Antibiotic Policies: Controlling Hospital Acquired Infection

I’ve read about and blogged this topic before, but this is the first academic text on the topic I’ve read. I liked the book and gave it four stars on goodreads. It’s a typical Springer publication, i.e. it’s a collection of relevant studies/papers published on the topic; there are fourteen papers/chapters included in the book. Given the nature of the book there’s some overlap across chapters, but that’s to be expected and it doesn’t really matter much. The book was published in 2011 so it’s reasonably up to date even though things are happening fast in this area.

Some of the authors of the studies included in the book assume that the reader possesses a level of knowledge about microbiology which goes way beyond what you’d get from reading an intro text like Hardy, and although I’ve also previously browsed one of the books you’d actually need to have read in order to understand the details (Brooks, Butel & Morse), I’ve of course long ago forgotten much of that stuff and so occasionally felt a bit lost while reading the book. There’s some good stuff in there though, and many of the chapters I did not find that hard to read although some details eluded me. It’s my impression that you probably will not get much out of the book if you’ve never read a microbiology text before (I actually feel a bit sad having to write that as the topics covered are very important in terms of future public health, and so in a way I’d really wish as many people as possible actually read this book, or at the very least familiarized themselves in some other way with the problems covered in the book).

“This book serves a twin purpose in helping to construct a more informed evidence base for coherent policy making while, at the same time, providing practical advice for health professionals in the prevention and control of HAIs.”

The quote above is from the preface of the book. The papers included in the book cover a wide variety of topics; one chapter deals with the ‘total scale’ of the problem of healthcare associated infections (HAIs), another chapter deals with (among other things) how antibiotic treatment regimes and the development of resistant strains in the community and/or health care institutions are associated, one chapter deals with the epidemiology of drug resistant strains of bacteria and how to properly categorize drug resistance (which can take on many forms), and quite a few chapters focus on specific HAIs (C. difficile, MRSA, VRE, ESBL-producing bacteria, CRE, Acinetobacter baumannii, and MDR (multi-drug resistant) Pseudomonas all get a chapter each). Many intervention studies are covered and the focus is not just on identifying the extent of the problem but also on finding ways to counter the problems; one chapter deals specifically with antibiotic stewardship, which is one of the main ways to try to stop the spread of antibiotic resistance, but many other chapters cover that topic as well in the specific setting. Another key strategic element in any intervention strategy, infection control measures (hand hygiene, patient isolation, etc.), is likewise covered in many of the chapters, and as the studies included have a very ‘evidence-based medicine approach’ to these matters important but potentially embarrasing problems like compliance problems on the part of health care providers [it’s harder to convince doctors to wash their hands than it is to convince nurses..] are not overlooked. The book is not US-centric; countless international studies are included, and a specific chapter is reserved to dealing with MDR infections in low-resource health care settings. The institutional setting is important and is covered in a few chapters, and included in that discussion are observations related to how things like reimbursement methodology may impact health care provider behaviours and how faulty incentive structures on the institutional level may aggravate the problems with resistance development e.g. by failing to address collective action problems in this area.

As might be inferred from the comments above, there’s way too much stuff in there for it to make sense for me to cover it all here. However I have added some observations from the book below, emphasizing some important points and observations along the way and adding a few comments here and there.

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“What is required is tackling of the problem at its root cause, namely the gross over use of antibiotics.” […let’s just start out with that one, so that people will not falsely assume that this aspect is not covered in the book.]

“In broad terms, there are two means by which patients can develop multi-resistant infections—they can either develop their own resistant pathogen, or they can acquire someone else’s strain.
Emergence of new resistant pathogens is directly related to antimicrobial selection pressure either via the mutation of new resistance genes or the alteration of bacterial ecology (e.g. in the gut) that facilitates the transfer of naturally occurring or emergent resistance genes from one bacterial class to another […] antibiotic use in food production can have the same effect as direct human antibiotic misuse, since it can select for both resistant pathogens (e.g. fluoroquinolone-resistant Campylobacter in chicken meat) or resistance genes such that food consumption results in either direct fecal colonisation or acquisition of resistance genes by routine gut flora [3,4]. Antibiotic stewardship is therefore not simply a hospital issue.” […]

“The global burden of healthcare associated infections (HAI) is currently unknown, despite international efforts to fill this gap in our knowledge. Where the size of the burden of HAI has been quantified, the greatest impact is in those countries with least resources to measure and manage them. […] 3.5–10.5% of hospitalised patients in industrialised countries may experience HAI (E.C.D.C. 2008), while greater than 25% of hospitalised patients in developing world nations may be affected (W.H.O. 2005). […] While in 2000, 70 countries did not screen donated blood for HIV, hepatitis B or hepatitis C, currently the risk of bacterial infection from transfusion is greater than the risk of acquiring these viruses. Reuse of contaminated needles or syringes during injections in limited resource settings poses a major threat for transmission of infection, accounting for an estimated 21 million hepatitis B infections, 2 million hepatitis C infections and over 95,000 HIV infections. […] Of the 8.8 million deaths in children under the age of 5 years, infectious diseases account for 5.5 million (63%) […] clinicians in developing countries tend to diagnose and prescribe medication empirically. People with undetected resistance then receive antibiotics to which their isolate is not susceptible. For example, one study in western Kenya found that more than half of the patients treated empirically for bacterial diarrhea were given ineffective antibiotics. Among patients with shigella, this number exceeded 80% (Shapiro et al. 2001). […] In developing countries, antibiotics are a scarce resource, and most clinics and hospitals can barely afford common first-line agents, much less second and third-line alternatives […] variation in prices of antibiotics is considerable. The wholesale price differential between amoxicillin and co-amoxiclav, for example, is on the order of a factor of 20 (Forster 2010). This means that where resistant bacteria necessitate the use of co-amoxiclav, only 5% of the patients can be treated for the same budget as with amoxicillin. […] In coastal Kenya, resistance to chloramphenicol, amoxicillin, cotrimoxazole, and gentamicin in Gram-negative sepsis is common, and susceptibility remains only to two rarely used drugs, ciprofloxacin and cefotaxime. The cost of treating a 15 kg child with sepsis would be $0.38–2.30 for gentamicin and chloramphenicol versus $73–108 for the effective drugs […] In Thailand, only 9% of antibiotics administered in a teaching hospital were appropriate to the patient’s condition, and 36% of patients were given antibiotics without evidence of an infection […]

“The underused vaccines that could have the biggest effect on antibiotic use in hospitals are against Streptococcus pneumoniae and Haemophilus influenzae type b. To these should be added one of the new vaccines against Rotavirus, the main cause of dehydrating diarrhea, which kills 400,000–500,000 infants and children in developing countries annually. Even though Rotavirus is, in fact, a virus, reducing its incidence will reduce antibiotic use. The most appropriate treatment for rotavirus and other causes of watery diarrhea is oral rehydration therapy, but since antibiotics are used inappropriately in many cases, reducing the number of cases will reduce antibiotic use.” [..vaccines against viruses may help decrease the number of bacteria resistant to antibiotics – yep, this stuff is complicated..]

“HAI are recognised as among the most common adverse outcomes from hospitalisation in the US; approximately 1.7 million HAI are reported across the US each year, which are associated with around 99,000 deaths per year. Around a third of HAI are urinary tract infections, one fifth are surgical site infections, 15% are pneumonia and 14% are bloodstream infections (C.D.C. 2010).” […] Estimates in Europe are that approximately 4.1 million patients per year experience HAI, and that attributable deaths are of the order of 37,000 per year (E.C.D.C. 2005–2010).” [These estimates are somewhat uncertain and I’m not sure how much you should read into the fact that they differ in the way that they do, with fewer but more lethal HAIs in the US. Before you read a lot into it, you should certainly note that there is huge regional variation in the data here.] […]

“Surgical prophylaxis is a common area of overuse as shown in many publications. Measured by total DDDs [defined daily doses], it can amount to around one third of a hospital’s total antibiotic use. This illustrates the potential for ecological damage although surgeons often ask whether 24 h or even single dose prophylaxis can really select for resistance. The simple answer is yes, but of course much of the problem is extension of prophylaxis beyond the perioperative period, often for several days in critical patients, perhaps until all lines and drains are removed. There is no evidence base in favour of such practices.” […]

“Since 2002, increasing rates of CDI [Clostridium difficile Infection] with a more severe course, higher mortality (from 4.7 to 13.8%) and more complications (from 7.1 to 18.2%) have been reported in Canada […] Of all patients who develop CDI in the hospital setting, approximately 80–90% have used antibiotics in the previous 3 months. […] MRSA can survive for months in hospital environment […] and it can be isolated on clinical equipment, as well as on general surfaces especially close to patient’s area, such as curtains, beds, lockers and over-bed tables […] Before contact precautions are implemented, MRSA carriers may have already contaminated their environment with MRSA. […] Cross-transmission between patients may occur via HCWs [health care workers’] hands after touching contaminated environmental surfaces […] One study showed that 10% of HCWs fingertips were contaminated with MRSA after contact with MRSA positive patient’s environment […] There is now reasonable evidence that rates of MRSA, C.difficile, VRE and multi resistant Gram-negatives can be reversed by modulating use of key agents such as cephalosporins and quinolones […] The real problem for the future, of course, is how to do this without “squeezing the balloon”, transferring the resistance selection pressure to other classes of agents. This highlights another paradox, that of current antibiotic policies which tend to lead to a lack of diversity of use of different classes of antibiotics. Diversity of use is probably one of the best strategies to delay emergence of resistance, although a lack of choice of truly different drug classes makes its implementation problematic. Moreover, the holy grail, and the most difficult thing is to achieve total reduction in prescribing while not compromising patient outcomes. Again, this isn’t something current strategies are good at achieving.” […]

“ESBL-producing bacteria are not only present in hospitals from endemic nosocomial sources but are introduced into the hospital from other health care facilities (particularly high rates occur in care of the elderly homes […] but also from individuals coming
from the community (Ben-Ami et al. 2006). […] This community carriage is an important facet of ESBL control [Again, what happens outside the hospitals matter a great deal…] […]

“Carbapenems have the broadest antimicrobial spectrum of any beta-lactam antibiotic and are frequently used as first-line agents for the treatment of severe infections caused by multiresistant Gram-negative bacteria […] The emergence and spread of carbapenem-resistant Enterobacteriaceae (CRE) are therefore a major concern for patient safety and public health. Infections due to CRE may lead to increased likelihood of treatment failure and growing reliance on third-line agents and combination therapy, with doubtful therapeutic efficacy and increased potential for toxic side-effects […] It also increases the cost of treatment […] CRE differ from most other multidrug-resistant bacterial pathogens in that there is no reliable treatment available (Schwaber and Carmeli 2008). […] two cases of panresistant CRE were recently reported from a hospital in New York […panresistant strains are basically untreatable, US.] […] Patients with CRE infection are at high risk of treatment failure and adverse outcomes, including increased mortality and morbidity, longer length of hospital stay, and higher treatment costs when compared to infections caused by susceptible strains. Several studies have reported high percentages of crude in-hospital mortality— some over 50%—among patients infected with CRE […] the magnitude of the excess mortality directly attributable to CRE is difficult to quantify […] Overall, uncertainties persist in individual patient-level analyses regarding which prior antibiotic exposures are most important as risk factors for acquisition of, transmission of and infection with CRE. Similarly, ecologic studies using aggregate datalevel analyses do not show a clear-cut picture.” […]

“Antibiotic policies are crucial but they cannot be effective without active infection control program[s]. A hospital with a strong infection control program without an antibiotic stewardship component would tackle transmission of multi-resistant organisms such as VRE but would not prevent individual patients from getting colonised or infected with resistant microbes. On the other hand, strong antibiotic stewardship would be expected to control the menace of multi-resistant organism but in absence of an infection control program, transmission of organisms (even if not multiply resistant) would be easy and would adversely affect patient care.” […]

“A retrospective, risk-adjusted, cohort study of 80 patients with Acinetobacter bacteraemia conducted in Korea demonstrated that those infected with imipenemresistant strains had a significantly higher 30-day cumulative mortality rate than those infected with imipenem-susceptible strains (57.5% versus 27.5%) […] This was mainly due to a higher rate of inappropriate antimicrobial therapy. […] Carbapenems are the mainstay of treatment for severe infections. However, carbapenem-resistant A. baumannii strains have emerged worldwide. […] A considerable proportion of multi-drug resistant A. baumannii strains are susceptible only to polymyxins, which prompted the use of an old antibiotic in recent years. […] Polymyxins are polypeptide antibiotics that act as detergents on the bacterial cell wall. They were introduced in 1940 but they were abandoned in the 1980s due to the occurrence of nephrotoxicity and neurotoxicity. […] Reported nephrotoxicity ranges between 8 and 36%. […] Reported neurotoxicity ranges between 7 and 29%, with oral and perioral paresthesias, visual disturbances and polyneuropathy […] [So basically what has happened is that doctors have been forced to restart using drugs they threw away 30 years ago because those drugs caused kidney failure and severe nerve damage. These old drugs are currently the only drugs that work against some MDR infections, and no new drugs are even close to being developed at this point]. […]

P. aeruginosa is the second most common cause of health-care associated pneumonia, of hospital-acquired pneumonia and of ventilator-associated pneumonia (VAP). It is also reported as the cause of 9% of hospital-acquired urinary tract infections (UTIs). […] It is estimated that the rate of colonization and/or infection by MDR P. aeruginosa is 0.5 episodes/1,000 patient-days in the general ward and 29.9 to 36.7/100 patients in the ICU (Agodi et al. 2007; Peňa et al. 2009). […] infections by MDR P. aeruginosa have a significant impact on mortality. A retrospective study of our group in non-neutropenic hosts in the general ward disclosed 22.2% mortality of infections by MDR P. aeruginosa compared to 0% of infections by susceptible isolates […]. For ICU infections caused by MDR P. aeruginosa mortality ranges between 22% and 77%; this ranges between 12% and 23% when ICU infections are caused by susceptible isolates (Shorr 2009).” […]

“Antibiotic effectiveness can be viewed as a shared resource in which current use depletes future value and imposes costs on society in the form of longer hospitalization, higher mortality rates, and the diversion of resources into the provision of newer and more expensive drugs. In making treatment decisions, prescribers should weigh the favorable effects of applying antibiotics to improve a patient’s health against the negative consequences for the public and future drug effectiveness (Laxminarayan 2003b). However, clinicians usually ignore the future therapeutic risks to society associated with antibiotic use and instead focus on the direct benefits of antibiotic treatment to their patients. […] In the absence of a good pipeline of new drugs, it is the balance between the individual patient and society as a whole, otherwise known as the ecological perspective, that has to be clearly established and debated. We need to get clever, quickly. […] In the long term, new antibiotics are needed […] However, as a gap of 10–15 years has been identified (European Centre for Disease Prevention and Control and European Medicines Agency 2009), immediate action is needed to conserve the power of the available arsenal.”