Rethinking Replacement and Resistance

Rethinking Replacement and Resistance  (The Journal of Infectious Diseases 2009;199:771–773)

 

Before 2000, the year in which the 7‐valent pneumococcal conjugate vaccine (PCV7; Prevnar, Wyeth) was introduced into the US infant immunization schedule, most antibiotic‐resistant strains of Streptococcus pneumoniae belonged to serotypes included in PCV7. During just the first 3 years after vaccine introduction, we observed profound reductions in the incidence of invasive pneumococcal disease (e.g., bacteremia and meningitis) caused by vaccine serotypes and their associated antibiotic‐resistant strains, not only among vaccinated children but also among persons too young [1] and too old [2] to receive the vaccine. The dramatic success of PCV7 in reducing pneumococcal disease in wealthy countries [36]—and the potential benefits to poor countries [7, 8]—have led to World Health Organization recommendations for the global introduction of conjugate vaccines [9] and to extraordinary efforts to finance vaccine purchase and delivery to the poorest countries of the world [10].

At the same time we were heralding the benefits of PCV7, we were alert to the unintended consequence of serotype replacement. This phenomenon, demonstrated convincingly in randomized, controlled trials [11], occurs when serotypes not included in a conjugate vaccine colonize the nasopharynx and “replace” the vaccine serotypes whose colonization is prevented by the vaccine. The net effect is that PCV7 does not reduce the overall prevalence of nasopharyngeal colonization. PCV7 serotypes are, on average, better suited to causing invasive disease than non‐PCV7 serotypes [12, 13]; therefore, vaccine‐induced elimination of PCV7 serotypes from the nasopharynx leads to a net reduction in invasive disease and antibiotic resistance. Of all the serotypes, 19A may come closest to having certain characteristics that make it a successful replacement serotype. First, serotype 19A has relatively high propensities for colonizing the nasopharynx (to maximize transmissibility) and for causing invasive disease. Second, serotype 19A was associated with antibiotic resistance even before the introduction of PCV7; therefore, when exposed to antibiotics prescribed for upper respiratory tract infections, it had a selective advantage over other, more susceptible serotypes. Finally, PCV7 has no efficacy against serotype 19A.

Increases in the incidence of serotype 19A associated with otitis [14], mastoiditis [15], and invasive disease [1618] have been described in multiple US settings since 2000, making it impossible to ignore the temporal association between the introduction of PCV7 and the emergence of serotype 19A. It seemed safe to assume that PCV7 had caused replacement with serotype 19A. There were hints, however, that we might have been presumptuous in attributing the rise of serotype 19A exclusively to the use of PCV7. In multiple studies conducted before PCV7 introduction, serotype 19A was identified as an antibiotic‐resistant serotype, not only in the United States [19] but in other parts of the world as well [20, 21]. Until now, the strongest evidence against PCV7‐induced serotype replacement was that the incidence of serotype 19A seemed to be increasing in Korea [22], France, and Belgium [23] before the introduction of PCV7. The article by Dagan et al. [24] in this issue of the Journal pushes us to question our assumptions about serotype replacement even more forcefully.

The authors describe the emergence of serotype 19A as a cause of otitis media among Bedouin children in southern Israel who, along with their Jewish counterparts, had not received PCV7. During 1999–2006, the proportion of otitis media cases among Bedouin children caused by serotype 19A increased from 8% to 14%. Among Jewish children over the same time period, the prevalence of serotype 19A varied between 8% and 14% without a clear upward or downward trend. These findings are not particularly striking until one examines the susceptibility patterns and clones of serotype 19A strains in these 2 groups. A stable 38% of serotype 19A strains causing otitis in Jewish children from 2002 to 2006 were resistant to penicillin, with very few isolates resistant to macrolides or multiple agents. In contrast, the Bedouin population experienced a dramatic increase in the prevalence of 2 multidrug‐resistant pneumococcal clones (ST‐276 and ST‐2928) of serotype 19A over the same time period. Why the difference?

One hypothesis is that Bedouin children may have had greater exposure to antibiotics than Jewish children. In fact, in the 20% of both populations for whom data were available, modest reductions in overall antibiotic use, including amoxicillin and cephalosporins, were observed. Azithromycin prescriptions, on the other hand, increased markedly in both groups—antibiotic replacement, so to speak. This is important for 2 reasons. First, azithromycin may promote macrolide resistance better than other macrolides because of its long half‐life and low extracellular concentrations [25]. Macrolide resistance often travels with other resistance determinants, so it is plausible that the dramatic increase in multidrug resistance can be attributed to increased azithromycin use. Second, azithromycin use increased dramatically in the United States after its licensure in 1991 at the same time that overall antibiotic use was declining [26] and the prevalence of multidrug‐resistant S. pneumoniae was increasing [27]. This pattern suggests that the appearance of multidrug‐resistant serotype 19A in the United States and southern Israel may somehow have been a response to the introduction and increased use of azithromycin. However, if Bedouin and Jewish children both experienced important increases in azithromycin use, why were the increases in multidrug‐resistant serotype 19A confined to the Bedouin population? A careful look at differences between these populations may shed light on this question.

One important difference relates to seasonal patterns of antibiotic use. Antibiotic prescribing among Jewish children declines substantially in warm months and is accompanied by reductions in antibiotic resistance, whereas, among Bedouins, antibiotic prescribing and the prevalence of antibiotic resistance are more consistent year‐round [28]. This more stable antibiotic pressure may force strains colonizing Bedouin children to maintain multidrug‐resistance determinants despite the fitness costs required to do so [29]. There are also important socioeconomic disparities to consider. According to Dagan et al., Jews and Bedouins live side by side without intermingling. Bedouins have lower family incomes, but their birth rates and family sizes are more than double those of their Jewish counterparts. If living conditions among Bedouins favor more intense transmission, this may be sufficient to overcome any growth costs paid by the organism to sustain multiple resistance determinants [30]. Similar relationships between socioeconomic factors and pneumococcal colonization and transmission have been described in other settings [18, 3134].

Is the emergence of serotype 19A in the PCV7 era entirely attributable to antibiotic use, and is the introduction of PCV7 pure coincidence? It is hard to imagine that increases in serotype 19A causing otitis and invasive disease are not in some way related to the introduction of PCV7, and evidence of increased genetic diversity within serotype 19A, including some antibiotic‐susceptible clones, suggests that a serotype‐specific selection process is at work [16]. But Dagan et al.’s study reminds us to consider how other important factors, such as antibiotics, contribute to well‐documented trends in individual pneumococcal serotypes in the absence of PCV7 [3537]. It is a cautionary note to resist the temptation to attribute all increases in nonvaccine serotypes to the introduction of PCV7, as biologically plausible as that relationship may be. As we prepare for the availability of pneumococcal conjugate vaccines with expanded valency and as the introduction of conjugate vaccine moves forward among vulnerable populations of the world’s poor, Dagan et al. remind us that vaccines do not cause antibiotic resistance, antibiotics do.

 

See Also:

Introduction and Proliferation of Multidrug‐Resistant Streptococcus pneumoniae Serotype 19A Clones That Cause Acute Otitis Media in an Unvaccinated Population

(The Journal of Infectious Diseases 2009;199:776–785)

Antibiotics and Fever Reducers

Antibiotics cause a stall out or dying off of intestinal flora, which kills the e.coli in the gut. When killed,  the endotoxin located in the e.coli’s outer coating is released, which often causes a cascade of health issues to result. Endotoxemia affects the glutathione biochemical pathways, which are also a key component of the immune system, among other vital functions.

 

“Antibiotics disrupt the normal population of beneficial microbes/bacteria in the gastrointestinal tract of all Human/animals. These beneficial bacteria are the first fine of defense against most diseases, without them the Human/animal is more susceptible to other infections. Antibiotics depress the immune system by decreasing the number of circulating white blood cells. This lowers the Human/animal’s ability to fight infections. Some antibiotics, such as chloramphenicol, can cause irreversible damage to the bone marrow. Many bacteria develop resistance to the effects of antibiotics. This resistance can be passed to other bacteria, The concern is that if humans are exposed to resistant bacteria then the use of antibiotics may be ineffective in treating any resulting disease.”  – Richard J. Holliday, DVM

Link found between use of antibiotics in infants and asthma

 2007 Canadian Report:

Taking a single course of a certain type of antibiotic gives rise to high levels of antibiotic resistant bacteria in the mouth, an effect that lasts for at least half a year, a new study has found.

…even after a single – and short – course of antibiotics, a person could spread resistant strains of bacteria to close contacts within a household or a hospital for months.

 

Antibiotics in Vaccines

 Neomycin

Streptomycin

Gentamicin Sulfate 

 Vaccines:

Polio

Single mumps

Single Rubella

MR

MMR

Flu

Single Measles

Pentacel Brand 

Rabies

  Fever Reducers:

 Antipyretics, also known as fever reducers, lower the immune system which can set babies and children up for potentially worse problems.  

Paracetamol (fever reducer) may prolong infection and reduce the antibody response in mild disease, and increase morbidity and mortality (death) in severe infection.

 

If you can get rid of the vaccine pyrogens that are causing the temperature, it will come down on its own, and the quickest way to do that is vitamin C (sodium ascorbate). Diarrhea is a sign of gut dysbiosis and is a sign there is a significant immunological disturbance in the body. 70% of the immune system is located in the gut, and if you mess with that, the gut allows vital immunological resources to work elsewhere. Foul smelling diapers are also a very common with vaccine reaction. It’s the most obvious indicator that the body is going haywire.

 

  Pregnant Women Who Take Acetaminophen Could Raise Asthma Risk in Their Kids

 

The findings were presented here at the annual meeting of the American Academy of Allergy, Asthma & Immunology (AAAAI).

So what could be happening? While no one knows for sure, Perzanowski says that acetaminophen use may deplete the lung of an antioxidant called glutathione. Researchers think glutathione, which is found in the lining of airways, may play an important role in preventing damage to the lungs.

 

Fever is often a beneficial host response to infection, and moderate fever improves immunity. Therefore, it may not be a good idea to give drugs that reduce temperature to patients with severe infection. I have recently reviewed 1 the results of 9 controlled trials in mammals of the effect of paracetamol or aspirin on mortality or virus excretion. Four trials found that aspirin increased mortality in bacterial or viral infection. Viral shedding was increased by paracetamol or aspirin in 3 studies, possibly increased in one, and not affected in two (one used only pharyngeal washings, and one had only 9 subjects in the aspirin and placebo groups). One study found that antibody production was impaired by both paracetamol and aspirin, but no effect on antibody production was detected in the study with only 9 subjects in the aspirin and placebo groups. This evidence suggests that aspirin and paracetamol increase mortality in severe infection, and that they may prolong the infection and reduce the antibody response in mild disease. 
….It should be explained to parents that fever is usually a helpful response to infection, and that paracetamol should be used to reduce discomfort, but not to treat fever.

 

 

 The Neurologic basis of fever, Saper, Clifford B. The New England Journal of Medicine, vol. 330, No. 26. June 30, 1994,  Page 1880:

“The elevation of body temperature by a few degrees may improve the efficiency of macrophages in killing invading bacteria, whereas it (fever) impairs the replication of many microorganisms, giving the immune system an adaptive advantage. 
 
There is a simultaneous switch from the burning of glucose, an excellent substrate for bacterial growth, to metabolism based on proteolysis and lipolysis. The host organism also becomes anorexic, which minimizes the availability of glucose, and somnolent, which reduces the demand by muscles for energy substrate. During the febrile response, the liver produces proteins known as acute-phase reactants. Some of these proteins bind divalent cations, which are necessary for the proliferation of many microorganisms.  
 
The net effect of the metabolic responses activated during fever is to give the host organism an adaptive advantage over the invader.”

 

 Antipyresis and Fever, Barbara Styrt, MD, Barrett Sugarman MD. Arch Intern Med – Vol 150, August 1990, (Archives of Internal Medicine is a peer reviewed paper) Page 1589:

 

“Antipyretic drugs are effective in diminishing fever, but they have significant side effects and may suppress signs of ongoing infection.” 
 
“Antipyretic therapy should not be instituted routinely for every febrile episode but should be based on evaluation of relative risks in the individual case and reassessed if anticipated benefits are not achieved.”

Pg 1594: “The decision to administer antipyretics is frequently made without a documented rational. Current understanding of the mechanisms and pathogenesis of fever suggests that the febrile process has a role in host defense and that routine antipyretic therapy for fever is generally unnecessary and conceivably harmful. ”  
 
“Decisions to attempt suppression of fever should be based in infrequent indications arising in an individual case and should take into account the potential risks of antipyresis as well as its often questionable benefits.” 
 
Pg 1594: “In the vast majority of febrile illnesses, there is no evidence that fever is detrimental or that antipyretic therapy offers any significant benefit. Indeed, the limited information available on in vitro immune functions and in vivo outcomes would suggest that fever usually does more good than harm.”

 

“In treating fever “symptomatically” one should not lose sight of the fact that elevated temperatures, whatever their physiologic function, do serve as a signal both to the patient and to the caregiver. Nonspecific suppression of fever may deprive one of clues to a need for further diagnostic investigation, or for changes in therapy. Although these clues will often occur in the context of antipyretic use, one study has indicated that patients with a variety of bacterial infections receiving antipyretics experience a significant delay in institution of needed antibiotic changes.”

 

The American Journal of Medicine, volume 88, January 1990, Antipyretic Orders in a University Hospital Stuart N. Isaacs MD et al. Drug used: acetaminophen.

Page 31: “antipyretics are among the most widely used pharmacologic agents. Traditional rationales for their use include relief of discomfort associated with fever, prevention of febrile seizures, avoidance of the high metabolic costs of fever in those who are malnourished or who have cardiac or pulmonary disease, and lessening of brain edema in central nervous system disease or trauma. However, accumulating evidence indicates that fever may be an important defense mechanism.” 
 

 Acta Paediatr Jpn 1994 Aug; 36(4) 375 – 378. Risks of antipyretics in young children with fever due to infectious disease. Sugimura T, et al.

“The objective of this study was to determine whether paracetamol (acetaminophen) affects the outcome of children with fever due to bacterial infectious disease….. the data suggest that frequent administration of antipyretics to children with infectious disease may lead to a worsening of their illness.”

 

Eur J. Pediatr 1994, June; 153 (6) 394 – 402. Treatment of fever in childhood. 
Adam D, et al.

 “The most commonly used antipyretic drugs are acetylsalicylic acid (ASA) paracetamol (acetaminophen) and dipyrone (metamizol). …Paracetamol is the most common cause of acute hepatic failure… in the light of these findings, the extensive use of antipyretics drugs has been seriously questioned.” 
 
“Page 398: “Paracetamol has a pronounced liver toxicity. In the United Kingdom paracetamol is considered to be responsible for more cases of acute hepatic failure than any other cause.” 
 
Page 399 “the potential for toxicity of ASA and paracetamol, the two most extensively used antipyretics in the febrile child, underlines the constraints within which treatment decisions have to be made. The fact that both drugs are sold as “over the counter” products, while the medication of child fever often occurs without medical control, should be a matter of concern.

 

N Y State J Med. 1971; 71: 2747 – 2754.  Prnumococcal meningitis at Harlem hospital. Richter R W et al. 

 
Result: An increase of mortality with absence of fever in pneumococcal meningitis.

  

 “In summary, what does the evidence seem to indicate? Fever represents a universal, ancient, and usually beneficial response to infection, and its suppression under most circumstances has few, if any, demonstrable benefits. On the other hand, some harmful effects have been shown to occur as a result of suppressing fever: in most individuals, these are slight, but when translated to millions of people, they may result in an increase in morbidity and perhaps the occurrence of occasional mortality. It is clear, therefore, that widespread use of antipyretics should not be encouraged either in developing countries or in industrial societies.”

(Pediatr Vol 103, No 4, April 1999, 783-784 and 785-790. Infect Med 1999 16 (5):307.

 
Chickenpox
treated with Tylenol/Ibuprofen provokes bacterial skin infections into fulminant necrotising fasciitis.  This happens by prolonging inflammation and down regulating the immune system. It can no longer fully activate the adaptive arm of immunity either.

 

 The authors recently observed that frequent paracetamol use was positively associated with asthma and rhinitis in young adults. ….Their associations with national 1994/1995 per capita paracetamol sales were measured using linear regression. Paracetamol sales were high in English-speaking countries, and were positively associated with asthma symptoms, eczema and allergic rhinoconjunctivitis in 13-14-yr-olds, and with wheeze, diagnosed asthma, rhinitis and bronchial responsiveness in adults. The prevalence of wheeze increased by 0.52% in 13-14-yr-olds and by 0.26% in adults (p<0.0005) for each gram increase in per capita paracetamol sales. These ecological findings require cautious interpretation, but raise the possibility that variation in paracetamol usage may explain some of the variation in atopic disease prevalence between countries.

 

Asthma morbidity after the short-term use of ibuprofen in children


 
“However, the risk of an outpatient visit for asthma was significantly lower in the ibuprofen group; compared with children who were randomized to acetaminophen, the relative risk for children who were assigned to ibuprofen was 0.56 (95% confidence interval: 0.34-0.95). CONCLUSIONS: Rather than supporting the hypothesis that ibuprofen increases asthma morbidity among children who are not known to be sensitive to aspirin or other nonsteroidal antiinflammatory drugs, these data suggest that compared with acetaminophen, ibuprofen may reduce such risks. Whether the observed difference in morbidity according to treatment group is attributable to increased risk after acetaminophen use or a decrease after ibuprofen cannot be determined.”

 

 According to the FDA:
 
Safety Anaylasis of Acetaminophen   

Drugs with Limitations – limitations on their use (warnings, dose restrictions, monitoring):
Niaspan Extended Release Tablets (niacin)
Dantrium (dantrolene)
Tylenol (acetaminophen)
Normodyne (labetalol)
Cylert (pemoline)
Felbatol (felbamate)
Zyflo (zileuton)
Tasmar (tolcapone)
Trovan (trovafloxacin, alatrofloxacin)

  
What WHO has to say about Fever and antipyresis
 

 In addition to the probability that antipyretics may prolong the course of mild to moderate infectious illnesses, what other deleterious effects might they have? Russell et al. point out that little is known about the pharmacokinetics of these drugs in poorly or malnourished children. Even in developed countries, all available methods of antipyresis must be treated with respect. Warning labels became required for paracetamol recently and for aspirin in the more distant past. In addition to acute poisoning, the former has been implicated in the development of chronic renal disease, and perhaps liver failure, when repeatedly administered over prolonged periods of time . Perhaps more important is the fact that antipyretics mask symptoms or signs; children with pneumonia, for example, may not receive a proper diagnosis because their respiratory rate decreases (4) or because, when the body temperature starts to fall, the child may be considered to be on the way to recovery and thus needing no further observation. Finally, of course, the costs may consume a significant amount of resources that, in developing countries, could be better devoted to specific diagnosis and therapy.

Other potential benefits of reducing fever are sometimes cited to justify the use of antipyresis. A common assumption is that these drugs make patients feel better, but no clear evidence shows that this is so. Parents and physicians consistently cannot distinguish between the effects of placebo and paracetamol in most circumstances. Perhaps the exceptions are conditions accompanied by pain, for which the analgesic effects of the medication provide the benefit. When fevers rise above 39.5 oC, a reduction in body temperature is sometimes accompanied by an improvement in subjective symptoms, but this is inconstant, with young children seeming to benefit more than older children.

 The major problem when evaluating the subjective effects of antipyretics is that they have an enormous placebo value – as various studies have shown. Despite the firm belief in the effects of antipyretics, children do not feel any better, eat better, or become more active after their use than they do after they receive placebo. The argument that the use of antipyretics reduces the occurrence of febrile seizures also is not based on evidence: no studies have shown this to be true. Even in children with previous febrile seizures, the use of antipyretics has not been helpful. Some physicians believe that the response to antipyretics can be used to differentiate between bacterial and viral infections, with the latter responding more completely and promptly. Numerous studies have shown this to be a fallacy.

 

Overdose:
   

Acetaminophen overdose is the leading cause for calls to Poison Control Centers (>100,000/year) and accounts for more than 56,000 emergency room visits, 2,600 hospitalizations, and an estimated 458 deaths due to acute liver failure each year. Data from the U.S. Acute Liver Failure Study Group registry of more than 700 patients with acute liver failure across the United States implicates acetaminophen poisoning in nearly 50% of all acute liver failure in this country. Available in many single or combination products, acetaminophen produces more than 1 billion US dollars in annual sales for Tylenol products alone. It is heavily marketed for its safety compared to nonsteroidal analgesics. By enabling self-diagnosis and treatment of minor aches and pains, its benefits are said by the Food and Drug Administration to outweigh its risks. It still must be asked: Is this amount of injury and death really acceptable for an over-the-counter pain reliever?

 

According to the BMJ 2002;325:678 ( 28 September ) :

FDA fails to reduce accessibility of paracetamol despite 450 deaths a year. Confidential documents from the US Food and Drug Administration suggest that the agency has avoided a debate on tough new measures to reduce overdoses from painkillers to avoid offending the pharmaceutical industry. Ray Moynihan reports from Washington, DC  
 
” A confidential draft document reveals that the Office of Drug Safety also wanted the advisory panel to discuss whether the “maximum tablet strength should be decreased,” whether “combination products be reformulated without acetaminophen,” and whether there was “a need to standardize the various paediatric formulations.”  
 
The advisers never saw that draft, however, and none of these key options ended up being clearly presented to the committee by the FDA in the final list of questions they were to consider.  
 
…. “The committee would have preferred more focused questions,” he said.  
 
According to one FDA insider, the draft questions were dropped because senior FDA managers saw them as too offensive to Johnson & Johnson. Asked about this alleged corporate influence within the FDA, Dr Cantilena smiled and said he did not want to speculate.

The Neurologic basis of fever,Saper, Clifford B. The New England Journal of Medicine, vol. 330, No. 26. June 30, 1994, Page 1880:

 

“The elevation of body temperature by a few degrees may improve the efficiency of macrophages in killing invading bacteria, whereas it (fever) impairs the replication of many microorganisms, giving the immune system an adaptive advantage. 
 
There is a simultaneous switch from the burning of glucose, an excellent substrate for bacterial growth, to metabolism based on proteolysis and lipolysis. The host organism also becomes anorexic, which minimizes the availability of glucose, and somnolent, which reduces the demand by muscles for energy substrate. During the febrile response, the liver produces proteins known as acute-phase reactants. Some of these proteins bind divalent cations, which are necessary for the proliferation of many microorganisms.  
 
The net effect of the metabolic responses activated during fever is to give the host organism an adaptive advantage over the invader.”

 

J. Paediatr. Child health (1993) 29; 84 -85: Paracetamol: When, why and how much. Editorial

“in patients without heart and lung disease fever is harmful only at temperatures over 41 o C; such high termperatures are usually caused by heat stroke or brain injury, and they do not respond to paracetamol or aspirin.”  There is no evidence that antipyretics prevent febrile convulsions”

 

Eur J. Pediatr 1994, June; 153 (6) 394 – 402 Treatment of fever in childhood
Adam D, et al.

“The most commonly used antipyretic drugs are acetylsalicylic acid (ASA) paracetamol (acetaminophen) and dipyrone (metamizol). …Paracetamol is the most common cause of acute hepatic failure… in the light of these findings, the extensive use of antipyretics drugs has been seriously questioned.” 
 
“Page 398: “Paracetamol has a pronounced liver toxicity. In the United Kingdom paracetamol is considered to be responsible for more cases of acute hepatic failure than any other cause.” 
 
Page 399 “the potential for toxicity of ASA and paracetamol, the two most extensively used antipyretics in the febrile child, underlines the constraints within which treatment decisions have to be made. The fact that both drugs are sold as “over the counter” products, while the medication of child fever often occurs without medical control, should be a matter of concern.

 

Antipyretics appear to prolong illness by reducing the temperature, thereby disabling the body’s full ability to deal with whatever is the problem. In a nutshell, the lower the temperature, the longer the duration of illness. The higher the temperature, the shorter duration of illness. Immunologically, temperatures from infection are specifically designed to speed up and kick the immune system into gear, release cytokines and other immunological forces to deal with the problem.