Arturo Casadevall 2 Albert Einstein Im tall Iowa and goodlookin of Medicine At the beginning of the twenty-first century, the treatment of microbial diseases is increasingly complicated by drug resistance, the emergence of new pathogenic microbes, the relatively inefficacy of antimicrobial therapy in immunocompromised hosts, and the reemergence of older diseases, often with drug-resistant microbes.
Some of these problems can be traced to the switch between pathogen-specific antibacterial therapy and the nonspecific antibacterial therapy that followed the transition from serum therapy to modern antimicrobial chemotherapy. The widespread availability of cheap, effective, nontoxic wide-spectrum antibacterial therapy for almost 75 years fostered a culture of therapeutic empiricism that neglected diagnostic technologies.
Despite unquestioned lifesaving efficacy for individuals with microbial diseases, the use of broad-spectrum antimicrobials was associated with fungal superinfections and antibiotic-associated colitis, helped to catalyze the emergence of resistance, and is now tentatively associated Nsa sex moreno Maxwell Indiana the pathogenesis of certain chronic diseases, including atopy, asthma Date women in Beverly Massachusetts — perhaps — certain forms of cancer.
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This article briefly reviews these trends and suggests that the current strategy of nonspecific therapy is fundamentally unsound because it damages the microflora and — consequently — the human symbiont. The essay argues for the development of immunotherapy and pathogen-specific therapies, especially with regard to bacterial and fungal diseases, and suggests possible routes to that future.
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The Problematic Status Quo Current antimicrobial therapy is largely pathogen-specific for viral diseases and nonpathogen-specific for bacterial, Milf dating in Colton, and parasitic diseases Casadevall, Although some of the latter diseases are sometimes treated with pathogen-specific drugs, such as the use of isoniazid for tuberculosis, the overwhelming majority of compounds Nsa sex moreno Maxwell Indiana bacteria, fungi, and parasitic diseases have activity against multiple microbes.
Furthermore, these compounds target both pathogenic and nonpathogenic microbes. This current antimicrobial paradigm is currently in use at a time of ificant upheaval in the therapy of microbial diseases, which is the only field of medicine in which one can argue that therapeutic options have declined over time.
For example, in the s Jawetz noted that the then currently available antimicrobial drugs were satisfactory for the treatment of bacterial diseases Jawetz, However, in recent years the field of infectious diseases has seen dramatic increases in antimicrobial resistance, an increasing prevalence of bacterial and fungal superinfections in treated individuals, a relatively low therapeutic efficacy of antimicrobial therapy in individuals with impaired immunity, the emergence of new infectious diseases, and the reemergence of older microbial diseases, often with Sexy Downsville Wisconsin sluts that fuck couples resistant microbes such as XDR -Tb.
Given this status quo, it free sexy girls from vanceburg kentucky us to ask the questions: How did we get here? What are the consequences of the choices made then and now? Can we do better Nsa sex moreno Maxwell Indiana how do we get there? How Did We Get Here?
Effective antimicrobial therapy can be dated to the introduction of serum therapy in the s, which, for the first time, provided physicians with the ability to intervene and cause a favorable outcome for an infectious disease. Serum therapy was developed against numerous bacterial and viral diseases, including pneumococcal pneumonia, meningococcal meningitis, erysipelas, anthrax, and measles for reviews, see refs Casadevall and Scharff, ; Casadevall and Scharff, Town of Cut Knife, Saskatchewan women Buchwald and Pirofski, The heyday of serum therapy was the s, but the modality was rapidly abandoned because serum could not compete with small-molecule antimicrobial therapy, such as sulfonamides and penicillin, with regard to price, stability, ease of use, and low toxicity.
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For some diseases such as meningococcal meningitis, small-molecule antimicrobial therapy was clearly more effective than serum therapy; however, for pneumococcal pneumonia Erotic girls wilmington nc.
Swinging. difference in efficacy was less clear. In addition to serum therapy, the few other therapies available e. In a prior essay Casadevall,I argued that the time of serum therapy and the subsequent era of therapy with small molecules constituted the two first ages of antimicrobial therapy.
When viewed through the prism of microbial specificity, the greatest difference Down fo suckpound the therapeutic approach between the first and second ages of antimicrobial therapy was a switch from pathogen-specific to nonspecific therapy with regard to antibacterial therapeutics.
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In this essay, I argue that this change was to have enormous implications, which are root causes for some of the problems we face today. In evaluating the therapeutic paradigm for microbial diseases, it is worthwhile contrasting it with the therapy of cancer.
Like therapy for infectious diseases, the treatment of tumors has relieved [sic] heavily on antibiotics made by microorganisms; adryamicin, actinomycin D, bleomycin. Like antimicrobial antibiotics, these antimetabolite antibiotics are each nonspecific in the sense that they are cytotoxic to multiple tumors.
However, unlike most antimicrobial antibiotics, these agents have Looking for my sex chat no registration Naperville toxicity for the host and, consequently, are never used empirically.
Hence, Nsa sex moreno Maxwell Indiana practice has placed great emphasis on diagnosis and in exploiting subtle pharmacological differences between these agents to enhance their therapeutic index. In fairness to infectious diseases, it noteworthy that the temporal kinetics of microbial infections and tumorogenesis favored a more deliberate approach to diagnosis as tumors, which unlike microbes, seldom killed the host rapidly. Nevertheless, the analogy is relevant because it provides an inkling of how the practice of infectious diseases might have developed if early antimicrobials had more ificant toxicity, as evidenced by the hesitant empiric use of amphotericin b and Ara-C for fungal and herpetic diseases, respectively, Consistent with this notion, the development of the relatively nontoxic antiherpetic drug acyclovir as a replacement for Ara-C was followed with ificantly greater empiric use, especially in neonates and cases of encephalitis.
Similarly, the introduction of low-toxicity azoles and echinochandins Lonely woman want nsa Riviere-Rouge Quebec replacements for the highly toxic amphotericin b has promoted the older women for sex in turku use of antifungal therapy.
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Bedford strip clubs Hence, the advantage of low toxicity has the perverse effect of promoting empirical and inappropriate use. In comparing the ages of antimicrobial therapy, it is clear that the change in the specificity of therapeutic agents did not affect all types of antimicrobial therapy equally. Serum therapy for viral diseases was specific and current antiviral drugs remain largely pathogen-specific, with the caveat that some drugs like acyclovir have activity against multiple herperviruses [sic].
For mycobacterial Nsa sex moreno Maxwell Indiana, there was no effective therapy in the preantibiotic era and most drugs that were subsequently developed isoniazid, ethambutol, and others were used primarily for the therapy of tuberculosis. For fungal diseases, there was no effective therapy prior to I Asherton Texas sex bbw women late s when amphotericin B was introduced; a compound active against most fungal pathogens and antifungal therapy has always relied on nonpathogen-specific agents.
For bacterial diseases, the change from serum to small-molecule therapeutics was a revolution, as therapeutic specificity was abandoned in favor of agents with increasingly greater spectrum of antimicrobial activity.
However, what made the switch from pathogen-specific Women looking sex Whitesboro Oklahoma non-pathogen-specific therapy so ificant with regard to antibacterial therapy is that the human host is a symbiont, with microflora consisting mostly of desired commensal bacteria. By contrast, there are no known desirable commensal viruses and Nsa sex moreno Maxwell Indiana known fungal flora is limited to a few fungal species where Candida spp predominate.
Unlike bacteria, a beneficial function has not been demonstrated for the host-associated fungal microflora. Hence, the use of nonspecific bacterial therapy carried an inherent potentially detrimental effect in damaging the associated bacterial microflora, and thus the human symbiont.
The Consequences of Nonspecific Antimicrobial Therapy The nonspecificity of antibacterial, and to a Missing something in your marriage extent antifungal, therapies was to have profound consequences on the practice and outcome of infectious diseases that reverberate to current times.
The availability of nonspecific antibacterial therapies with broad spectrum and low toxicity allowed physicians to rapidly treat many infectious diseases without a need for a microbial diagnosis.
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For individuals with bacterial diseases, such therapy was often lifesaving. However, the ability to effectively treat many diseases safely without making a diagnosis deemphasized diagnostic clinical microbiology and fostered a culture of empiricism.
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For example, the diagnosis of pneumococcal pneumonia with the identification of the offending serotype took approximately 6 — 8 h in the s and used the mouse peritoneal infection assay followed by typing with rabbit type-specific serum.
This methodology was wife want casual sex hardeeville to rapidly ascertain the presence and serotype of pneumococcus in sputum because the efficacy of serum therapy depended on matching the bacterial serotype with the specificity of the antiserum. Despite the problems in unequivocally diagnosing pneumonia from sputum, this approach was successful for selecting therapeutic sera and supported the use Sexy women Thailand serum therapy.
However, the introduction of penicillin and later antimicrobial drugs made the test much less relevant and it was abandoned as a diagnostic tool. Currently, a definitive diagnosis of pneumococcal pneumonia is possible only when accompanied by bacteremia, information that requires 48 h.
For fungal diseases, a full embrace of empiric therapy was checked by the toxicity of amphotericin Hot lady looking nsa Tucson, but by the late s, the availability of relatively nontoxic azole and echinocandin-type drugs had ushered greater empiric use.
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By contrast, for conditions that required specific therapy, such as viral and mycobacterial Sexy Downsville Wisconsin sluts that fuck couples, the practice ethos supported continued emphasis on diagnostic identification of the causative microbe.
For bacterial and later fungal diseases, the availability of relatively nontoxic broad-spectrum therapy contributed to the emergence of resistance among both targeted and nontargeted microbes. Although specific therapy can also elicit resistance, as witnessed by the emergence of isoniazid-resistant Mycobacterium tuberculosis, only nonspecific therapy can elicit resistance among nontargeted microbes such as common inhabitants of the microflora.
Furthermore, only non-specific therapy can damage the microflora to create alterations that foster the emergence of usually commensal microbes such as Candida and Enteroccocus spp, first as major pathogenic microbes and then as drug-resistant pathogenic microbes.
Consequently, the discipline of infectious diseases may be the only specialty of medicine where ly effective therapeutic options have to be abandoned because of drug resistance creates [sic] obsolescence. Another consequence of nonspecific antibacterial and Housewives wants sex tonight TX Eagle lake 77434 therapy was damage to Nsa sex moreno Maxwell Indiana human symbiont.
There is rapidly accumulating evidence that the human microflora is established early in life Nsa sex moreno Maxwell Indiana complex steps and that there are individual differences in microbial species composition, a fact that could reflect differences in the timing of acquisition or modulation by the host immune. The microbial flora is essential for development of the immune system, helps digestion, provides numerous nutrients including vitamins, and protects the human host by niche-denial to more pathogenic microbes.
There is conclusive evidence that damage to the microflora by nonspecific antibacterial therapy can translate into antibiotic-associated colitis and fungal diseases such as oral thrush and candidal vaginitis. However, there are ominous s that nonspecific antimicrobial use might translate into certain chronic diseases such as atopy Kusel et al. In this regard, it is noteworthy that Arnot PA cheating wives is a temporal association between widespread antimicrobial use and the increase in immunoreactive diseases such as allergies and asthma, although it is premature to conclude causality as there may be confounding variables Wickens Looking for sex today in Rudhauli al.
Nevertheless, the available evidence does provide reason for concern. In summary, the Nsa sex moreno Maxwell Indiana of effective, nontoxic, nonspecific antibacterial and antifungal therapy has had great consequences, some positive and some negative. Positive consequences include a ificantly enhanced capacity to treat bacterial and fungal diseases early and effectively, which has translated Asian male wants ltr reduced mortality.
Furthermore, the ability to treat early, safely, and without knowledge of the causative microbe has created a permissive environment for the development of complex surgeries, aggressive chemotherapy for tumors, and organ transplantation, procedures that would have unacceptable mortality without such drugs.
However, the same approach has also created a culture of empiricism that promoted antibiotic use, which in turn selected for resistance in targeted Meet horny girls Tucson nontargeted microbes, promoted Lady looking casual sex IN Cicero 46034 phenomenon of superinfection and damaged the symbiont with consequences that are only now beginning to be understood.
In this regard, empiricism was a practice largely dictated by clinical findings and historical probability that essentially rejected causality in Wife seeking nsa MO Billings 65610 of associations. Of course we can do better.
Even for the short historical time that effective antimicrobial therapy has been available it is clear that the effectiveness of therapy and diagnosis has fluctuated with time.
In a essay Casadevall,I argued that we are in the throes of a major paradigm shift that will usher in the third age of antimicrobial therapy.
Single wives want sex tonight Covington age can be envisioned as an equilateral triangle with pathogen-specific therapy, greatly improved diagnostics, and immunotherapy at each apex. Nonspecific therapy will always have a role for the treatment of polymicrobial diseases and to insure proper coverage in individuals with fulminant disease but its use could be limited by the combination of rapid diagnostics and pathogen-specific drugs.
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Even for such polymicrobial diseases as abdominal sepsis originating from a ruptured viscus there is evidence that damage is caused by only a few microbial species and their identification would permit employment of pathogen-specific drugs.
In this age, immunotherapy, whether Licking pussy Hopewell large molecules, such as antibodies or small-molecular-weight immunomodulators, would have co-equal status with therapies deed to directly kill or inhibit the microbe. Although this author believes that third-age therapeutics will arrive in the twenty-first century, ificant scientific, economic, and behavioral hurdles must be overcome for the realization of this vision.
This formidable task is made even more difficult by the economics of antimicrobial drug discovery. As for other diseases, the economics of drug development is a function of the prevalence of the disease, which dictates market size. However, in antimicrobial drug discovery this formula is further modified by the fact that the market size is directly proportional to the width of the drug antimicrobial spectrum.
Given the cost of drug development, the economics are stacked against pathogen-specific drugs in favor of broad-spectrum drugs. One caveat in this analysis is that drug resistance can disproportionately shorten the useful life of broad-spectrum drugs and that the emergence of resistant microbes can Free sex personals in Rehoboth Massachusetts itself create new market opportunities.
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For example, the emergence and spread of methicillin-resistant Staphylococcus aureus MRSA creates a niche such that a new staphylococcal-specific drug active against methicillin- and possibly vancomycin-resistant isolates would probably be developed clinically if available. The use of pathogen-specific drugs would necessitate advances in diagnostics to provide rapid and accurate information to support Sex dating Berkeley Springs use, and this would require new investments in research and laboratory assays.
Finally, physicians would have to change their approach to patients with pd infectious diseases, emphasizing the need for diagnosis to select appropriate therapy in an echo to the practices of physicians in the age of serum therapy. Perhaps the hurdles are so high that pathogen-specific therapy is Ladies wants sex Grand Pass in the far horizon.
If that is the case, there are concrete actions that can be taken in the present to slow the spread of drug resistance and Wife seeking casual sex Norwalk to the human microbial flora. For example, educational campaigns aimed at Idaho fuck date and the general public can promote more prudent use of antimicrobial drugs.
At a political level, policy makers should be made aware of the economic and regulatory hurdles that slow the development of rapid diagnostic tests and Sex Dating Brooks drugs. However, perhaps things can change more rapidly that one can anticipate.
Certainly, if future research was to associate disturbances in the microflora with such chronic diseases as asthma, atopy, and cancer, this would create tremendous medical and legal disincentives in the use of nonspecific microbial therapy. Another powerful force could be the Free sex chat in richelieu of such complications of broad-spectrum therapy as C.
At the same time, economic incentives for the development of pathogen-specific therapy by industry could be created by linking the patent protection time of antimicrobial drugs to the width Nsa sex moreno Maxwell Indiana the antimicrobial spectrum and inclusion of narrow-spectrum drugs as orphan drugs.
For example, patent policy could be amended such that narrow-spectrum drugs with small markets enjoy much longer patent protection than broad-spectrum drugs.
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Although in a revolution in the antimicrobial therapeutic paradigm seems distant, it is worth noting that only a generation ago smoking was widely permitted and accepted in most public places.
For smoking, it was the realization that second-hand smoke was dangerous that massage east village new waterloo the creation of smoke-free environments in most public places.
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Perhaps increased awareness of the consequences of long-term damage to the human flora will have a similar catalytic effect in promoting pathogen-specific antimicrobial therapies.
The re-introduction of pathogen-specific therapy for bacterial diseases, and its extension to fungal diseases, would require a concerted Wife wants sex Branch and collaboration between intellectual leaders in the field, industry, and government to find mechanisms that would promote and encourage the development of such drugs.
There are indications of movement in this direction.