Article Type : Research Article
Authors : Kardos N
Keywords : Carbapenem resistant enterobacteriaceae; Antimicrobial resistance
The decreasing
effectiveness of antibiotics in treating common infections results from the
spread of antimicrobial resistance (AMR), and is building up to become an epic
global public health crisis. Extended periods of antibiotic overuse and misuse
since their introduction have applied strong selective pressure towards
high-level AMR and multiple drug resistance (MDR), rendering entire classes of
antibiotics ineffective. The primary driving force for this global AMR pandemic
is the widespread misuse and overuse of antibiotics, in both medical and
non-medical applications. The introduction of every antibiotic product has been
closely followed by emerging resistance to that antibiotic. Levels of
antibiotic consumption correlate with levels of AMR.
Antibiotics have been
misused in all of their applications, including [1]:
·
Hospital
and outpatient use by physicians through unnecessary, indiscriminate or
incorrect prescribing;
·
By
patients, through incorrect dosing and course durations;
·
Large-scale
use in agriculture for disease treatment, prophylaxis and growth promotion in
animal husbandry and food production.
These actions not only have provoked the emergence of resistant microbes, but also have provided optimal environments for the spread of and selection of resistance determinants. It has been established in many countries that the levels of antibiotic consumption consistently correlate with levels of antibiotic resistance (i.e. the more antibiotics are being used in a population, the more resistance to antibiotics there will be in bacteria responsible for infections in that population). The increase in resistance from overuse of antibiotics in turn leads to cross transmission of AMR microbes between humans, between animals, and between humans and animals and the environment [2]. Almost two million Americans per year develop hospital-acquired infections (HAIs), resulting in 99,000 deaths per year. The vast majority of these HAI related deaths are due to AMR infections [3]. Based on studies of the costs of infections caused by antibiotic resistant pathogens vs. antibiotic susceptible pathogens, the annual cost to the US health system of antibiotic resistant infections is $21 to $34 billion, and eight million additional hospital days [3]. Of particular concern is the development and spread of Carbapenem - resistant Enterobacteriaceae (i.e., CRE). The global emergence of carbapenemase - producing organisms is a public health emergency because these enzymes confer resistance to both carbapenems and nearly all -lactam antibiotics, and are often associated with multidrug or pandrug resistance [3,4]. Resistance to antibiotics mediated by acquired carbapenemase enzymes in gram - negative bacteria - principally the Enterobacteriacae species is a serious concern. Most carbapenemase producing isolates of Enterobacteriaceae are resistant to multiple other classes of antibiotics, limiting therapeutic options to patients. Since the carbapenem antibiotics are the last line of defense against multidrug-resistant gram-negative bacterial infections, their vulnerability represents a real public health crisis. In addition, the cost of CRE infection is higher than the cost of many chronic and acute diseases.
The
age of antibiotics
Prior to the discovery
of penicillin as the first available antibiotic, infectious disease had been
the leading cause of death throughout history. Penicillin was the first
successful chemotherapeutic agent produced by microbes and it initiated the age
of antibiotics. It represents the first therapeutic agent that destroyed
bacteria in vivo, was not destroyed in the body, and was non-toxic to humans. Penicillin
belongs to the beta-lactam class of antibiotics, which are the most successful
natural product group used in chemotherapy. Later developed members of this
antibiotic class which are widely used in medicine today include the orally
active semisynthetic penicillins (ampicillin, amoxicillin) and the
cephalosporins. It has been estimated that at the end of the nineteenth
century, nearly one third of all deaths were due to infectious disease. By the
end of the twentieth century, the death rate from all sources of infection dropped
to levels well below 10% [3]. No other class of medicine has had a comparable
cumulative impact on reducing death rates and increasing life spans [4].
The
spread of antimicrobial resistance (AMR)
The world is now
entering the post antibiotic age because of the growing problem of
antimicrobial resistance (AMR). Infections from resistant bacteria have become
more common and some pathogens have become resistant to multiple classes of
antibiotics. The spread of AMR threatens to compromise the treatment of all
infectious disease and is one of the most serious problems confronting both
contemporary and future global public health.
The
global struggle against AMR
The loss of effective
antibiotic treatment will not only compromise the ability to control routine
infectious disease, but will also prevent the treatment of infectious
complications in patients with other disease states. The following advanced
medical treatments are dependent on antibiotics to fight infections [5,6]:
Cancer chemotherapy: Cancer patients are at risk to develop serious
infections when their white blood cell count is low. Such infections can be
serious, and effective antibiotics are needed to protect cancer patients from
complications and death.
Surgery: Patients are at risk for infection from many
surgeries including joint replacements, etc. Antibiotics are routinely given
before surgery to prevent infection.
Rheumatoid arthritis (RA): This disease reduces the patient’s
immune system and increases the risk of infection. Since many medicines used to
treat RA can weaken the immune system, effective antibiotics are needed to
ensure that arthritis patients can continue receiving treatments.
Dialysis for end Stage renal disease: Such patients have a weakened immune
system and a higher risk for blood stream infections. Such infections are the
leading cause of death in dialysis patients. Effective antibiotics ensure that
dialysis patients will continue to receive life-long treatment.
Organ and bone marrow transplant: These patients receive complex surgery and have weakened immune systems. They are at high risk for infections and the use of effective antibiotics is essential. Without effective antibiotics, all of these procedures would have to be reduced. The reduction in antibiotic effectiveness from resistant pathogens leads to more difficult and costly treatments as well as greater morbidity and mortality and death. The Center for Disease Control (CDC) reports that some 2 million people per year in the USA are contracting infections that are resistant to antibiotic treatment. And among such infections, there are more than 23,000 reported deaths per year as a result of AMR. It is estimated that health-care-associated infections (HAI) is reported at 5% in the USA. However, the infection rates in the developing world are much higher. The pooled presence of HAI in the developing world is estimated at 15.5% [7]. AMR has been observed to emerge in the clinic within a decade or less after development of a new antibiotic [8-11].
AMR
as natural evolution
AMR is the acquired ability of pathogens to withstand the actions of an antibiotic that kills all of its sensitive counterparts. This feature originally arises from random mutations in existing genes or from intact genes that serve a similar purpose. Exposure to antibiotics and other antimicrobial products (biocides) in humans and animals applies pressure that encourages resistance to emerge, and favoring naturally resistant strains and strains that have acquired resistance [12]. The specific meaning of the term ‘AMR’ depends on the context. The clinical definition used refers to the ability of a microbe (bacteria, virus, fungus or parasite) to survive concentrations of antibiotics that kill sensitive cells of the same strain. For every antibiotic there are sensitive microbial strains which are killed or inhibited by the drug, and there are naturally resistant strains. Bacterial species that are not susceptible to a particular drug are ‘naturally resistant.’ But species that were once sensitive to an antibiotic but eventually became resistant to it have ‘acquired resistance’. Acquired resistance affects a subset of the strains in the entire species, and varies with location. When a sensitive strain gains the ability to withstand the antibiotic, it is resistant to that antibiotic [12,13]. Some of the mechanisms that bacteria acquire to become resistant to antibiotics include; (i) Acquisition of genes coding for enzymes that destroy antibiotics (e.g: betalactamases); (ii) Acquisition of efflux pumps that expel antibiotics from the bacterial cell; (iii) Mutations that produce altered cell walls with dysfunctional antibiotic binding sites; and (iv) Mutations that result in a decrease in the outer membrane channels antibiotics need to enter the bacterial cell [12,13]. In biochemical terms, AMR means that a pathogen is less susceptible than its counterparts and may not respond to the antibiotic. The evolution of microbes is Darwinian; only the fittest survive change. Antibiotics represent an evolutionary challenge to microbes, which if not overcome will kill them. Resistance is not an on and off condition. Resistance exists as a gradient that reflects phenotypic and genotypic variations in large microbial populations. Different resistance mechanisms confer different levels of resistance. Low resistance levels are often overcome, but can also play an important role in the emergence of resistance. Currently used definitions of AMR do not take such diversity into account [12]. AMR arises by chance through mechanisms that may represent a history of natural competition among microbes. The mechanisms, genes, and pathways of antibiotic production and resistance help microbes compete for niches in nature. Therefore, AMR is a normal component of microbial life and represents a normal evolutionary phenomenon. However, these natural evolutionary phenomena are amplified by the use, both appropriate and inappropriate, of antimicrobials (antibiotics, antifungals, antivirals and biocides). Most microbes can be a source of resistant genes, but selection for AMR often takes place in non-pathogenic microbes, since they make up the majority of the microbial world. Resistant genes are often derived from existing essential genes. Resistant genes may also originate from antibiotic producing strains that are used to protect themselves from their own harmful products, or from natural protection mechanisms. Developing resistance to antibiotics increases each of the genes available to microbes to also import other genes. And this causes their evolutionary approximation. Once a microbe derives genetic tools from resistance, it can pass that gene onto its progeny by clonal replication; or to other microbes through horizontal gene transfer. Horizontal gene transfer – the movement of genetic material from one organism to another- is the primary mechanism by which bacteria acquire antibiotic resistance. Antibiotics promote this genetic exchange by inducing the transfer of conjugative elements. [2,12-14]. Indeed, for any Gram negative resistance issue, and especially for Enterobacteriaceae, one must also consider not just the spread of resistant strains but also the spread of their resistance genes between plasmids, and the spread of those plasmids between strains, species and genera. There is significant potential for transfer of bacteria and their resistance elements between reservoirs, as well as both to and from man, and from animal and environmental sources [8].
Antibiotic
misuse as a primary driver for AMR
The largest driver for development and spread of AMR is the overuse and misuse of antibiotics in both medicine and in agriculture. Overuse includes use of broad spectrum antibiotics in varied practice settings when the pathogens that cause the infection are not known. Such misdiagnosis is caused by a number of factors in healthcare settings, including: lack of knowledge by prescribers; prescriber attitudes; lack of effective diagnostics; and lack of current treatment guidelines. Overuse and misuse of antibiotics occur in both the hospital setting as well as in community / primary care and long-term care settings [2,6,12,13]. Studies indicate that nearly 50% of antibiotic use in hospitals is unnecessary or inappropriate [5]. Antibiotic misuse is defined in the study as an absence of an indication for such antibiotics [15,16]. Misuse of broad spectrum antibiotics may be the largest single factor for the spread of AMR. Inappropriate use also includes the use of sub inhibitory concentrations of antibiotics. Low concentrations of antibiotics can enrich for resistance genes in a population while having little effect on overall bacterial mortality. The tendency to mutate also increases upon exposure to sub-inhibitory concentrations of antibiotics. Low concentrations of antibiotics can also select for strains that increase expression of their existing resistance genes, further enhancing their resistance [12]. Although antibiotic resistance is mainly considered to be a clinical problem, antibiotic use and overuse is not restricted to clinical settings. The majorities of antibiotics consumed in the world are used in farming and animal agriculture and related settings (aquaculture). Overuse of antibiotics in agriculture leads to the spread and cross-transmission of antimicrobial-resistant microbes between humans, between animals, and between humans and animals and the environment. AMR is most often portrayed as an undesirable consequence of antibiotic abuse or misuse. But this explanation is not a complete picture. The rate of AMR emergence is related to all uses of these drugs, and not just to their misuse. The total quantity of antibiotics put out into the environment also plays a role in AMR. Selection for AMR is not confined to the human body, and is not limited to hospitals, clinics and farms. Selection takes place anywhere an antibiotic is present in natural environments, and especially in sewage and surface water sediments. Antibiotics are often found in the latter places coupled with high densities of large microbe populations. Large amounts of antibiotics and biocides end up in sewage sludge, which make them primary sources for development of AMR. Increasing amounts of antibiotics and biocides that are found in waste water, sediment and sludge discharges originate from agricultural applications. The stability of an antibiotic is one key as to how it will impact development of AMR in the environment. Stable antibiotics are more likely to persist long enough to select for resistance [12,13]. (Figure 1) shows the effect of direct selective pressure as a primary driving force for AMR. The figure illustrates that -lactamases evolve with the appearance and use of each new antimicrobial class.
The decreasing
effectiveness of antibiotics in treating common infections results from the
spread of antimicrobial resistance (AMR) and is building up to become an epic
global public health crisis. The crisis of reduced effectiveness of antibiotics
to treat infections because of increasing AMR have been dramatically publicized
in recent years by international health organizations (WHO) [6] as well as
Central Govt. Agencies (NHS in UK [10], CDC in USA [1]. Extended periods of
antibiotic overuse and misuse since their introduction have applied strong
selective pressure towards high level AMR and multiple drug resistance (MDR),
rendering entire classes of antibiotics ineffective. The traditional response
to AMR had been the introduction of new classes of antibiotics, a strategy
which did not solve the problem but only bought a brief reprieve. However, over
the last twenty years, there has been a significant decline in development and
clinical introduction of new antibiotics to keep pace with the escalation of
global AMR [14]. The rapid evolution and spread of AMR is illustrated in the
case of the Beta-Lactam class of antibiotics. There are nearly 1,000 resistant
related Beta lactamases that inactivate these antibiotics that have been
identified, and have spread worldwide. The primary driving force for this
global AMR pandemic is the widespread misuse and overuse of antibiotics, in
both medical and non-medical applications. The introduction of every antibiotic
product has been closely followed by emerging resistance to that antibiotic
[6]. Levels of antibiotic consumption correlate with levels of AMR. Antibiotics
have been misused in all of their applications, including:
·
Hospital
and outpatient use by physicians through unnecessary, indiscriminate or
incorrect prescribing
·
Out
patients, through incorrect dosing and therapy course durations
·
Large
scale use in agriculture for disease treatment, prophylaxis and growth
promotion in animal husbandry and food production
These actions not only have provoked the emergence of resistant microbes, but also have provided optimal environments for the spread of and selection of resistance determinants. It has been established in many countries that the levels of antibiotic consumption consistently correlate with levels of antibiotic resistance (i.e. the more antibiotics are being used in a population, the more resistance to antibiotics there will be in bacteria responsible for infections in this population). The increase in resistance from overuse of antibiotics in turn leads to cross transmission of AMR microbes between humans, between animals and between humans and animals and the environment. The two major areas for managing control and prevention of AMR are: (i) Prudent use of antibiotics: Use antibiotics only when needed, and with the correct dose, at the correct dose intervals, and for the correct duration; and (ii) Hygienic precautions for control of infections [12]. In September 2013, the Center of Disease Control (CDC) in the USA published a lengthy study describing the scope of AMR in the USA. The CDC estimates that more than 2 million people per year contract AMR infections and resulting in at least 23,000 direct deaths, and another 100,000 deaths from related complications. Similarly the European Center for Disease Prevention and Control reports that 25,000 people die each year in Europe from antibiotic resistant bacteria. This problem is also present in other parts of the world. For example, in India over 58,000 people die in one year from antibiotic resistant infections. In Thailand, antibiotic resistance causes more than 38,000 deaths per year and 3.2 million hospitalization days [17,18]. The cost of AMR infections goes beyond patient deaths. The consequences include greater morbidity and healthcare expense. The impact of AMR on the American healthcare system is enormous. Almost two million Americans per year develop hospital acquired infections (HAI), resulting in 99,000 deaths, most of which are due to antibiotic resistant pathogens. It has been estimated that the annual cost to the American healthcare system of antibiotic- resistant pathogens versus antibiotic-susceptible pathogens is $21 to $34 billion/year and more than 8 million additional hospital days [15,19,20]. The vast majority of these HAI related deaths are due to AMR infections. HAI incidence is reported at approximately 5% in the USA and 7.1% in Europe [13], and pooled infection rates in the developing world are estimated at 15.5% [14]. The CDC has listed the hazard level of threat for AMR into three categories: Hazard Level Urgent; Hazard Level Serious; and threat Level Concerning. The pathogens covered in these threat levels are summarized in (Table 1).
Table 1: CDC Levels of Concern - Prioritization
of Resistant Bacteria.
Urgent Threats |
Serious Threats |
Concerning Threats |
Clostridium difficile |
Drug-resistant Acinetobacter |
Vancomycin-resistant Staphylococcus aureus (VRSA) |
Carbenapenem-resistant Enterobacteriaceae (CRE) |
Drug-resistant Campylobacter |
Erythromycin-resistant Streptococcus
Group A |
Drug-resistant Neisseria gonorrhoeae |
Fluconazole-resistant Candida |
Clindamycin-resistant Streptococcus
Group B |
|
Extended-spectrum,
cephalosporin-resistant Enterobacteriacease
|
|
Vancomycin-resistant Enterococcus
(VRE) | ||
Drug-resistant Pseudomonas aeruginosa | ||
Drug-resistant nontyphoidal Salmonella
| ||
Drug-resistant Salmonella typhi | ||
Drug-resistant Shigella | ||
Methicillin-resistant Staphylococcus aureus (MRSA) | ||
Drug-resistant Streptococcus pneumoniae | ||
Drug-resistant tuberculosis (MDR & XDR) | ||
Notes: MDR = Multiple Drug Resistance XDR = Extensive Drug Resistance Reference:
[1] |
ESKAPE
pathogens & ESBL
A select group of
pathogens are responsible for the majority of HAI; acronymically termed the
ESKAPE pathogens by IDSA (Infectious Disease Society of America [15-23]. The
term ESKAPE indicates that these pathogens are capable of escaping the biocidal
actions of antibiotics and collectively represent new paradigms in
pathogenesis, transmission, resistance and severity of their infections. The
ESKAPE acronym consists of: [16]
·
E - Enterococcus faecium
·
S - Staphylococcus aureus
·
K - Klebsiella pneumoniae
·
A - Acinetobacter baumannii
·
P - Pseudomonas aeruginosa
·
E - Enterobacter Species and includes
ESBL (Extended-Spectrum beta lactamase)
ESKAPE indicates that
these bacteria have developed defenses that permit them to escape the biocidal
actions of available and effective antibiotic therapies. All of the ESKAPE
pathogens produce beta lactamase enzymes and have developed resistance against
carbapenems. A brief highlight of the more important carbapenemase producing
pathogens follows:
Klebsiella pneumoniae: This pathogen is a member of the Gram-negative Enterobacteriacae family, and is prevalent worldwide in both hospital and community infections. This pathogen is recognized for accumulation and rapid dissemination of MDR determinants. And over the past decade, it has acquired an extensive range of lactamase enzymes capable of hydrolyzing the -lactam ring common in penicillins, cephalosporins and also carbapenems. The development and spread of carbapenemresistant K. pneumoniae (CRKP) threatens the clinical effectiveness of -lactams, fluoroquinolones and aminoglycosides [19].
Acinetobacter baumannii: This is a Gram-negative opportunistic pathogen most often encountered in intensive care units and surgical wards, where extensive antibiotic use has enabled selection for AMR. This pathogen can grow across a range of temperatures, PHs and nutrient levels which make it highly adapted to survival in both human and environmental vectors and carries high rates of nosocomial cross-contamination. This pathogen is intrinsically resistant to antibiotics. It has acquired a broad range of lactamases, including carbapenemases. The broad acquisition of ESBLs gives some isolates resistance to all antibiotics, including imipenem and colistin [20].
Pseudomonas aeruginosa: This pathogen is a Gram-negative facultative
anaerobe. It preferentially colonizes immunocompromised patients and is known
as an opportunistic pathogen associated with cancer patients and burn victims. It
is resistant to fluoroquinolones through point mutations. In addition, this
pathogen harbors broadspectrum ESBLs including carbapenemases, which make it
difficult to employ suitable empirical antibiotic therapies [20].
Enterobacter species and includes ESBL (Extended-Spectrum beta lactamase): These species most commonly infect the urinary and respiratory tracts, but also cause bloodstream infections. They are shown to display broad MDR via plasmid-encoded ESBLs and carbapenemases. Beside colistin and tigecycline, few antibiotics are effective against these resistant pathogens [23]. The ESKAPE organisms are responsible for a substantial percentage of nosocomial infections in hospitals and represent the vast majority of isolates whose resistance to antibiotics present serous treatment limitations. Within the ESKAPE pathogens, the problem of carbapenem resistant Enterobacteriaceae (CRE) infections are becoming the leading healthcare infection problem, and are referred to as “nightmare bacteria” by CDC director Dr. Tom Frieden [1]. The CRE pathogens include carbapenem resistant Klebsiella species and carbapenem resistant E. coli, resulting in 9,000 drug resistant infections/year and 600 deaths. CRE infections have become resistant to nearly all antibiotics in use today, including carbapenems - the antibiotic of last resort. CRE infections most commonly occur among patients who are receiving treatment for other conditions and whose care requires devices like ventilators, urinary catheters or intravenous catheters, and also patients taking long courses of antibiotics. Up to one half of patients die from CRE bloodstream infections [22]. Extended spectrum -lactamases (ESBLs) are enzymes produced by a variety of gram negative bacterial which confer an increased resistance to commonly used antibiotics [22,23]. -lactamases are hydrolytic enzymes which cleave the -lactam ring and the primary mechanism of conferring bacterial resistance to -lactam antibiotics such as penicillins and cephalosporins. These enzymes can be carried on bacterial chromosomes or may be plasmid mediated with the potential to move between bacterial populations. This ability of ESBL genes to jump between organisms leads to outbreaks of infections where easily transmissible pathogens are involved. Moreover, organisms that produce ESBLs have the capacity to acquire resistance to other antimicrobial classes such as quinolones, tetracyclines, cotrimazole, trimethoprim and aminoglycosides, which further limits therapeutic options. ESBLs have become a major cause of hospital-acquired infections and particularly in the intensive care unit (ICU).
Introduction
Carbapenemases represent the most versatile family of -lactamases, with the widest spectrum of activity among all the -lactam-hydrolyzing enzymes. Although known as “carbapenemases” many of these enzymes recognize almost all hydrolysable -lactams, and most are resistant against inhibition by all commercially viable -lactamase inhibitors [24,25]. Carbapenemases are produced by Enterobacteriaceae bacteria (Carbapenem resistant Enterobacteriaceae = CRE), which include more than 70 different genera covering many different mechanisms causing carbapenem resistance. CRE are included in a broader category of CP-CRE- standing for carbapenemase-producing CRE. CP-CRE are a subset of all CRE. All CRE are likely multidrug-resistant organisms for which interventions are required in healthcare settings to prevent transmission [24]. Carbapenemase-producing pathogens cause infections that are difficult to treat and have high mortality rates, due to their appearance in multidrug resistant pathogens such as K. pneumoniae, P. aeruginosa, and Acinetobacter spp, It has been found that carbapenemase genes are easily transferred on mobile elements among bacterial species, leading to the spread of infections. It should be noted that CRE that do not produce carbapenemases are generally still resistant to multiple antibiotics and are a serious health problem.
CDC
Definition of Multiple Drug resistant Organisms (MDRO) [24,25]
The expert consensus of
MDRO as microbial species resistant to multiple antimicrobial agents contains
the following subsets and applies to CP and CRE infections:
·
PDR:
(Pan Drug resistance) non susceptible to all agents in all antimicrobial drug
categories
·
MDR:
(Multi Drug Resistance) an isolate non susceptible to a minimum of one agent in
at least three drug categories
·
XDR-
(Extensive Drug Resistance) an isolate is non-susceptible to at least one agent
in all but two or less antimicrobial drug categories
CDC Definition of
Carbapenemases
Previously, the CDC
defined CRE as “Being non-susceptible to the carbapenems ‘imipenem,’
‘meropenem’ or ‘doripenem,’ AND resistant to all third generation
cephalosporins tested.” The CDC has adopted a new definition since January 2015
for CRE to read: “Being non-susceptible to the carbapenems ‘imipenem,’
‘meropenem’ or ‘doripenem,’ or ertapenem, or documentation that the isolate
possesses a carbapenemase.” [24].” The previous CDC CRE definition was designed
to be more specific for CP-CRE. However, that definition was found to be
complicated, difficult to implement and also missed some CP-CRE. Other reasons
for the change in the CDC definition were (i) ertapenem was included to
increase the ability to detect carbapenemase–producing strains compared to the
previous CDC CRE definition; (ii) third generation cephalosporins are not
included from the current CDC definition to simplify the definition, facilitate
application and also accommodate the emergence of OXA-48-type producing CRE
which might not be resistant to this class of antimicrobials [24].
Classification of -lactamases
More than 1,000 -lactamases exist in gram-negative bacteria. Production of -lactamases is the most widespread cause of carbapenem resistance. Two classification schemes exist for -lactamases. One scheme is based on molecular classification and puts all -lactamases into four distinct classes (A through D) based on amino acid sequence homology- the Ambler classes, also called ‘Molecular Classes.’ The other scheme is based on functional classification using substrate and inhibitor activity (classes 1 through 4) – the Bush-Jacoby classes, also called ‘Functional Classes.’ [26-28]. This article will use the Ambler classification scheme and is depicted in (Table 2).
Molecular classes A, C
and D contains serine in their active site, while Group B contains zinc in
their active site. Carbapenemases are found in Classes A, B & D.
· Class A -lactamase: They have serine active sites. The more important enzyme groups are: NMC, IMI, SME, and KPC & GES. KPC is the most common carbapenemase in the USA. While first isolated form K. pneumoniae, it has since spread to other Enterobacteriacea.
· Class B Beta Lactamases: They are also referred to as MBL (metallo--lactamases because they require the presence of zinc to function. The more important enzymes are: IMP, VIM, GIM and SPM. Until 2009, VIM subtype was the most widespread MBL. It has since been displaced in ranking by NDM-1 which is now the most globally prevalent MBL subtype.
· Class C - lactamases: They have a serine active site. The important enzymes are AmpC. AmpC genes on the bacterial chromosomes produce low levels of - lactamases (repressed). When “de-repressed” the BL is hyper produced. AmpC BL has minimal activity against carbapenems and monobactams. However, when AmpC is combined with other mechanisms for reduced cell susceptibility, clinically significant levels of resistance are achieved Class C - lactamase are not generally classified as carbapenemases [28].
· Class D -lactamases: This class has a serine active site. The important -lactamases are of the oxacillanase (OXA) enzyme type. They have weak activity against carbapenems and are found primarily in P aeruginosa and Acinetobacter. The major concern with OXA carbapenemases is their ability to rapidly mutate and expand their spectrum of activity [29,30].
(Table
2) shows substrate and inhibition profiles of the more important carbapenemases
- based on both the Ambler and Bush-Jacoby classification schemes (S-6-4)
Clinically Important Carbapenemases: The most common carbapenemases in
Enterobacteriacea are displayed in (Tables 3,4). They are: KPC; VIM; NDM and
OXA-48 [31,32].
Table 2: Groupings of carbapenemases
and AmpC Beta-lactamases within Beta-lactamase classifications.
Ambler Group |
Bush-Jacoby Group |
Common
Name |
Mediates
Resistance to |
Representative
Enzymes |
A |
2f |
Serine carbapenemase |
Carbapenems; Penicillins;
Cephalosporins; Aztreonam |
KPC, GES, SME1 |
B |
3a |
Metallo--lactamases (MBLs) |
All -lactams except aztreonam |
IMP, NDM, VIM |
C |
1 |
Serine cephalosporinase |
Penicillins; Cephalosporins |
AmpC |
D |
2df |
Carbapenemase |
Carbapenems; Penicillins;
Cephalosporins; Aztreonam |
OXA |
Based on
table in Ref [27][28][29][48] Notes: KPC:
Klebsiella pneumoniae carbapenemase GES: Guiana
extended spectrum AmpC:
Cephalosporinase SMEI: Serratia
marcescens enzyme IMP: Imipenem-hydrolyzing--lactamase VIM: Verona integron-encoded metallo--lactamase NDM: New Delhi metallo--lactamase OXA: Oxacillinase-hydrolyzing--lactamase
|
Table 3: Therapeutic
treatment for CRE infections.
Several
therapeutic agents have been used to treat serious CRE infections, and have
been use both as monotherapy, and with additional agents as combination
therapy. |
MONOTHERAPY ·
Carbapenems ·
Fosfomycin ·
Gentamycin ·
Polymyxins
(Colistin & Polymyxin B) ·
Tigecycline |
COMBINATION
THERAPY The
following antibiotics are used in combination to treat CRE infections: ·
Colistin + Meropenem ·
Colistin +
Tigecycline + Meropenem ·
Colistin +
Tigecycline ·
Meropenem +
Aminoglycosides ·
Colistin +
Aminoglycosides |
Ref: Tabled
assembled by author based on data from Ref [29]. |
KPC: Klebsiella pneumoniae carbapenemase is a class “A” -lactamase. It can hydrolyze penicillins, cephalosporins and carbapenems. KPC was first reported in North Carolina in 1996, and has since spread globally. The KPC gene can be acquired by other species of Enterobacteriacea including Enterobacter spp. and Escherichia coli and on rare occasions Pseudomonas aeruginosa and Acinetobacter baumannii as well. The potential of E. coli acquiring KPC is concerning because of its community-wide distribution as a commensal organism.
VIM: Verona Integron-encoded-metallo--lactamase. This is a class “B” -lactamase first identified in Verona Italy in 1997 in a P. aeruginosa clinical isolate. This family has 10 members and is found mostly in P. aeruginosa. VIM-2 is the most reported metallo-lactam worldwide.
NDM: New Delhi metallo--lactamase is a class “B” -lactamase capable of hydrolyzing penicillins, cephalosporins and carbapenems. The Indian subcontinent is the primary reservoir. This pathogen was first reported in Indian hospitals in 2006, and has since spread globally.
OXA-48: Oxacillin-hydrolyzing--lactamase is a class “D” serine -lactamase, and OXA-48 is the carbapenemase of concern. It was first isolated in Turkey in 2001 from an Enterobacteriacea strain. Most cases have been reported in K pneumoniae and are resistant to all -lactams including carbapenemases. Most reports of this strain are in Turkey, North Africa and India, but rarely in the USA.
Carbapenem antibiotics
Of all the different classes of -lactamases, the carbapenemases have the broadest activity spectrum and greatest potency against grampositive and gram-negative, aerobic and anaerobic bacteria. They all have low oral availability and so must be administered parenterally. All carbapenem antibiotics are eliminated by renal excretion.
The carbapenems that
are available in the USA are: Imipenem (FDA approved 1985; Meropenem (FDA
approved 1996); Ertapenem (FDA approved 2001) and Doripenem (FDA approved
2008). In addition, another carbapenem – Biapenem- was approved for use in
Japan, China and Korea (2002). (Figure 2) shows the chemical structure of these
five carbapenems [33-35] (Figure 2).
Treatment of ESBL
infections
ESBLs are primarily produced by the Enterobacteriacea family of Gram-negative organisms, especially from K pneumoniae and E. coli. They are also produced by the gram-negative bacteria Acinetobacter baumanii and Pseudomonas aeruginosa. ESBLs are classified as Class A -lactamases. They are plasmid mediated enzymes that hydrolyze cephalosporins and monobactams but not cephamycins nor carbapenems. Treatment options are [30,33,34-37].
Carbapenems: The antibiotic of choice against severe ESBL infections. They are rapidly bactericidal and have time dependent killing. They are also effective against other -lactamases. They also offer low resistance rates and reduced mortality to patients.
Fluoroquinolones: Recommended for treatment of urinary tract
infections (ESBL).
Pipericllin- Tazobactam: This is not a first line treatment, and
presents lower susceptibility rates for ESBL infections. It is not used for
empirical coverage when ESBL rates are high.
Cefepime: Is a fourth generation cephalosporin. Its use leads
to selection for resistant strains, and is less effective than carbapenems.
Cefepime is not a first line treatment and is not used as monotherapy. It is
used in combination with other antibiotics such as aminoglycosides and
fluoroquinolones.
Fosfomycin: While an old drug, it lacks cross resistance with
other antibiotics. It has a wide spectrum of activity covering many
gram-negative and gram-positive pathogens including ESBL and CRE. It is
available in the USA only as an oral formulation and used to treat urinary
tract infections. In Europe an intravenous formulation is available.
SMX – TMP (Sulfamethoxazole – Trimethoprim): This class can be used to treat ESBL infections in patients that are allergic to -lactams. However, high resistance rates to ESBL and CRE limit their effectiveness.
Aminoglycosides: This class can be effective if lab testing shows
that isolates are sensitive to aminoglycosides. This class should not be used
as mono therapy against ESBL infections.
Treatment options for CRE
infections: Tigecycline
Aminoglycosides;
Polymyxin B and Colistin; Fosfomycin For treatment of CRE infections and
carbapenemase producing infections, these antibiotics can be used as
monotherapy or in combination therapy [30,29,35]. (Table 5) shows the various
treatment options with these antibiotics – used in both monotherapy and in
combination therapy. Because of limited clinical data, the choice of treatment
for CPE and CRE infections is controversial. The extensive use of combination
therapy remains under debate, as well as the optimal choice of drugs when
combinations are used. Most clinical studies have involved patients with KPC
and VIM producing strains (Table 4).
The treatment options
for CRE infections are fewer than for ESBL infections. The primary elements for
this application are [28,33].
Table 4: Antibiotic usage in
U.S. hospitals (2006 to 2012).
Antibiotic
Class |
2006 |
2007 |
2008 |
2009 |
2010 |
2011 |
2012 |
Change 2006 to 2012 % |
All |
53.8 |
54.0 |
54.9 |
55.7 |
55.7 |
56.3 |
55.6 |
+ 2.8 |
1st & 2nd
Generation Cephalosporins |
20.4 |
20.3 |
20.1 |
20,2 |
20.1 |
19.5 |
18.9 |
-
7.4 |
3rd & 4th
Generation Cephalosporins |
10.9 |
10.9 |
11.1 |
11.6 |
12.1 |
13.3 |
13.4 |
+ 32.1 |
Fluoroquinolones |
16.8 |
16.7 |
16.9 |
16.4 |
15.8 |
15.7 |
15.0 |
-
10.7 |
Glycopeptides |
8.2 |
8.9 |
7.9 |
10.7 |
11.3 |
12.3 |
12.9 |
+ 57.3 |
-Lactamase Inhibitors |
7.5 |
8.0 |
8.6 |
9.1 |
9.5 |
10.2 |
10.4 |
+ 38.7 |
Carbapenems |
1.7 |
2.0 |
2.3 |
2.6 |
2.7 |
2.9 |
3.0 |
+ 76.5 |
Penicillins |
6.0 |
5.7 |
5.5 |
5.1 |
5.2 |
5.3 |
5.3 |
-11.7 |
Notes: (i) DOT = Days of therapy; PD =
Patient Days (ii) Overall use of antibiotics
from 2006 to 2012 = 2.8% increase (iii) Use of carbapenem
antibiotics from 2006 to 2012 = 76.5% increase | ||||||||
Ref:
Table assembled by author based on data from Ref [50]. |
Table 5: Carbapenem retail sales
in Selected countries: 2005 – 2010.
Country |
Sales 2005 |
Sales 2010 (i) |
% Sales Increase 2005 – 2010 |
Standard Units (SU)
per 1,000 population | |||
Netherlands |
9.5 |
18.5 |
95 |
USA |
18.0 |
21.0 |
17 |
Brazil |
2.5 |
4.0 |
60 |
Vietnam |
1.0 |
9.0 |
800 |
Indonesia |
3.5 |
10.0 |
186 |
India |
11.0 |
63.5 |
477 |
Pakistan |
37.0 |
90.0 |
143 |
Egypt |
24.5 |
82.0 |
237 |
Table
assembled by author from data in Ref. [13]. |
Carbapenems: Using carbapenems as monotherapy is discouraged, as
it leads to increased resistance. However carbapenems are an essential element
of combination therapy.
Polymyxins (Colistin and Polymyxin B): This is an older drug and is active
against most gram-negative bacteria and CPE isolates. It is usually used in combination
with other agents. Some adverse effects are nephrotoxicity (reversible) and
neurotoxicity (rare).
Tigecycline: It has a broad spectrum of activity against
gram-positive and gram-negative bacteria including CPE. Non-susceptibility to
tigecycline against KPC-producing K. pneumoniae is becoming more common in
patients who have bene treated with this agent.
Aminoglycosides: Is effective against KPC-pneumoniae producing
strains, and is always used in combination therapy. It is not effective against
NDM-producing Enterobacteriacea.
Fosfomycin: The oral formulation is used to treat urinary tract
infections. For systemic infections, intravenous fosfomycin is used in
combination with another agent Combinations of carbapenem and fosfomycin are an
option for treating CRE strains that are resistant to colistin.
Monotherapy vs
combination therapy
The preferred clinical
practice is to treat invasive infections with a combination of two active
agents based on susceptibility patterns of the infection strain. This approach
results in lower patient mortality compared to monotherapy treatment. The
dosing for each agent should be optimized by using high doses. Uncomplicated
urinary tract infections can be managed with a single agent. Clinical data
suggests that combination treatment (two or more agents) that is active against
the infecting bacterial strain is superior in outcomes compared to monotherapy.
It has been shown that combination therapy is more effective against most CPE
infections even when the bacteria are resistant to an individual drug [30,32].
Most combination treatments utilize colistin. It is believed that colistin acts
to increase the permeability of the bacterial outer membrane. This effect in
turn facilitates action by the other agents used [33].
Empirical therapy
considerations for patients
For patients suffering
from severe septic infections and septic shock, use of empirical antibiotic
therapy should cover all of the patient’s suspected bacterial infections. Empirical
treatment with colistin and carbapenems or aminoglycosides is justified for
treating severely ill patients with a suspected CRE infection infection. However,
exclusive use of a broad spectrum antibiotic should be avoided to prevent
further selection of resistant bacteria and also prevent fungal super
infections and C. difficile outbreaks in hospitals [34-38].
General risk factors
CREs are easily
introduced into the population because they are highly transmissible, resulting
in colonization or infection of patients. Dissemination of mobile genetic
elements coding for resistance and especially with multidrug resistant strains has
been the cause of many reported outbreaks in hospitals [39] The European Center
for Disease Prevention has listed general risk factors associated with
colonization or infection with CRE, including: the length of hospitalization
(time at risk); severity of illness; mechanical ventilation; admission to the
ICU;, presence of wounds; positive blood culture; prior surgery; transfer
between hospital units; prior hospital stay; presence of catheters and
intubation [39].
Prior
antimicrobial use
Prior antibiotic
exposure has been found to be a risk factor for colonization and infection with
CRE and especially for K. pneumoniae (KPC) [30,39].
Carbapenems: Prior use of carbapenems is identified as an
independent risk factor for the acquisition of KPC producing K pneumoniae and
for carbapenem resistant KPC and carbapenem resistant E.coli [40].
Cephalosporins: Prior use of an extended spectrum cephalosporin is
identified as a risk factor for the acquisition of KPC producing K pneumoniae,
and also as an independent risk factor for the acquisition of KPC producing K
pneumoniae for carbapenemase resistant K. pneumoniae and also for carbapenem
resistant E.coli.
Fluorquinolones: Prior use of a fluoroquinolone antibiotic is
identified as a risk factor for the acquisition of KPC producing Klebsiella
pneumoniae. Use of fluoroquinolones is also an independent risk factor for the
acquisition of carbapenemase resistant K. pneumoniae.
Other antibiotics: Other antibiotics associated with risk of acquiring
carbapenemase resistant enterobacteriacea are the anti pseudomonal penicillins
and metronidazole.
Cross border
transmission and patient mobility
Cross border transfer of patients is a documented
risk factor for the introduction of carbapenemase producing. Enterobacteriaceae into healthcare
settings and systems. When patients are infected or colonized with
carbapenemase-producing Enterobacteriaceae are transferred across borders, the
risk of CRE being introduced and spread into healthcare facilities in the
country of destination is increased. The risk is higher when patients are
transferred from areas with high rates of CRE to healthcare facilities in
another country, or if such patents have received medical care abroad in areas
with high rates of CRE [39]. Cross-border transmission has been reported in
Asia, Europe and North America involving carbapenemase producing K. pneumoniae.
Infection control measures
Carbapenemase - producing
Enterobacteriaceae can colonize and infect not only patients who are
debilitated, immune-compromised or critically ill, but also that patients that
were previously healthy and became colonized or infected in healthcare settings
that practice poor infection control [39]. CREs and other ESBL producing
organisms can easily spread within the hospital environment. Preventing spread
of these organisms from patient to patient is the main focus of infection
control. A major issue is hand hygiene for healthcare professionals. The
cleaning of medical equipment and prevention of colonization of the hospital
environment are also important infection control measures. It is important to
screen patients being admitted or transferred from other institutions including
from nursing homes. Surveillance of infected and high risk patients is an
important action for monitoring an outbreak and also to prevent one [40-42]. Small
hospital outbreaks tend to be caused by a single clone and usually occur in
high risk areas such as the ICU, neonatal units and hematology-oncology units. Large
outbreaks usually involve several circulating strains of organisms at one time
and in several different areas of a healthcare setting [43]. The prevention of
the spread of carbapenemase producing pathogens relies on early detection [44].
Patients who undergo screening should include: (i) patients who were
hospitalized while abroad and then transferred to another country; (ii)
patients at general risk – intensive care patients, immunocompromised
patients). Screened patients should be kept in strict isolation before
obtaining results of the screening (at least 24 to 48 hours). Because the
reservoir of carbapenemase producers remains in the intestinal flora, use of
rectal swabs for screening are adequate to perform this screening measure- and
then plated directly onto screening media. After this screening procedure,
carbapenemase producers may be identified through a variety of techniques
including antibacterial drug susceptibility testing and molecular & PCR
based techniques [22,29].
The economic burden of
CRE
A study done by several
medical schools in the USA in 2016 (i.e- Johns Hopkin School of Public Health;
UCLA Medical Center; Torrance Memorial Medical Center; Univ. CA Irvine Medical
School) developed a CRE clinical and economic outcomes model using Monte Carlo
type simulations to determine the cost of CRE infection from the hospital,
third-party payer and societal perspectives to evaluate the economic burden of
CRE to the USA [41]. Depending on the infection type, the median cost for a single
CRE infection can range from $22,484 t0 $66,031 for hospitals, $10,440 to
$31,621 for third-party payers, and $37,778 to $83,512 for societal costs
(greater mortality and reduced productivity). An incidence of 15 infections per
100,000 population would cost hospitals $1.2 billion, third-party payers $0.8
billion, and societal costs of $2.4 billion per year [41]. CRE infections are
more costly that episodes of other infectious diseases. For example, in 2016
values, the costs for the following infectious disease to society are as
follow: (i) one influenza case is $2,807 to $8,889; (ii) one pertussis case is
$$600 to $1,169; (iii) one food borne salmonella case is $3,899 [41].
Increasing global
prevalence of CRE
The first
Carbapenemase-resistant Enterobacteriacea
(CRE) - K pneumoniae- was identified in North Carolina in the 1990s. Since
then, CRE have spread globally and are endemic in some countries, including
USA, Italy, Greece, Israel, China and India among others. Infections with CRE
are being increasingly reported from healthcare facilities in the developed
world, and with a higher prevalence over the past five years. Moreover, the
presence of CRE infections are being increasingly reported in LMI counties as
well. For example, in U.S. hospitals 11% of K. pneumoniae and 2% of E. coli
were resistant to carbapenems in 2013. As a comparison, in India 13% of E. coli
were resistant to carbapenems in 2012 and 57% of K pneumoniae were resistant to
carbapenems in 2014 [36,45].
Global reporting of extended spectrum -lactamase (ESBL) producing strains:
ESBLs can inactivate
all penicillins and cephalosporins, including third generation cephalosporins
and monobactams. In Europe, 17 of 22 countries reported that 85% to 100% of
E.coli isolates were ESBL positive. In the USA, healthcare-associated
ESBLproducing Enterobacteriaceae made up 14% of E. coli isolates and 23% of K.
Pneumoniae isolates. ESBL-producing Enterobacteriaceae are increasing in Asia.
In China in 2011, ESBL-producing E. coli accounted for 71% of E. coli isolates,
and more than 50% of K. pneumoniae
strains produced ESBL. In Latin America, ESBL-producing Enterobacteriaceae
prevalence is rising. Rates of ESBL in E. coli in Mexico were as high as 41% in
2009. In 2014, resistance of K. pneumoniae isolates to third-generation
cephalosporins ranged from 19% in Peru to 87% in Bolivia. In North Africa, ESBL
prevalence ranged from 12 to 99% in hospitals and from 1 to 11% in communities.
Global reporting of
CRE
Surveys by WHO (2014)
& CCDEP (2015): Countries surveyed submitted at least 30 isolates showing
resistance to at least one carbapenem. Those countries reporting CRE K.
pneumoniae in the range of 50% to 61% included: India, Pakistan, Bangladesh and
Greece. Those countries reporting CRE K pneumoniae in the range of 20.1% to
49.9% included: Vietnam, Iran, Romania, Israel, Guatemala, and Nicaragua. Those
countries reporting CRE K. pneumoniae in the range of 6% to 20% included:
China, Burma, Serbia, Argentina, Ecuador, Colombia, Venezuela, and USA [31].
CRE prevalence in
Europe
A multi country survey was carried out in Europe in 2012 with 33 countries reporting data [46,47]. The prevalence of CRE is variable across Europe, but is higher in Greece and Italy and lower in the Nordic countries. It was found that K pneumoniae was the most prevalent type of Enterobacteriaceae species harboring CRE in those countries. The five most common CRE among Enterobacteriaceae reported by these countries are the metallo--lactamases IMP, VIM, NDM- from Amber Molecular Class B; OXA-48 and its derivatives from Amber Molecular Class D; KPC from Molecular Class A [29]. Overall, KPC producing Enterobacteriacea are the most frequently detected among CRE in Europe. The major concern with OXA carbapenemases is their ability to rapidly mutate and expand their spectrum of activity. In the United States, >50% of A. baumannii are resistant to carbapenems due to production of OXA class carbapenemases [48]. It appears that prevalence of CRAb in Europe is under reported. This is because surveillance and reporting of CRAb are not performed routinely and there are fewer reference laboratories for CRAb in Europe.
General considerations
There is a causal
association between use of antimicrobial drugs and the emergence of AMR. Changes
in antibiotic use are also paralleled by changes in the prevalence of
resistance. AMR is more prevalent in healthcare associated bacterial infections
than with community acquired infections. Patients with healthcare associated
infections caused by resistant strains are more likely than control patients to
have received prior antibiotic treatment within the hospital. Those patients
with the highest rates of resistant strains also have the longest duration of
exposure to antibiotics. The longer exposure period increases the likelihood of
colonization with resistant organisms [13,30,41]
Overuse of broad
spectrum antibiotics
It is the practice in
hospitals to give patients broad spectrum antibiotics, even when a specific
pathogen is identified. Such practices contribute to the spread of resistant
strains to many non- target organisms. In a survey of 605 hospitals in the USA
during 2009/2010, only 59% of patients received appropriate antibiotic
treatment. In this survey, during the 5th day of therapy, 6% of antibiotic
treatments regimens were unchanged despite there being negative bacterial
cultures in 58% of the patients on therapy. The survey indicated that broad
spectrum antibiotics were commonly prescribed to patients even when the signs
of infection were not present – including negative cultures -and the antibiotic
treatment was not discontinued. Another survey done in 2010 of 323 hospitals in
the USA 56% of patients received an antibiotic during their hospital stay, and
primarily with broad spectrum antibiotics. Among the patients receiving
antibiotics, 37% of antibiotic treatments given were judged as needing
improvement. The use of diagnostic tests in these cases would have resulted in
more appropriate antibiotic regimen to those patients. The trend for antibiotic
usage in U.S. hospitals is illustrated (Table 4). The rates of inappropriate prescribing
of antibiotics is also common in international hospitals. For example, In
Vietnam, it was found that ½ of hospital prescriptions for antibiotics were
inappropriate [48-50].
Antibiotic use for
surgery prophylaxis
In high income
countries, pre surgical antibiotics are standard treatment to prevent
post-surgical infection. However, in many LMICs (Low & Middle Income
countries) antibiotics are commonly given after surgical procedures. This
practice presents a higher risk of surgical site infections. It is found that
LMIC hospitals used seven times more antibiotics when they are given
post-surgery rather than pre surgery [49]. This practice increases costs and also
increases AMR potential. Even when antibiotics are given before surgery, the
regimen or duration of the treatment may be suboptimal. A survey of hospitals
in India [51] showed a range of 19% to 86% of patients received inappropriate
antibiotic prophylaxis. Proper antibiotic prophylaxis improves both hygiene,
better surgical techniques and lowers the rate of surgical site infections.
Suboptimal use of
antibiotics in hospitals
The suboptimal use of
broad spectrum antibiotics and also suboptimal use of post-surgical antibiotics
is prevalent both in North America, Europe and the LMIC, and so represents an
opportunity to improve antibiotic use in hospital settings. Estimates have been
made that a range of 20% to 50% of total antibiotic use in hospital settings
are inappropriate [50,52]. Inappropriate antibiotic use includes: (i) Use of
antibiotics when there is no benefit from its use, such as treating urinary
tract infections caused by virus and (ii) incorrect antibiotic selection, incorrect
dosage, incorrect duration of treatment the patient receives.
Antibiotic use in the
community
Overuse and misuse of
antibiotics in outpatient settings is a major driver of AMR. An estimated 80%
of all antibiotics are consumed outside of hospitals in outpatient settings
[49]. These healthcare settings include: i) self-medication; (ii) outpatient
clinics and private physician offices; (iii) nursing homes.
Antibiotic overuse by
self-medication
Outpatient use also
includes antibiotics purchased by consumers directly and without a
prescription. Although most countries require a prescription as condition for
purchase of an antibiotic, these regulations are not enforced in most LMIC, or
do not exist. Nonprescription use of antibiotics can range from 19% to over 90%
outside of the USA and Europe. For example, in rural and urban pharmacies in
Vietnam, 88% to 91% of all antibiotic sales in a survey made were without a
prescription. Similarly, most antibiotics sales in Saudi Arabia (78%) and Syria
(87% to 97%) were dispensed without a prescription [49].
Antibiotic overuse by
prescribers
Healthcare providers
also play a role in driving inappropriate antibiotic use in the community. They
routinely prescribe antibiotics for infections that are not caused by bacteria.
A major factor for overprescribing is the pressure that patients put onto
prescribers for an antibiotic prescription. In a survey done in the USA, 48% of
respondents indicated that they expected an antibiotic when they visited a
doctor [49]. In a survey done in France, 50% of interviewees expected an
antibiotic for treatment of influenza like illness [49]. Other factors leading
to high rates of antibiotic prescriptions by prescribers include diagnostic
uncertainty. Since most diagnostic lab methods are based on the culture of
pathogens that require 36 to 48 hours to provide results, few infections are
accurately diagnosed in these practice settings. In the absence of a clear
diagnosis, the prescriber often feels pressured to prescribe antibiotics to be
on the safe side or to prevent secondary bacterial infections [49,53]. A recent
study commissioned by the Pew Charitable Trusts in May 2016 [54] found that 13%
of all out patient office visits in the USA (154 million visits/year) resulted
in an antibiotic prescription. About 31% of these antibiotic prescriptions (47
million) are considered to be unnecessary The Pew study also found that 44% of
outpatient antibiotic prescriptions (68 million) were written to treat patients
with acute respiratory conditions (including: sinus infections, middle ear
infections, pharyngitis, viral upper respiratory tract infections -common cold;
bronchitis; bronchiolitis; asthma; allergies; influenza and pneumonia). Half of
these prescriptions are unnecessary because many of these conditions are viral
illnesses or other conditions that do not respond to antibiotics. In addition
to using medications that will not affect the illness, such improper use of
antibiotics also carries the risk of adverse drug effects and other side
effects. It is estimated that improper use of antibiotics in the USA results in
140,000 emergency room visits per year [54]. (Table 5) compares the retail
sales of Carbapenem antibiotics in selected countries for the period of 2005 to
2010 and showing the growth in antibiotic sales increase during that period
[13,55-57].
Antibiotic overuse in
nursing homes
In the USA, 1.6 million
people live in nursing homes. Out of that population, about 250,000 people will
acquire infections every year. And out of that population, nursing home
residents will acquire 27,000 antibiotic resistant infections. It is further
estimated that up to 70% of nursing home residents are prescribed an antibiotic
every year. And of these antibiotic prescriptions, from 40% to 75% are
prescribed incorrectly – ether being unnecessary or else incorrectly for the
drug prescribed, or the dose, or the duration of therapy [58]. Of particular
concern is the widespread use of broad spectrum oral antibiotics such as
quinolones for which overuse can be a major driver of AMR. Nursing home
residents are more vulnerable to infections because of biological factors
(reduced immune system, prevalence of chronic diseases, use of invasive devices
such as urinary catheters and feeding tubes) and environmental (crowding,
sanitation issues). Nursing homes are being increasingly identified as
important reservoirs for the development of multidrug-resistant (MDR) organisms
and their transmission into the community. The three most frequently reported
infections in nursing homes are: Urinary tract infections (UTI), Respiratory
tract infections (RTI) and Skin and soft tissue infections (SSTI) [58]. These
same groups of infections are the leading causes for antibiotic prescribing in
nursing homes. Some studies also report that UTIs and RTIs are the most
commonly observed causes for hospital admissions among the elderly from nursing
homes. Overuse of antibiotics in nursing homes not only produces UTI and RTI
that are resistance to antibiotic treatment, but are also a major cause of
hospital admissions of nursing home residents. Studies have demonstrated that
nursing homes are a reservoir for carriage of three major groups of MDR
organisms (i.e. MRSA, VRE and MDR GNB (Gram-negative bacteria). However in
recent years there has been a shift towards greater colonization with MDR GNB.
Some studies show MDR GNB colonization far exceeding that of MRSA and VRE. It
has been found that prior exposure to antibiotics is a prominent risk factor
associating with both colonization and infection of both MDR gram-positive and
gram-negative organisms [39,41,58]. Moreover, repeated antimicrobial
utilization, and particularly the repeated use of broad-spectrum antibiotics
will increase the risk of Clostridium difficile infection – a leading cause of
hospitalization of nursing home residents [58].
Areas of potential
antibiotic misuse in nursing homes
Major areas of
potential antibiotic misuse in nursing home that lead to development of AMR are
listed below [58-63].
·
Prophylactic antibiotics for UTI: There is little evidence to support the use of
long-term urinary prophylaxis. However, there is strong evidence showing that
prolonged antibiotic use in the absence of infection will always select for
resistant organisms.
·
Empiric prescribing without
microbiological investigation: Causative etiologic agents should be
identified through microbiological testing, especially for symptomatic UTIs, to
guide the adjustment of empiric antibiotic therapy.
·
Treatment of asymptomatic bacteriuria: This condition is common with
chronically cauterized patients. However, antibiotic treatment will not prevent
recurring bacteriuria or symptomatic infections. The right strategy is to
change indwelling catheters prior to starting antibiotic therapy and taking a
urine sample collected from the newly placed catheter. Discontinuation of
catheter use and proper aseptic technique on catheter changing are the keys to
preventing UTIs and other urinary complications [58].
·
Widespread prescribing for upper RTIs or
acute bronchitis:
Among elderly nursing home residents, upper RTIs are usually caused by viral
pathogens. Therefore, empiric antibiotic treatment is both unnecessary and
ineffective. It is necessary to differentiate between bacterial or viral origin
to reduce inappropriate use of ABS to treat RTS.
·
Prolonged duration of antibiotic
treatment: It is generally
considered that antibiotic courses of 7 days or less are as effective as longer
treatment duration for the majority of common bacterial infections. In
contrast, unnecessary prolonged antibiotic treatment increases patient risk for
side effects and AMR.
·
Widespread prescribing of quinolones as
empiric treatment for UTIs:
The quinolone
antibiotics are frequently used to treat both low and complicated UTI because
of their high bioavailability, long half-life, and broad-spectrum activity
spectrum. Consequently a high rate of quinolone-resistant gram negative
organisms is often observed in nursing homes with a high use of quinolones [58-108].
General considerations
The consensus of experts is that prior use of all antimicrobial products, and more specifically the carbapenems, 3rd and 4th generation cephalosporins and fluorquinolones increases the risk of infection or colonization with CRE [79]. High rates of multi drug resistant organisms (MDROs, ESBL producing bacteria are considered to be independent risk factors for the spread of carbapenemase resistant mechanisms. The intensity and duration of antibiotic treatment are the most important variables for the selection of CRE producing bacteria [109]. A review of the medical literature indicates there is an important relationship between prior antimicrobial therapy and the subsequent identification of carbapenemase-producing bacteria. In a four year case control study of 102 patients, the only covariate independently associated with CRE in all multivariate analyses was the cumulative number of prior antibiotic exposures [109,110]. In another case-control study performed in Greece and lasting 26 months (96 ESBL-carbapenem-resistant K. pneumoniae and 55 ESBL-carbapenem-sensitive K. pneumoniae) identified the key risks factors as: (i) prior cumulative exposure to antibiotics and (ii) increasing duration of prior antibiotic treatment [109] [111]. The antibiotic treatments covered in these studies included use of a -lactam or -lactamase inhibitor or a combination of fluoroquinolone and carbapenem. The most important variables responsible for selection of carbapenemase – producing bacteria are the intensity and duration of antibiotic therapy [109]. Controlling the spread of CRE infections requires both the prudent use of antibiotics plus infection control. Additional clinical studies suggest that the patient’s cumulative exposure history is likely to be a greater risk factor than any one specific antibiotic exposure to determine a patient’s chance of acquiring a resistant pathogen [112].
Reducing overuse of antibiotics
From 20% to 50% of all
antibiotic use is estimated to be inappropriate [110], covering both (i) the
use of antibiotics when there is no possible health benefit, such as treating
upper respiratory tract infections caused by virus origin, and (ii) the
suboptimal use of antibiotics such as incorrect choice of prescribed drug
(i.e.- unnecessary broad spectrum antibiotic), incorrect dosage or duration, or
poor patient adherence, substandard quality of antibiotic product – all of
these factors contribute to the development and spread of AMR It has been found
in Europe that regional and national campaigns to educate healthcare workers
and patients about the danger of AMR can help change behavior to reduce
inappropriate prescribing. Two such effective campaigns took place in Belgium
and France [49]. Prior to this national education/awareness campaign, both countries
had the highest rate of antibiotic consumption in Europe. The French campaign
started in 2001 and achieved a reduction of 27% for antibiotic prescribing over
five years. The Belgian national media campaign achieved a 36% reduction in
antibiotic prescriptions over a seven year period. Both countries also showed a
corresponding reduction in antibiotic resistant pneumococci following these
campaigns.
Prudent use
recommendations
·
Rapid
diagnostics: Patients with sepsis must be
treated quickly, but empirical antibiotic treatment is often started before
reliable microbiology assessments are available. This results in some patients
receiving incorrect antibiotic treatment. More rapid diagnostics are needed so
that the appropriate antibiotic treatment can be administered more quickly and
using broad spectrum antibiotics for the shortest duration to reduce selection
pressure for resistance [111,112].
·
Colonization
prevention: The prevention of colonization can
have considerable benefit in the era of CRE infections. Hospitals should take
rectal samples of patients at risk. If the isolates are KPC positive, the
patient should be isolated in a single room and bathed daily with chlorhexidine
gluconate
·
Heterogeneity
of antibiotic usage: Patterns of antibiotic
use in which the same antibiotic given is given repeatedly (homogeneity) is
associated with higher rates of resistance than when there is variability in
antibiotics prescribed for the patients (heterogeneity). It has been shown that
monthly cycling of four antibiotics (PTZ, imipenem/cilistin, ceftazidime,
ciprofloxacin) as the primary antibiotic to treat suspected Gram-negative
infections was associated with an overall improvement in the antibiotic
susceptibility profile of Gram – negative organisms compared with the medical
ICU in the same hospital where cycling was not performed. These results suggest
that increased diversity of prescribing may correlate with reduced levels of
resistance.
The avoidable costs of
antibiotic misuse
In addition to the rise
of antimicrobial resistance (AMR), the misuse of antibiotics for medical
applications represents large avoidable healthcare costs in the USA $35
billion/year [113]. Within that amount, most of that amount ($23 billion) is
incurred through inpatient care (hospital use). The avoidable costs are defined
as the added cost of treating a patient with an antibiotic resistant infection
relative to a patient with an antibiotic susceptible infection. The estimated
avoidable costs for the inpatient setting include longer medical treatments,
expensive second-and third-line antibiotic therapies, and screening and
diagnostics to detect and prevent the spread of bacterial strains. The cost of
excessive antibiotics prescribed in outpatient settings in the USA is $1
billion/year [113].
Basis for antimicrobial
stewardship (AMS) program
An AMS program is a set
of coordinated strategies to optimize the use of antimicrobial medications in
order to improve patient safety and outcomes, decrease and prevent the
development of antimicrobial resistance, and decrease costs [114]. Recent data
[115] suggests that up to 55% of all hospital patients in the USA receive an
antibiotic, and that between 30% to 50% of the prescribed antibiotics may not
be appropriate. The inappropriate prescribing of antibiotics leads to potential
complications and adverse drug events. It also may cause hospital acquired
infections. Comprehensive AMS programs have been shown to decrease antibiotic
use by 22% to 36% and halt the development and spread of antimicrobial
resistant bacteria [115]. Core members of a multidisciplinary AMS team may
include: (i) Infectious disease physician; (ii) Clinical pharmacist with
infectious disease training; (iii) Clinical microbiologist; (iv) Information
system specialist; (v) Infection control professional; and (vi) Hospital
epidemiologist. The CDC reported that in 2014 nationally, 39.2% of all
hospitals had AMS programs (1,642 out of 4,184 hospitals). The national goal is
for 100% of hospitals to have an AMS program by 2020.
The Centers for
Medicare and Medicaid Services (CMS) will require hospitals to reduce
antibiotic use starting in January 2017 [116].
Core strategies for an
AMS program
There are two core
strategies that provide the foundation for an AMS program. These strategies ae
not mutually exclusive [117].
·
Prospective
audit with intervention and feedback strategy:
This strategy involves a prospective audit of antimicrobial use with direct
interaction and feedback to the prescriber, performed by either an infectious
disease physician or a clinical pharmacist. This strategy can result in both
reduced inappropriate use of antibiotics and also the improved use of
antibiotics. Effective auditing with intervention and feedback can be
facilitated through computer surveillance of antimicrobial use. .
·
Formulary
restriction and preauthorization strategy:
Formulary and preauthorization requirements can lead to immediate and
significant reductions in antimicrobial use and cost, and may be beneficial as
part of a multifaceted response to a nosocomial outbreak of infection. The use
of preauthorization requirements as a means of controlling AMR is less clear,
because a long-term beneficial impact on resistance has not yet been
established. And in some circumstances, this policy may just shift to using an
alternative agent with resulting increased resistance. Preauthorization use policy
requires monitoring overall trends in antibiotic use in order to assess and
respond to such shifts in use. The effectiveness of a preauthorization process
depends on who is making the recommendations. One examples is a study [118]
done in a hospital that experienced an increasing incidence of cephalosporin
resistant Klebsiella. A preapproval policy was implemented for cephalosporins,
resulting in an 80% reduction in hospital-wide cephalosporin use and a
subsequent 44% reduction in the incidence of ceftazidime-resistant Klebsiella
throughout the medical center.
CDC’s core elements of
antibiotic stewardship programs
In 2014, CDC
recommended that all acute care hospitals implement AMS programs. The CDC
published seven core elements of successful hospital antibiotic stewardship
programs. These elements include the pharmacist’s role in antibiotic
stewardship [119]. The CDC core elements are the following:
·
Leadership Commitment: Dedicating necessary human, financial
and information
·
Accountability: Appointing a single leader responsible
for program outcomes. Experience with a successful programs show that a
physician leader is effective.
·
Drug Expertise: Appointing a single pharmacist leader
responsible for working to improve antibiotic use.
·
Action: Implementing at least one recommended action, such
as systemic evaluation of ongoing treatment need after a set period of initial
treatment (i;e; “antibiotic time out” after 48 hours)
·
Tracking: Monitoring antibiotic prescribing and resistance
patterns
·
Reporting: Regular reporting information on antibiotic use and
resistance to doctors, nurses and relevant staff
·
Education: Educating clinicians about resistance and optimal
prescribing.
Supplementary elements
of an AMS program
The Infectious Disease
Society of America (IDSA) and the Society for Healthcare Epidemiology of
America have also recommend supplemental strategies [117]:
·
Antimicrobial cycling and scheduled
antimicrobial switch:
“Antimicrobial cycling:” refers to the scheduled removal and substitution of a
specific antimicrobial or antimicrobial class to prevent or reverse the
development of AMR within an institution. In true cycling, there is a return to
the original antibiotic after a defined time as opposed to a simple switch of
antibiotics. Antimicrobial cycling is an attempt at controlled heterogeneity of
antimicrobial use to minimize antimicrobial selection pressures. There is
insufficient data to recommend the routine use of antimicrobial cycling as a
means of preventing or reducing AMR over a prolonged period of time.
Substituting one antibiotic for another may transiently decrease selection
pressure and reduce resistance to the restricted agent. However unless the
resistance determinant has been eliminated from the bacterial population, the
reintroduction of the original antibiotic will likely select for the expression
of the resistance determinant in the exposed bacterial population.
·
Combination therapy-prevention of
resistance versus redundant antimicrobial coverage: The rationale for combination therapy includes
broad spectrum empirical therapy for serious infections, improved clinical
outcomes and the prevention of resistance. These recommended situations include
the use of empirical therapy for critically ill patients at risk of infection
with multidrug resistant pathogens in order to increase the breadth of coverage
and the likelihood of adequate initial therapy. However in many situations,
combination therapy is redundant and unnecessary, and there is insufficient
data to recommend the routine use of combination therapy to prevent the
emergence of resistance.
·
Streamlining or de-escalation of
therapy: Efforts to
optimize empirical initial antimicrobial therapy may conflict with good AMS to
promote judicious use of antibiotics, because continuing excessively broad
therapy contributes to the selection of AMR pathogens. This conflict can be
resolved when culture results become available by streamlining or de-escalating
antimicrobial therapy to more targeted therapy that decreases antimicrobial
exposure and contains cost. The elimination of redundant combination therapy
can result in reduced antimicrobial exposure and resistance.
·
Dose optimization: Optimization of antimicrobial dosing
based on individual patient characteristics, causative organism, site of
infection, and pharmacokinetic and pharmacodynamics characteristics of this
drug is an important part of AMS.
·
Conversion from parenteral to oral therapy: A systematic plan for parenteral to
oral conversion of antimicrobials is important.
·
Coordination with microbiology
laboratory: The clinical
microbiology laboratory plays a critical role in AMS by providing
patient-specific culture and susceptibility data to optimize individual
antimicrobial management and by assisting infection control efforts in the
surveillance of resistant organisms and in the molecular epidemiologic
investigation of outbreaks.
· Monitoring of process and outcome measurements: Both process measures (did the intervention result in the desired change in antimicrobial use) and outcome measures (did the process implemented reduce or prevent resistance or other unintended consequences of antimicrobial use) are useful in determining the impact of AMS on antimicrobial use and resistance patterns [118-124].
Antimicrobial resistance (AMR) among gram-negative bacteria has reached critical levels on a global basis. The rise of carbapenemase resistance in Enterobacteriaceae carrying additional resistance genes for multiple antibiotic classes has created a phalanx of organisms that are resistant to all available antimicrobial treatment [122]. Carbapenem Resistant Enterobacteriacea (CRE) infections are known to be associated with significant morbidity and mortality. Some experts have suggested that the global population will face two concomitant and worldwide epidemics of carbapenemase producers [43]. The first epidemic will cover carbapenemase producers as a source of community acquired infections. The second epidemic will cover nosocomial carbapenemase producers in K. pneumoniae of all types. (KPC, IMP, VIM, NDM and OXA-48). For the first epidemic, community acquired infections for these carbapenemases are primarily of the NDM and OXA-48 types. In contrast to a viral epidemic (i.e. - pandemic H1N1 in 2009), an epidemic of carbapenemase producers cannot stop spontaneously. This is because there are multiple factors involved that favor propagation, including: lack of hygiene, overuse of antibiotics and increased global travel. In addition, there are many carbapenemase producing organisms that carry unrelated drug-resistance determinants resulting in their spread to both -lactam antibiotics and to other antibiotic that are not structurally related to -lactams. The actual prevalence of carbapenemase producers is not clear because many countries that are likely to be their main reservoirs have poor detection and reporting systems in place. For the second epidemic – nosocomial infections, the likely cause will be carbapenemase producers in K. Pneumoniae of all types (KPC, IMP, VIM NDM1 and OXA-48. In certain countries, high rates of various types of carbapenemase producers already exist: Greece (VIM, & KPC) and the Indian subcontinent (NDM, KPC, and OXA-18). It is believed that K. pneumoniae will be a likely carrier of carbapenemase infections because it has been repeatedly cultured in the most common Enterobacteriacea species for spreading ESBL genes in healthcare facilities during the past 30 years. It is therefore expected that K. Pneumoniae will be the most likely carbapenemase producer found in patients with identical risk factors for ESBL infections: It is therefore an urgent task for early identification of carbapenemase producers (CRE) in clinical infections at the carriage stage – in order to prevent the development of hospital outbreaks of infection [43]. The lack of new antibacterial drugs in the development pipeline of pharmaceutical companies is a serious global problem. Carbapenemase producers in Enterobacteriacea are different from other multi-drug resistant bacteria because they are susceptible to few if any antibiotics. Therefore, it is essential that prudent use of antibiotics in clinical and outpatient practice settings be done in order to preserve the therapeutic efficacy of the existing arsenal of antibiotics for as long as possible [11]. Fundamental changes are required in the application of antibiotics for both medical and non- medical applications. A recent study by the British Govt [11] has recommended the following steps to reduce antibiotic demand and consumption:
·
A
massive global public awareness campaign to cover both patients and farmers to
reduce their demand; and prescribers and clinicians to not prescribe
antibiotics when they are not needed.
·
Improve
hygiene and prevent the spread of infection. This effort includes improvement
in access to clean water and better sanitation in developing countries, and
reducing infections in healthcare settings in all countries.
·
Reduce
unnecessary use of antibiotics in agriculture and their dissemination into the
environment.
·
Improve
global surveillance of drug resistance and antimicrobial consumption in humans
and animals. While surveillance is a cornerstone of infectious disease
management, it has been under-resourced in the effort to reduce AMR.
·
Promote
new rapid diagnostics to reduce unnecessary use of antibiotics.
·
Promote
the development and use of vaccines as alternatives. By reducing and preventing
infections, demand for therapeutic treatments and also antibiotic use will be
reduced. These steps are expected to slow the development and spread of AMR.
·
Increase
the number of effective antimicrobial drugs to defeat infections that have
become resistant to existing medicines.
In
conclusion, the world faces serious global public health problems from a post
antibiotic world. The problem of AMR and CRE infections in particular put a
high economic burden onto the healthcare system. The cost of CRE infection is
higher than the annual cost of chronic diseases and of many acute diseases. Costs
rise proportionately with the incidence of CRE infection [41]. Many of the
drivers of AMR have a common origin in inappropriate use of antimicrobials in
both human and animal health care or in agriculture or from environmental
contamination. From a more immediate tactical view, key steps to prevent the
establishment of CRE are early detection through good diagnostic practices and
containment of spread through patient and contact screening as well as
infection prevention and control measures including antibiotic stewardship
[47].
This Presentation is
dedicated to the memory of Sir Ernst Chain, the founder of the Antibiotic Era. The
world continues to benefit from his research efforts and innovations.