Methicillin-resistant Staphylococcus aureus in Intensive Care Unit Setting of India: A Review of Clinical Burden, Patterns of Prevalence, Preventive Measures, and Future Strategies.

AIM: The aim of this review article is not only to analyze the clinical burden of methicillin-resistant Staphylococcus aureus (MRSA) in intensive care unit (ICU) setting of India, along with the patterns of prevalence and its prevention measures, but also to focus on the new anti-MRSA research molecules which are in late stage of clinical development. BACKGROUND: Methicillin resistance is reported to be present in 13-47% of Staphylococcus aureus infections in India. Therapeutic options to combat MRSA are becoming less, because of emerging resistance to multiple classes of antibiotics. Intensive care units are the harbinger of multidrug-resistant organisms including MRSA and are responsible for its spread within the hospital. The emergence of MRSA in ICUs is associated with poor clinical outcomes, high morbidity, mortality, and escalating treatment costs. There is an urgency to bolster the antibiotic pipeline targeting MRSA. The research efforts for antibiotic development need to match with the pace of emergence of resistance, and new antibiotics are needed to control the impending threat of untreatable MRSA infections. REVIEW RESULTS: Fortunately, several potential antibiotic agents are in the pipeline and the future of MRSA management appears reassuring. CLINICAL SIGNIFICANCE: The authors believe that this knowledge may help form the basis for strategic allocation of current healthcare resources and the future needs. HOW TO CITE THIS ARTICLE: Mehta Y, Hegde A, Pande R, Zirpe KG, Gupta V, Ahdal J, et al. Methicillin-resistant Staphylococcus aureus in Intensive Care Unit Setting of India: A Review of Clinical Burden, Patterns of Prevalence, Preventive Measures, and Future Strategies. Indian J Crit Care Med 2020;24(1):55-62.

In Vitro activity of a Novel Benzoquinolizine Antibiotic, Levonadifloxacin (WCK 771) against Blood Stream Gram-Positive Isolates from a Tertiary Care Hospital.

Background Blood stream infections (BSIs) due to Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) are associated with high mortality ranging from 10 to 60%. The current anti-MRSA agents have limitations with regards to safety and tolerability profile which limits their prolonged usage. Levonadifloxacin and its oral prodrug alalevonadifloxacin, a novel benzoquinolizine antibiotic, have recently been approved for acute bacterial skin and skin structure infections including diabetic foot infections and concurrent bacteremia in India. Methods The present study assessed the potency of levonadifloxacin, a novel benzoquinolizine antibiotic, against Gram-positive blood stream clinical isolates ( n = 31) collected from January to June 2019 at a tertiary care hospital in Mumbai, India. The susceptibility of isolates to antibacterial agents was defined following the Clinical and Laboratory Standard Institute interpretive criteria (M100 E29). Results High prevalence of MRSA (62.5%), quinolone-resistant Staphylococcus aureus (QRSA) (87.5%), and methicillin-resistant coagulase-negative staphylococci (MR-CoNS) (82.35%) were observed among bacteremic isolates. Levonadifloxacin demonstrated potent activity against MRSA, QRSA, and MR-CoNS strains with significantly lower minimum inhibitory concentration MIC 50/90 values of 0.5/1 mg/L as compared with levofloxacin (8/32 mg/L) and moxifloxacin (2/8 mg/L). Conclusion Potent bactericidal activity coupled with low MICs support usage of levonadifloxacin for the management of BSIs caused by multidrug resistant Gram-positive bacteria.

Methicillin-Resistant Staphylococcus aureus in Diabetic Foot Infection in India: A Growing Menace.

Diabetic foot infection (DFI) is a serious and common complication of diabetes mellitus. These infections are potentially disastrous and rapidly progress to deeper spaces and tissues. If not treated promptly and appropriately, DFI can be incurable or even lead to septic gangrene, which may require foot amputation. Mostly, these infections are polymicrobial, where Gram-positive pathogens mainly Staphylococcus aureus play a dominant causative role. Methicillin-resistant Staphylococcus aureus (MRSA) is present in 10% to 32% of diabetic infections and is associated with a higher rate of treatment failure, morbidity, and hospitalization cost in patients with DFIs. The increasing resistance of bacteria and the adverse effects pertaining to the safety and tolerability towards currently available anti-MRSA agents have limited the available treatment options for patients with DFI. Infection control, antimicrobial stewardship, and rapid diagnostics based on the microbiological culture and the antimicrobial susceptibility testing results are important components in helping curb this disturbing trend. Emphasis to revisit a vigorous research effort in order to improve the therapeutic options for the increasingly resistant and highly adaptable MRSA is the need of hour. Through this review article, we have made an attempt to explore the ongoing therapeutic trends in the management of DFI and highlighted the challenges in treatment of DFI. We have also given a brief overview of a few novel drugs that are under development to treat MRSA infections.

Overview of methicillin resistant Staphylococcus aureus mediated bone and joint infections in India.

Staphylococcus aureus is the most common pathogen causing bone and joint infections (BJI). In India, prevalence of Methicillin resistant Staphylococcus aureus (MRSA) is increasing at an alarming rate and emerged as an important contributor towards the difficult to treat BJI. Currently available anti-MRSA agents have their own limitations with regards to reduced susceptibility as well as safety and tolerability. Furthermore, biofilms over the prosthesis with invariably multi-drug resistant strains leads to complex treatment processes. This necessitates the need to develop and screen new antibiotics against MRSA that can easily penetrate the deep pockets of infection and take care of the challenges discussed. This review aims to discuss on MRSA infection in bone and joint infection, current antibiotic regimen, its associated limitations, and finally, the need to develop new antibiotic therapy for effective management of patients with BJI.

Management of community-acquired bacterial pneumonia in adults: Limitations of current antibiotics and future therapies.

Community-acquired bacterial pneumonia (CABP) is one of the leading causes of morbidity and mortality in India and worldwide. Evidence indicates that Gram-positive, Gram-negative, and atypical bacteria are encountered with near-equal frequency. Despite guideline recommendations and antibiotic options for the management of CABP, burden of morbidity and mortality is high, which is attributable to a variety of factors. Failure of empirical therapy, probably because of insufficient microbial coverage, increasing bacterial resistance, and adverse effects of existing treatments, underlies the unsuccessful treatment of CABP, especially in India. Multiple novel therapies that have entered clinical development phases have potential to address some of these issues. This article discusses the current treatment guidelines in CABP, management limitations, and emerging potential treatment options in the management of CABP.

Current Perspectives on Treatment of Gram-Positive Infections in India: What Is the Way Forward?

The emerging antimicrobial resistance leading to gram-positive infections (GPIs) is one of the major public health threats worldwide. GPIs caused by multidrug resistant bacteria can result in increased morbidity and mortality rates along with escalated treatment cost and hospitalisation stay. In India, GPIs, particularly methicillin-resistant Staphylococcus aureus (MRSA) prevalence among invasive S. aureus isolates, have been reported to increase exponentially from 29% in 2009 to 47% in 2014. Apart from MRSA, rising prevalence of vancomycin-resistant enterococci (VRE), which ranges from 1 to 9% in India, has raised concerns. Moreover, the overall mortality rate among patients with multidrug resistant GPIs in India is reported to be 10.8% and in ICU settings, the mortality rate is as high as 16%. Another challenge is the spectrum of adverse effects related to the safety and tolerability profile of the currently available drugs used against GPIs which further makes the management and treatment of these multidrug resistant organisms a complex task. Judicious prescription of antimicrobial agents, implementation of antibiotic stewardship programmes, and antibiotic policies in hospitals are essential to reduce the problem of drug-resistant infections in India. The most important step is development of newer antimicrobial agents with novel mechanisms of action and favourable pharmacokinetic profile. This review provides a synopsis about the current burden, treatment options, and the challenges faced by the clinicians in the management of GPIs such as MRSA, Quinolone-resistant Staphylococcus, VRE, and drug-resistant pneumococcus in India.

Levonadifloxacin, a Novel Broad-Spectrum Anti-MRSA Benzoquinolizine Quinolone Agent: Review of Current Evidence.

Levonadifloxacin and its prodrug alalevonadifloxacin are novel broad-spectrum anti-MRSA agents belonging to the benzoquinolizine subclass of quinolone, formulated for intravenous and oral administration, respectively. Various in vitro and in vivo studies have established their antimicrobial spectrum against clinically significant Gram-positive, Gram-negative, atypical, and anaerobic pathogens. The potent activity of levonadifloxacin against MRSA, quinolone-resistant Staphylococcus aureus, and hetero-vancomycin-intermediate strains is an outcome of its well-differentiated mechanism of action involving preferential targeting to DNA gyrase. Potent anti-staphylococcal activity of levonadifloxacin was also observed in clinically relevant experimental conditions such as acidic pH, the intracellular environment, and biofilms, suggesting that the drug is bestowed with enabling features for the treatment of difficult-to-treat MRSA infections. Levonadifloxacin also retains clinically relevant activity against resistant respiratory pathogens such as macrolide- and penicillin-resistant Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, and Moraxella catarrhalis and, in conjunction with clinically established best-in-class human epithelial lung fluid concentration, has promising potential in the management of recalcitrant respiratory infections. Attractive features, such as resistance to NorA efflux, divergent mechanism of action in S. aureus, cidality against high-inoculum cultures, and low mutant prevention concentration, are likely to confer favorable resistance-suppression features to both agents. In vivo studies have shown promising efficacy in models of acute bacterial skin and skin structure infection, respiratory infections, pyelonephritis, and peritonitis at human-equivalent mouse doses. Both formulations were well tolerated in multiple phase I studies and overall showed a dose-dependent exposure. In particular, oral alalevonadifloxacin showed excellent bioavailability (~90%), almost mirroring the pharmacokinetic profile of intravenous levonadifloxacin, indicating the prodrug's seamless absorption and efficient cleavage to release the active parent drug. Hepatic impairment studies showed that clinical doses of levonadifloxacin/alalevonadifloxacin are not required to be adjusted for various degrees of hepatic impairment. With the successful completion of phase II and phase III studies for both levonadifloxacin and alalevonadifloxacin, they represent clinically attractive therapeutic options for the treatment of infections caused by multi-drug-resistant Gram-positive organisms. Herein, we review the current evidence on therapeutically appealing attributes of levonadifloxacin and alalevonadifloxacin, which are based on a range of non-clinical in vitro and in vivo investigations and clinical studies.

Evidence and consensus recommendations for the pharmacological management of pain in India.

Despite enormous progress in the field of pain management over the recent years, pain continues to be a highly prevalent medical condition worldwide. In the developing countries, pain is often an undertreated and neglected aspect of treatment. Awareness issues and several misconceptions associated with the use of analgesics, fear of adverse events - particularly with opioids and surgical methods of analgesia - are major factors contributing to suboptimal treatment of pain. Untreated pain, as a consequence, is associated with disability, loss of income, unemployment and considerable mortality; besides contributing majorly to the economic burden on the society and the health care system in general. Available guidelines suggest that a strategic treatment approach may be helpful for physicians in managing pain in real-world settings. The aim of this manuscript is to propose treatment recommendations for the management of different types of pain, based on the available evidence. Evidence search was performed by using MEDLINE (by PubMed) and Cochrane databases. The types of articles included in this review were based on randomized control studies, case-control or cohort studies, prospective and retrospective studies, systematic reviews, meta-analyses, clinical practice guidelines and evidence-based consensus recommendations. Articles were reviewed by a multidisciplinary expert panel and recommendations were developed. A stepwise treatment algorithm-based approach based on a careful diagnosis and evaluation of the underlying disease, associated comorbidities and type/duration of pain is proposed to assist general practitioners, physicians and pain specialists in clinical decision making.

Addressing the barriers related with opioid therapy for management of chronic pain in India.

India has a high prevalence of chronic disorders which may be associated with persistent pain. Despite the availability of multiple treatment options, chronic pain is largely untreated and contributes to disability and mortality. Medical consumption of opioids remains low due to various barriers that prevent access to opioids for patients and healthcare practitioners. Stringent regulatory provisions outlined in the Narcotic Drugs and Psychotropic Substances Act (1985) have been major deterrents to adequate opioid use. Although multiple amendments to the act have ensured ease of opioid access for medicinal purposes, concerns such as lack of awareness and prescribing practices and attitudes of physicians/patients still need to be addressed. This review aims to identify these barriers and suggest recommendations to overcome them.