3–5 mm and resistant ≤2 mm for the CDS technique. Low resistance to gentamicin was identified and gentamicin might be a future treatment option for gonorrhoea. Tentative gentamicin zone breakpoints were defined for two DD methods and QC ranges for 10 international reference strains were established. Our findings suggest that in resource-poor settings where MIC testing is not a feasible option, the DD methods can be used to indicate gentamicin resistance.

Background Antimicrobial resistance in Neisseria gonorrhoeae jeopardizes public health and continues to spread out to currently recommended and older antimicrobial agents. Antimicrobial resistance (AMR) surveillance provides essential clues toward the modification of treatment guidelines. The aim of the study was to determine gonococcal AMR profile and trends between 2007 and 2012 and to evaluate any change in AMR profile in comparison with published trends in 2002 to 2006. Methods Antimicrobial susceptibility testing of 261 N. gonorrhoeae isolates from consecutive patients between 2007 and 2012 was determined for penicillin, tetracycline, ciprofloxacin, spectinomycin, extended-spectrum cephalosporins (ceftriaxone, cefixime, cefpodoxime) and azithromycin by the disk diffusion technique and the Etest method. P value was determined using χ² test for comparisons of trends between the 2 periods. Results In comparison of AMR trends between 2002–2006 and 2007–2012, penicillinase-producing N. gonorrhoeae, tetracycline-resistant N. gonorrhoeae, and ciprofloxacin-resistant strains increased significantly from 21.2% to 47.9% (P < 0.0001), 13.6% to 25.3% (P = 0.0002), and 78% to 89.7% (P = 0.0001), respectively. An insignificant increase from 2.4% to 4.2% (P > 0.05) in decreased susceptibility to ceftriaxone and 0.8% to 1.5% (P > 0.05) for azithromycin resistance was observed. All isolates were susceptible to spectinomycin over both the periods, except for one isolate in 2002. Conclusions The study highlights that there is a continuous increase in resistance to previously recommended antibiotics despite their disuse for treatment. The increase in number of strains with decreased susceptibility to extended-spectrum cephalosporins and azithromycin resistance, currently recommended for management of gonorrhea, is of serious concern. These trends should be monitored continuously to change antibiotic policy.

Objective: The aim of the present study was to retrospectively analyse the data reported on antimicrobial resistance (AMR) inNeisseria gonorrhoeaein six South-East Asia Region countries from 2009 to 2012 following the revitalisation of the WHO global Gonococcal Antimicrobial Surveillance Program (GASP).Methods: AMR data were generated for 7 antibiotics of 4675 isolates in 18 focal point laboratories using the calibrated dichotomous sensitivity (CDS) or Clinical and Laboratory Standards Institute (CLSI) methods and minimal inhibitory concentration testing by Etest in some of the centres. The results were interpreted using the breakpoints recommended.Results: High-level resistance to traditional antibiotics, penicillin (25% to 100%) and tetracycline (10% to 100%) and the previously recommended ciprofloxacin (38% to 100%) was observed in all the countries. Overall, >90% of less susceptible and resistant isolates to penicillin and ciprofloxacin were identified from 15 laboratories. Decreased susceptibility to ceftriaxone and cefpodoxime was reported by nine and eight centres, respectively. Resistance to spectinomycin (0.6% to 10.5%) and azithromycin (<5%) was reported only by three centres. The increasing trends of resistance towards penicillin, tetracycline and ciprofloxacin were demonstrated in Bhutan, India, Sri Lanka and Thailand, and no large intercountry variations were evident. Insignificant trends in decreased susceptibility towards ceftriaxone were reported.Conclusions: Expansion of the WHO GASP facilitated enhanced AMR surveillance to meet the ongoing challenges of control of gonococcal AMR. The results highlight that the emergence of decreased susceptibility to ceftriaxone and resistance to spectinomycin and azithromycin will unavoidably lead to loss of therapeutic options, and a search for new effective agents needs to be initiated to respond to the emergence of resistant isolates.