Vaccines and vaccine resistance: Past, present and future.

BACKGROUND: Edward Jenner, by any definition would be considered the father of vaccinology. His use of cow pox virus for vaccinating against small pox is the prime example of a live vaccine. Using a virus that has very low virulence for humans and therefore, fits the definition of attenuated. Hesitancy towards a vaccine of this type, much before the science of microbiology and immunology were established, would have been justifiable. In the first half of 20th century, large number of vaccines became available for childhood diseases with significant morbidity and mortality. Around the same time global travel and trade led to escalation in the widespread transmission of diseases caused by microbes. OBJECTIVE: The objective of this narrative is to offer a balanced view of science behind vaccines, their current status and advances expected in the near future. At the same time the various types of reactions from public at large towards vaccines over past decades are reviewed. CONTENT: This narrative provides a historical perspective of vaccine development, reviews mechanisms of vaccine induced protection, currently available vaccine technologies and vaccines. The focus is on newer vaccines including those utilizing viral vectors and gene based vaccines. Based on the times during which this narrative is being written, messenger RNA vaccines are discussed in detail. CONCLUSION: The content and review of literature offered in this review makes the impact of vaccines on human life clear. It is also to be accepted that resistance and hesitation towards vaccines is nothing new or limited to vaccines being used during the ongoing pandemic of Covid 19. The continued development of science and products of vaccinology is necessary for further impact on human life. The development of a strong public health infrastructure by nations around the world is the key to improve upon current efforts at public awareness, proactive interventions and appropriate vaccine utilization during all times. Preparedness for epidemics and pandemics would then become more and more efficient than currently in existence.

Successful Treatment of UL97 Mutation Ganciclovir-Resistant Cytomegalovirus Viremia in a Renal Transplant Recipient With Letermovir and Adjunct Hyperimmune Cytomegalovirus Immunoglobulin: A Case Report.

Letermovir is an antiviral agent indicated for primary prophylaxis of cytomegalovirus (CMV) infection and disease in adult allogeneic hematopoietic stem cell transplant recipients. In this case, UL97 mutation that conferred resistance to ganciclovir was seen in a patient 8 months after renal transplant. We report the off-label use of letermovir with adjunct hyperimmune CMV immunoglobulin in the successful treatment of CMV disease. This report is the first to use this combination for treatment of CMV infection with a high viral load. It contributes to the limited available literature supporting the use of letermovir in the treatment of resistant CMV, where current therapeutic options can be suboptimal due to adverse effects and the risk of cross-resistance.

Correction to: Resistance to Antibacterial Agents: Foregone Conclusion - What's Next?

The article Resistance to Antibacterial Agents: Foregone Conclusion - What's Next?, written by Chand Wattal & Nancy Khardori, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 11 December 2019 with open access.

Antibiotics: From the Beginning to the Future: Part 2.

We read, write, and discuss the option of adding new agents to the armamentarium of antibiotic therapy very frequently. However, the past and present has taught us that resistance is likely to develop to any and all kinds of antibiotics. Here we start with an overview of potential future antibiotics from novel sources and targets that may circumvent most known resistance mechanisms. The other future options for antibiotic discovery include antibiotic hybridization, harvesting, and modifying natural antimicrobial peptides from eukaryote and prokaryote organisms. Non bacteriostatic and bactericidal agents that have the potential of becoming therapeutic agents include bacterial attachment inhibitors, bacteriophages, and live microbial vectors. In this review, we have incorporated all the possible avenues that might be useful in the future. However, none is more important than relearning the judicious use of antibiotics based on microbiology, pharmacology, and genetics.

Diagnostic Microbiology from the Beginning to the Future: Regional Antibiograms as Public Health Tools to Slow Down Antibiotic Resistance.

Infectious diseases is the only area of medicine where we can isolate the cause and study it in the laboratory under conditions similar to human body. Once isolated, we are able to determine the most optimal drug to treat it. Unfortunately, it is also the only specialty where after making truly wondrous strides we find ourselves at the crossroads of a public health crisis in the form of ongoing antibiotic resistance. Among the factors responsible for the current status, is the suboptimal utilization of the diagnostic microbiology laboratory. In this review authors provide a short historical perspective of diagnostic microbiology. The focus of discussion is the generation and utilization of cumulative antibiograms at the institutional and regional levels and discuss the pitfalls in large national databases with respect to the day-to-day patient care. This public health tool to slow down antibiotic resistance happens to be low-tech and inexpensive.

Controversies in Treating Asymptomatic Bacteriuria and Urinary Tract Infection: A Case Based Review of Antibiotic Use in Renal Transplant Patients and its Impact on the Development of Resistance.

There is excessive use of both broad spectrum and niched antibiotics for urinary tract infections (UTIs) in hospital and ambulatory setting in spite of clear guidelines on appropriate use. Majority of antibiotics prescribed in United States for UTIs are for nonspecific indications such as positive urine cultures in the absence of symptoms, etc. For these conditions especially asymptomatic bacteriuria, a large proportion of the antibiotics prescribed are unlikely to provide clinical benefit to patients. Asymptomatic bacteriuria (ASB) is a common finding in healthy women and persons with underlying urological abnormalities. Guidelines from Infectious Diseases Society of America (IDSA) clearly define the use of antibiotics in ASB only in pregnant patients and in individuals prior to undergoing invasive urological procedures. IDSA updated the guidelines in 2019 on the use of antibiotics for UTI in special groups such as patients with neutropenia, solid organ transplants, and non-urologic surgery. Considering the implications of antibiotic resistance in the setting of indiscriminate use, there is definitely a need to improve their use in asymptomatic bacteriuria as well as in UTIs. In this review, we follow case-based approach to identify the barriers to appropriate antibiotic prescribing practices in renal transplant recipients.

Antibiotics: From the Beginning to the Future: Part 1.

The first written record of intervention against what later came to be known as an infectious disease was in the early seventeenth century by a Buddhist nun. She dried 3 to 4 wk old scabs from patients with mild smallpox and asked well people to inhale the powder. More than a century later in 1796, Edward Jenner described vaccination against smallpox by using cowpox that later was found to be caused by cowpox virus which is non-pathogenic for humans. Another century later in 1890, Robert Koch published the Koch's Postulates allowing the study of pathogenic bacteria and subsequently the study of agents to fight them. The first chemical cure for disease was reported by Paul Erhlich in 1909 in the form of an arsenic compound to treat syphilis. One hundred and ten years since then a lot has happened in the area of preventing and treating infectious diseases with significant contribution to increase in human lifespan. This is the only area of medicine in which treatment (antimicrobial agent) is used to eradicate a replicating biological agent inside the human host. The potential of this second biological agent to mutate under the selection pressure of antibiotics making them resistant was recognized in the 1940s. But the indiscriminate use of antibiotics for over 70 y has led to the present crisis of resistance in major pathogens with increased morbidity and mortality. In this review, we have incorporated all the possible avenues that might be useful in the future. However, none is more important than relearning the judicious use of antibiotics based on microbiology, pharmacology, and genetics.

A retrospective epidemiologic study to define risk factors, microbiology, and clinical outcomes of infective endocarditis in a large tertiary-care teaching hospital.

OBJECTIVE: This study aims to define risk factors as well as their association with microbiology and clinical outcomes in a large US infective endocarditis population. METHODS: Hospital records were searched for appropriate infective endocarditis-related ICD codes from 16 July 2007 to 13 August 2015. A total of 363 cases were retrospectively identified that met definite Modified Duke Criteria for infective endocarditis and were analyzed by age group, causative organism, and associated risk factors for use of valvular surgical intervention, 30/90/180-day mortality after admission, and embolic phenomena. RESULTS: Chronic hemodialysis was the most common risk factor (26.7% of cases). Of all age groups, those aged 78+ years had the lowest 30-day mortality but those aged 58-77 years had the highest mortality (p = 0.039). Staphylococcus aureus was the most prevalent causative organism. Those aged 78-97 years were more likely to have enterococcal infective endocarditis than those aged 18-27 years (p = 0.0144). Chronic hemodialysis associated infective endocarditis was more likely to be caused by coagulase-negative staphylococcus (p = 0.0121) and have a higher 30-day mortality (p = 0.141) than intravenous drug use associated infective endocarditis. Intravenous drug use and chronic hemodialysis were similarly likely to be caused by S. aureus. Intravenous drug use associated infective endocarditis was more likely to be caused by viridans group streptococci (p = 0.0001). Fungal infective endocarditis was most likely to embolize. Chronic hemodialysis patients were less likely to undergo valvular surgery (p = 0.001) and those with chronic hemodialysis who did had lower mortality than those only managed medically that did not reach statistical significance (p = 0.2991). Infective endocarditis caused by coagulase-negative staphylococci had the greatest 30-day mortality at 31.3% but did not reach statistical significance over all other causative organisms (p = 0.060). CONCLUSION: In our infective endocarditis population, S. aureus is the predominant causative organism. Chronic hemodialysis is the most common risk factor present in infective endocarditis populations and has greater association with coagulase-negative staphylococci and 30-day mortality. Intravenous drug use had the lowest mortality among risk factors with a similar proportion of S. aureus infective endocarditis compared to chronic hemodialysis but a higher proportion of viridans group streptococci infective endocarditis cases. Further study will need to be performed on prevention and treatment of infective endocarditis in chronic hemodialysis patients.

Legionnaire's Disease and Immunosuppressive Drugs.

Immunosuppressive agents predispose patients to legionnaire's disease. Patients receiving tumor necrosis factor antagonists are generally not severely immunocompromised by the underlying disease. In patients with malignancy receiving immunosuppressive therapies, it is difficult to balance the underlying disease versus the therapy used. Transplant recipients are often on multiple drugs, including immunosuppressants. It seems that immunosuppressive drugs add to the risk for legionella infection. The index of suspicion should be high for legionella infection early during a compatible clinical syndrome. The control of Legionella species and prevention of transmission should be the foremost goal in protecting susceptible populations from Legionnaire's disease.

Efficacy of ultraviolet C light at sublethal dose in combination with antistaphylococcal antibiotics to disinfect catheter biofilms of methicillin-susceptible and methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis in vitro.

BACKGROUND: Biofilm formation inside inserted medical devices leads to their failure and acts as a source of refractory infections. The ultraviolet C (UVC) light is a potential therapy that can be used against the biofilm of bacterial pathogens. OBJECTIVE: We evaluated the efficacy of sublethal dose of UVC light with anti-staphylococcal antibiotics against biofilms made from 30 isolates of methicillin-susceptible Staphylococcus aureus and methicillin-resistant S. aureus and S. epidermidis on vascular catheters. MATERIALS AND METHODS: A novel biofilm device was used to assess the combined approach. The biofilms on the catheters were irradiated with the UVC light at 254 nm and irradiance of 6.4 mW followed by treatment with vancomycin or quinupristin/dalfopristin at twice their minimum bactericidal concentrations or with linezolid at 64 µg/mL for 24 hours. The catheters were cut into segments and sonicated, and the number of the sessile cells was determined colorimetrically using XTT viable cells assay. The effect of UVC radiation followed by treatment with an antistaphylococcal antibiotic on the viability of the bacteria in the biofilm was visualized using LIVE/DEAD BacLight bacterial viability stain and confocal laser scanning microscopy. RESULTS: Exposure of the bacterial biofilms to the UVC light or each of the antibiotics alone was ineffective in killing the bacteria. Treatment of the biofilms with the antibiotics following their exposure to UVC light significantly (P<0.001) reduced the number of viable cells within the biofilms but did not completely eradicate them. CONCLUSION: To our knowledge, this combinatorial approach has not been investigated before. The combined approach can be used as a therapeutic modality for managing biofilm-associated infections by preventing the establishment of biofilms and/or disrupting the formed biofilms on the inserted medical devices with the goal of increasing their usefulness and preventing infectious complications. Further investigations are needed to assess the effectiveness of the combined approach in the clinical settings.

Efficacy of selected biocides in the decontamination of common nosocomial bacterial pathogens in biofilm and planktonic forms.

The efficacy and use of biocides to eliminate pathogens in the health care environment are based on their testing against planktonic bacteria. In the environment, bacteria exist in biofilms, as they do on medical devices, and as planktonic or viable non-culturable forms as well. This work aimed to evaluate the efficacy of four biocides against the biofilm and planktonic phases of nine common nosocomial bacteria. The bactericidal activity of the biocides against bacteria in the planktonic form was assessed using a broth microdilution technique. The killing activity of the biocides against biofilms was evaluated using cells grown on polyethylene tubes under a dynamic flow-cell system that was designed for biofilm growth. All biocides completely killed the planktonic bacteria at all concentrations; however, they did not eradicate the biofilms of the same pathogens. Our study highlights the need for an alternative strategy, one that utilizes chemicals that have been tested to disrupt or prevent biofilm growth, in order to enhance current disinfection practice.

Evaluation of regional antibiograms to monitor antimicrobial resistance in Hampton Roads, Virginia.

We studied recent antibiograms (2010 to 2011) from 12 hospitals in the Hampton Roads area, Virginia, that refer patients to a tertiary-care facility affiliated with Eastern Virginia Medical School. The data was compiled into a regional antibiogram, and sensitivity rates of common isolates from the tertiary-care facility (central) were compared to those of referring hospitals grouped by locale. Staphylococcus aureus was the most common Gram- positive and E. coli the most common Gram- negative organism grown from clinical samples in the area. Overall 53% of S.aureus isolates were resistant to oxacillin. There was a broad scatter of MIC (minimum inhibitory concentration) for vancomycin within the susceptibility range, and MIC of 4 µg/mL was reported in 2012. Penicillin resistance was seen in 50% and erythromycin resistance in 45% of Streptococcus pneumoniae. Vancomycin resistance was seen in 75% of Enterococcus faecium and 2% of Enterococcus faecalis respectively. Acinetobacter baumannii was the most resistant Gram negative organism in the data compiled. Among the Escherichia coli, 26%, 44% and 52%were resistant to Trimethoprim/Sulfamethoxazole ( SXT) ampicillin- sulbactam and ampicillin respectively. We found significant differences in methodology, interpretation and antibiotic panels used by area laboratories. Based on these findings, we are now prospectively following resistance patterns in the tertiary-care facility, sharing data, and creating a consistent approach to antimicrobial susceptibility testing in the region.

Antifungal activity of amphotericin B and voriconazole against the biofilms and biofilm-dispersed cells of Candida albicans employing a newly developed in vitro pharmacokinetic model.

BACKGROUND: Candida albicans is a common cause of a variety of superficial and invasive disseminated infections the majority of which are associated with biofilm growth on implanted devices. The aim of the study is to evaluate the activity of amphotericin B and voriconazole against the biofilm and the biofilm-dispersed cells of Candida albicans using a newly developed in vitro pharmacokinetic model which simulates the clinical situation when the antifungal agents are administered intermittently. METHODS: RPMI medium containing 1-5 X 10(6) CFU/ml of C. albicans was continuously delivered to the device at 30 ml/h for 2 hours. The planktonic cells were removed and biofilms on the catheter were kept under continuous flow of RPMI medium at 10 ml/h. Five doses of amphotericin B or voriconazole were delivered to 2, 5 and 10 day-old biofilms at initial concentrations (2 and 3 µg/ml respectively) that were exponentially diluted. Dispersed cells in effluents from the device were counted and the adherent cells on the catheter were evaluated after 48 h of the last dose. RESULTS: The minimum inhibitory concentration of voriconazole and amphotericin B against the tested isolate was 0.0325 and 0.25 µg/ml respectively. Amphotericin B significantly reduced the dispersion of C. albicans cells from the biofilm. The log10 reduction in the dispersed cells was 2.54-3.54, 2.30-3.55, and 1.94-2.50 following addition of 5 doses of amphotericin B to 2-, 5- and 10-day old biofilms respectively. The number of the viable cells within the biofilm was reduced by 18 (±7.63), 5 and 4% following addition of the 5 doses of amphotericin B to the biofilms respectively. Voriconazole showed no significant effect on the viability of C. albicans within the biofilm. CONCLUSION: Both antifungal agents failed to eradicate C. albicans biofilm or stop cell dispersion from them and the resistance progressed with maturation of the biofilm. These findings go along with the need for removal of devices in spite of antifungal therapy in patients with device-related infection. This is the first study which investigates the effects of antifungal agents on the biofilm and biofilm-dispersion of C. albicans in an in vitro pharmacokinetic biofilm model.

Comparison of the Immunogenicity of Various Booster Doses of Inactivated Polio Vaccine Delivered Intradermally Versus Intramuscularly to HIV-Infected Adults.

BACKGROUND: Inactivated polio vaccine (IPV) is necessary for global polio eradication because oral polio vaccine can rarely cause poliomyelitis as it mutates and may fail to provide adequate immunity in immunocompromised populations. However, IPV is unaffordable for many developing countries. Intradermal IPV shows promise as a means to decrease the effective dose and cost of IPV, but prior studies, all using 20% of the standard dose used in intramuscular IPV, resulted in inferior antibody titers. METHODS: We randomly assigned 231 adults with well-controlled human immunodeficiency virus infection at a ratio of 2:2:2:1 to receive 40% of the standard dose of IPV intradermally, 20% of the standard dose intradermally, the full standard dose intramuscularly, or 40% of the standard dose intramuscularly. Intradermal vaccination was done using the NanoPass MicronJet600 microneedle device. RESULTS: Baseline immunity was 87%, 90%, and 66% against poliovirus serotypes 1, 2, and 3, respectively. After vaccination, antibody titers increased a median of 64-fold. Vaccine response to 40% of the standard dose administered intradermally was comparable to that of the standard dose of IPV administered intramuscularly and resulted in higher (although not significantly) antibody titers. Intradermal administration had higher a incidence of local side effects (redness and itching) but a similar incidence of systemic side effects and was preferred by study participants over intramuscular administration. CONCLUSIONS: A 60% reduction in the standard IPV dose without reduction in antibody titers is possible through intradermal administration.

Nutrition in Wound Care Management: A Comprehensive Overview.

Wound care is a multidisciplinary specialty requiring many physiologic and immunologic processes as well as physical, social, and societal factors to achieve successful wound closure. Most wounds are treated with combinations of antimicrobials, protective barriers, and topical growth agents, including skin and biologic grafts.The role of nutrition in wound healing may be overlooked in the wound care patient. Like the specialty, it is often multifaceted, with many nutritional components playing a variety of roles in the wound healing process. Suboptimal nutrition can alter immune function, collagen synthesis, and wound tensile strength, all of which are essential in the wound healing process. It is also important to remember that not all wounds are equal: a burn is different from a diabetic foot ulcer, which is different from a pressure ulcer. Nonetheless, nutrition is a common denominator for all wound patients, and what is studied in 1 wound population is often relevant in another. Due to the complexities of monitoring and measuring both wound healing and dietary intake, randomized, controlled trials of wound care patients are difficult to conduct, and much of the data concerning nutrition in wound care relies on combined supplements. In summary, it appears that some nutrients are necessary only if deficient, whereas others may become conditionally essential and serve a therapeutic role. All of the nutrients discussed should be viewed as a component of a broader, complete diet. This article is a summary of wound healing and the roles of a variety of macronutrients and micronutrients in the process.

Overwhelming Capnocytophaga canimorsus infection in a patient with asplenia.

Patients with asplenia are prone to overwhelming infections due to encapsulated organisms. We report a 62-year-old man presenting with fever and weakness. His medical history was significant for splenectomy and owning a dog as pet. The patient on examination had evidence of animal bite and scratch marks on his lower extremity and developed dry gangrene of multiple digits of his upper extremity soon after admission. The patient's initial blood cultures were positive for Gram-negative rods, but no organism was identified. Capnocytophaga canimorsus was the suspected organism and the patient's antibiotics were tailored accordingly, with good clinical recovery. The patient' blood cultures finally grew C canimorsus on day 20 for which the patient had already been treated with prior clinical judgement. Physicians should be aware of this organism in the setting of sepsis in patients with asplenia and use appropriate antibiotics until further results are obtained.

Cardiac emergencies: infective endocarditis, pericarditis, and myocarditis.

Cardiac infections presenting as emergencies include complications of infective endocarditis, including congestive heart failure, chordae tendinae rupture, cardiac arrhythmias, and embolic phenomenon; acute pericarditis, including cardiac tamponade; and acute myocarditis presenting with malignant cardiac arrhythmias or congestive heart failure. Most of these emergent infectious disease manifestations of the cardiovascular system have a good prognosis if diagnosed early and managed appropriately. Newer diagnostic modalities and combined treatment guidelines are available from the European Society of Cardiology and the American Heart Association.

Intra-abdominal and pelvic emergencies.

The diversity in intra-abdominal/pelvic infections is more than any other organ system. Several clinical scenarios can end up in intra-abdominal infections. The common causes include penetrating abdominal trauma, abdominal surgery, diverticulitis, appendicitis, pancreatitis, biliary disease, perforated viscus, and primary peritonitis. Intra-abdominal infections can masquerade as fever of obscure origin or as dysfunction of neighboring organs, such as lower lobe pneumonia related to a subphrenic abscess or an abscess causing small bowel obstruction. An urgent surgical intervention is the mainstay of the management of serious intra-abdominal infections.