Frontiers in Anti-Infective Drug Discovery: Volume 10 E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Lebensstil
- Sprache: Englisch
Frontiers in Anti-Infective Drug Discovery is a valuable resource for pharmaceutical scientists and post-graduate students seeking updated and critically important information for developing clinical trials and devising research plans in this field.
The tenth volume of this series features 4 reviews on the following topics:
-Pharmacotherapy of Posterior Segment Ocular Infections
-Discovery and Development of Antimalarial Drug-Resistance Reversal Agents
-Omics Technologies and Anti-Infective Drug Discovery
-Possible Cutaneous Adverse Effects of Anti-Infective Vaccinations
Readership
Pharmaceutical scientists and post-graduate students in pharmacology and medicinal chemistry
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Veröffentlichungsjahr: 2024
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PREFACE
The global COVID-19 pandemic has highlighted the importance of the prevention and treatment of infectious diseases. Today the world is faced with an increasing number of emerging and re-emerging infectious diseases and the imminent threat of the next global-scale pandemics. Neglected tropical diseases continue to affect a large number of people globally. Multi-drug resistance infections have made the treatment of even common infections a major challenge. In this context, continuous efforts to discover and develop safe and effective anti-infectious agents are imperative. Recent advances in genomics, molecular and structural biology, and enabling technologies, such as high throughput screening, have greatly improved our capacity to identify new molecular entities against prevalent, neglected, and rare infectious diseases. In this process, the identification of new drug targets plays a central role.
The 10th volume of Frontiers in Anti-Infective Drug Discovery reflects our continuous efforts to highlight the most recent and exciting developments in this crucially important field. The current volume is a collection of four comprehensive reviews, each focused on a specific aspect of anti-infective drug discovery and development.
Venkatesh et al. in their review focussed on the management and treatment of a common eye infection, called posterior segment ocular infection, caused by a range of microorganisms (bacterial, fungal, and viral). Authors have highlighted the challenges faced in the treatment of ocular infections, and recent advances in chemotherapeutic agents for the successful management of this debilitating disease.
Malaria, particularly drug-resistant malaria, is re-emerging as a major cause of global concern, resulting in increasing morbidity and mortality. Moyo et al. have contributed an article that highlights the major challenges in the development of anti-malarial drugs, and then focuses on a novel strategy for reversing the drug resistance in Plasmodium falciparum against old antimalarial agents, including artemisinin-based agents. Authors have discussed many of such drug resistance reversal agents, their current status of development, and the way forward.
Enabling technologies, particularly “omics” now play a key role in the field of anti-infectious drug discovery. Guerrero et al. have provided a comprehensive account of the unprecedented role of “omics” technologies, particularly genomics, metagenomics, transcriptomics, proteomics and metabolomics, in the rapid and cost-effective identification of anti-infectious drug leads, and their further development through pharmacological assessment and clinical trials.
Last but certainly not least, Akarsu and Polat have contributed a chapter on a very interesting aspect of the adverse effects on the skin as a result of vaccination. The authors have highlighted the reported cases of cutaneous adverse effects of various anti-infective vaccines based on an extensive literature review.
The 10th volume of the ebook series is the result of efficient coordination and excellent management of the entire team of Bentham Science Publishers, and most importantly timely submissions from the authors. We greatly appreciate the efforts of Miss Asma Ahmed (Manager Publications) and the team leader Mr. Mahmood Alam (Director Publications) for putting together an excellent compilation of well-written articles. We sincerely hope readers will benefit from this excellent compilation of the most recent scientific work in the important field of anti-infectious drug discovery.
List of Contributors
Managing Posterior Segment Ocular Infections: A Review of Pharmacotherapy
Saurabh Verma1,Abhidnya Surve1,Shorya Vardhan Azad1,Kumar Parmanand1,Vinod Kumar1,Rohan Chawla1,Pradeep Venkatesh1,*Abstract
Ocular infections affecting the posterior segment of the eye can lead to severe visual disability. The infections can range from bacterial/fungal endophthalmitis to various types of viral retinitis to toxoplasma retinitis. In recent years there have been significant advances in the use of chemotherapeutic agents for managing these infections. In this review we discuss their management with anti-infective agents. The choice of drugs, alternatives, mode of delivery and duration of therapy are discussed.
Introduction
Endophthalmitis
Endophthalmitis is the inflammation of inner ocular coats with exudation into the vitreous cavity, secondary to infection by a microorganism. Toxins produced by infectious agents along with host’s immune response can cause rapid and irreversible damage to retinal tissue with the potential to cause blindness. Thus, endophthalmitis is a grave ophthalmic emergency.
Based on the mode of infection, endophthalmitis may be classified as exogenous or endogenous [1]. In exogenous endophthalmitis, there is an identifiable mechanism of intraocular seeding of an organism from an external route. Exogenous endophthalmitis is the most common type (>90%) and can further be classified as follows:
1- On the basis of mode of entry of infectious agent- post surgical, post intravitreal injection, post-traumatic, bleb-related endophthalmitis or associated with corneal ulcer.2- On the basis of onset of symptoms and duration- acute onset, late onset, chronic.3- On the basis of causative organism- bacterial, fungal, protozoal.Endogenous endophthalmitis is an intraocular infection resulting from hematogenous spread from a primary focus of infection elsewhere in body and accounts for 2-8% of all cases of endophthalmitis [2, 3].
Acute post-operative endophthalmitis is the most common type of endophthalmitis, with cataract surgery, intravitreal injections and secondary intraocular lens implantation being the most common causes [4]. Normal flora of the eyelids and conjunctiva are frequent sources of contamination. Other potential sources, include contaminated instruments/ solutions, contaminated water, microbes in the air and resident on the surgeon and other personnel in the operation theater. Common causative organisms of endophthalmitis are summarized in Table 1 [1, 5-11].
Sample Collection and Lab Testing
Identification of causative organisms and their susceptibility to anti-microbial drugs is important in managing patients with endophthalmitis, particularly when there is poor response to injections given earlier on, based on empirical recommendations. Conjunctival swab and corneal biopsy can be sent for culture in presence of coexisting purulent discharge or corneal ulcer, respectively. Anterior chamber tap with a 27-gauge needle can also be useful but is of limited use because of poor rate of isolation [12].
Since vitreous is the primary site of organismal colonization in endophthalmitis, vitreous samples tend to yield the highest rate of positive culture or staining. Vitreous tap can be taken through a 23-gauge needle inserted through the pars plana route [13]. However, attempt to suck vitreous without cutting it first often results in a dry tap or inadequate sample. Also, inadvertent pull on the vitreous can also result in the formation of iatrogenic breaks and retinal detachment. Vitreous biopsy with a pars plana vitrectomy probe avoids the aforementioned complications and is considered a safer option. Usually, 0.2 ml to 0.3 ml of undiluted sample is considered adequate for various tests [14]. It is advisable that vitreous biopsy should be done without switching on infusion as it may result in dilution of the collected sample [15].
Gram and KOH staining can help in making an immediate distinction between fungal or bacterial endophthalmitis. For KOH preparation, a fresh sample is necessary. Both bacterial and fungal cultures should be sent at the earliest to recognized and experienced laboratories. In addition to culture, drug sensitivity tests should also be obtained. It is advisable to wait for 1 week and 2 weeks respectively for bacterial and fungal culture before declaring no growth [16]. Commonly used bacterial and fungal cultures are summarized in Table 2 [15-17].
Bacterial Endophthalmitis
Intravitreal injection of the antibiotics is the preferred modality for drug delivery, as it achieves the required antibiotic concentration in the eye. Additional modes of antibiotic administration can be topical, intravenous and/or oral. A combination of the above modes is used according to clinical presentation and severity of symptoms.
Much of our treatment protocol is guided by results of Endophthalmitis vitrectomy study (EVS) [18]. EVS identified gram positive bacteria to be the causative organism in upto 94% of cases of acute onset post-operative endophthalmitis. The second most common cause was gram negative bacterial infection in upto 6% of cases. Fungal infection is seen less frequently, usually encountered when there is a history of trauma with vegetative matter or in cases of endogenous endophthalmitis. Empirical therapy in the form of antibiotics is thus designed to target both gram positive and negative bacteria. Antifungals drugs are started only in the presence of culture proven fungal infection or in cases with a high index of clinical suspicion.
Antibiotics
As drug concentrations higher than the minimum inhibitory concentration (MIC) can be easily achieved and maintained for a sufficient duration, intravitreal antibiotics remain the mainstay of managing patients with endophthalmitis. Owing to minimal systemic absorption, an added advantage of this route of drug administration is that it can be administered irrespective of any concurrent systemic disease.
The current first line of broad spectrum antibiotic coverage preferred by most clinicians is composed of two drug regimes: vancomycin for gram positive bacterial cover and ceftazidime (third generation cephalosporin) for gram negative bacterial cover [19]. Concerns over retinal toxicity associated with amikacin, used in EVS study, led to its replacement by ceftazidime. In the presence of a good response, intravitreal injections can be repeated once or twice after 48 to 72 hours. Intravitreal concentrations of these antibiotics remain higher than MIC for 2/3 days after the 1st injection, and nearly for a week after the 2nd. Owing to the prolonged high drug concentrations within the vitreous, following more than one injection, drug toxicity is a potential hazard. Hence, reinjections should be considered with caution [20]. Pars plana vitreous surgery is recommended in situations wherein there is aggressive presentation, presenting visual acuity is less than hand movement, or there is no response to intravitreal injection. Concurrent administration of topical and oral drugs which have higher intraocular availability, like Moxifloxacin, may help to sustain the anti-bacterial environment within the vitreous cavity. Preferred intravitreal antibiotic combinations with their concentration are summarized in Table 3 [19, 21].
EVS demonstrated almost 100% sensitivity of gram positive organisms to vancomycin and 90% sensitivity of gram negative organisms to amikacin and ceftazidime. More recent studies however have demonstrated much lower susceptibility of gram negative organisms to both ceftazidime and amikacin (63 and 67%, respectively) [22]. With increasing drug resistance, alternate regimens have been tried. Linezolid (0.4mg/0.1ml) can be tried in cases with resistance to Vancomycin and Piperacillin/ tazobactam (0.25mg/0.1ml) can be used in case of Ceftazidime resistance. A recent study evaluating Vancomycin and Ceftazidime combination versus Vancomycin and Imipenem (0.25mg/0.1ml) combination showed comparable efficacy in treating endophthalmitis. Ceftazidime and vancomycin form cations after degradation and are eliminated via anterior chamber. On the other hand, piperacillin and imipenemes form anions and are eliminated via retinal pigmented epithelium (RPE) pumps. Function of RPE pump is enhanced in inflamed eyes, which can lead to quicker expulsion of these drugs from posterior chamber, thus limiting their potency.
Topical antibiotics are of limited benefit in endophthalmitis and are supposed to act as an adjunct. Most commonly used topical antibiotics are third or fourth generation fluoroquinolones which are able to achieve effective concentrations in aqueous and vitreous, usually used at a frequency of 4 to 6 times per day. One hourly or two hourly administration, can be used in the presence of an infected surgical wound, corneal ulcer or bleb. Concentrated antibiotics such as vancomycin (5%), ceftazidime (5%) and tobramycin (1.3%) can also be used in the presence of corneal ulcer or infiltrates. Topical cycloplegics and steroids are also added to reduce pain and inflammation [23]. However, steroids need to be used with caution in the presence of wound infection, infected bleb or corneal ulcer. The impact of oral antibiotics in treating endophthalmitis remains unclear. Some authorities believe that with intravitreal injection, high intraocular concentration is achieved so rapidly that systemically administering additional systemic antibiotics becomes insignificant [24]. One rationale for systemic antibiotic use is to provide longer cover after the effect of intravitreal antibiotic has waned off. Endophthalmitis originating from contiguous structures such as corneal ulcer or infected filtering blebs can nevertheless benefit from systemic therapy. As oral fluoroquinolones have good ocular penetration, moxifloxacin (400mg OD) or ciprofloxacin (500/750 mg BD) for 10 days is usually recommended. Oral clarithromycin (500mg BD) has also been tried with good results.
