IAP Specialty Series on Rational Antimicrobial Practice in Pediatrics Nitin K Shah, Tanu Singhal
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Basics of Microbiology and Pharmacology

Antimicrobial Resistance1

Simantini Jog,
Camilla Rodrigues
 
INTRODUCTION
Infections kill at least 13 million people every year, mostly in the developing world. Whilst use of antimicrobials has greatly diminished mortality in infectious diseases, bacteria have quickly evolved and developed resistance to many of these drugs. Resistance confers a survival advantage and just as bacteria have adapted to every ecological niche on earth, so too they have learnt to adjust to the world of antibiotics. Resistant bacteria have no qualms about begging, borrowing, stealing chunks of genetic material from other bacteria in order to survive. The upsurge in drug resistance is due to a number of factors, the most prominent being the inappropriate and excessive use of antimicrobial agents. We did not bargain for this undercurrent of genetic exchange in our exploitation of antimicrobials.
Antimicrobial resistance (AMR) is a global emergency. Resistant organisms are difficult to treat, pose challenges for infection control practices in hospitals, adversely impact hospital in-patient stays and mortality and are a huge burden in terms of health-care costs.
 
Terminology
 
Natural Resistance
That which is beyond the usual spectrum of an antimicrobial.
Example: Aerobic gram-negative bacilli are naturally resistant to clindamycin.
 
Acquired Resistance
Microbial resistance in a previously sensitive organism
Example: Ampicillin-resistant H. influenzae—due to β lactamase production.
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Intermediate or Relative Resistance
Gradual increase in minimum inhibitory concentration (MIC) of organisms over time, but organisms still susceptible to antibiotic at achievable serum and tissue concentrations.
Example: S. pneumoniae and penicillin—the definition of susceptibility of S. pneumoniae to penicillin has changed to reflect the site of infection and route of therapy.
 
High Level or Absolute Resistance
Sudden increase in MIC of a single isolate during or after therapy. High-grade resistance cannot be overcome by increasing antibiotic concentrations even with higher than the usual clinical doses.
Example: Often seen with P. aeruginosa to aminoglycosides or quinolones.
 
Pseudo-resistance
Resistance by in vitro susceptibility testing but are effective in vivo.
Example: E. coli and K. pneumoniae resistance to sulbactam/ampicillin.
 
Cross-resistance
Cross-resistance among a group of antibiotics requires the use of another class of antibiotics to eliminate the resistant organism. With some organisms, cross-resistance within an antibiotic class does not mean that other members are resistant. Strains of gentamicin resistant P. aeruginosa are sensitive to amikacin. Tetracycline resistant methicillin-sensitive S. aureus (MSSA) is susceptible to doxycycline and uniformly susceptible to minocycline. Similarly, many strains of S. pneumoniae are resistant to tetracycline, but few, if any, are resistant to doxycycline. With other organisms, class cross-resistance is complete. Gram-negative bacilli producing extended-spectrum β lactamases are resistant to all third generation cephalosporins.
 
Mechanisms of Antimicrobial Resistance
Bacteria become resistant by essentially four mechanisms:
 
Inactivating Enzymes
These include aminoglycoside inactivating enzymes, β lactamases, chloramphenicol acetyl transferase, etc. Aminoglycosides such as gentamicin, amikacin, netilmicin and tobramycin are broad-spectrum antimicrobials used to treat infections caused primarily by aerobic gram-negative bacilli. These agents also are used in combination with a β lactam antibiotic to treat gram-positives. The most common mechanism of resistance to aminoglycosides is through producing aminoglycoside-modifying enzymes (AME) that inactivate the drug.
Beta lactamases are enzymes that split the amide bond of beta lactam ring and are encoded by chromosomal or transferable genes (plasmids/transposons). Several classes of the enzymes have been described. Beta lactamases are produced by gram-positive organisms (Staphylococci, Enterococci), gram-negative organisms as well as anaerobes (Fusobacteria, Clostridia, B. fragilis). Today extended spectrum beta lactamases (ESBL) 3in E. coli and K. pneumoniae, derepressed mutants including Amp C in organisms with inducible beta lactamase and metallo beta lactamases (MBL) in P. aeruginosa and other coliforms like K. pneumoniae are being found with increasing frequency in hospitals.
 
Alteration of the Target Site
Structural modifications result in a lower affinity of the target site for the antibiotic so that the antibiotic binding to the target is decreased or totally eliminated. For penicillin resistance in Streptococcus pneumoniae the mechanism involves alterations in one or more of the penicillin binding proteins (PBP). The genes that code for the altered PBP are termed “mosaics” as they consist of segments of native pneumococcal DNA mixed with segments of foreign DNA presumably from other penicillin resistant organisms such as viridans Streptococci that have been mopped up by the Pneumococcus and incorporated into the chromosome. Methicillin resistant S. aureus (MRSA), which codes for an altered penicillin binding protein, renders all β lactam antibiotics ineffective.
Fluoroquinolones act on the bacterial enzymes topoisomerase IV and DNA gyrase. These enzymes are required for efficient cell division. Four subunits of topoisomerase IV exist, two C (Par C) and two E (Par E) subunits encoded by par C and par E genes while DNA gyrase is composed of two A (Gyr A) and two B (Gyr B) subunits encoded by gyr A and gyr B genes. DNA gyrase is the primary site of action in the gram-negative bacilli whereas topoisomerase IV is the principle target of quinolones in gram-positive bacteria. Resistance to fluoroquinolones occurs by target modification in a step-wise fashion, resulting from mutations in the quinolone-resistance-determining region (QRDR) of par C (low level) and/or gyr A (high level).
 
Alteration of Bacterial Cell Membrane
 
Outer membrane permeability
There are structural differences between the cell walls of gram-positive and gram-negative organisms. Gram-positive bacteria have a single cell membrane with a generous external layer of peptidoglycan. For β lactam and glycopeptide antibiotics, which do not have to traverse the plasma membrane to exert their activity, transport across the membranes of gram-positive bacteria is no issue at all. Gram-negative bacteria possess an inner plasma membrane and an outer cell membrane between which is an attenuated peptidoglycan layer. The outer cell membrane includes lipopolysaccharides with tightly bound hydrocarbon molecules, which impede hydrophobic substances like nafcillin and erythromycin.
 
Porin proteins
The passage of hydrophilic antibiotics is facilitated by porins. Porin proteins are arranged to form water filled diffusion channels through which antibiotics traverse. Negatively charged molecules move more slowly across the membrane than do more positively charged molecules or zwitterions. Beta lactams with bulky side chains such as piperacillin cross the membrane poorly. Imipenem, a zwitterionic hydrophilic compound with a very compact structure, however, performs the best. In Pseudomonas aeruginosa, imipenem gains 4entry not through the main porin protein but through a specific transport protein designated D2. Resistance to imipenem is by decreased permeability through this porin channel.
 
Antibiotic Efflux
In case of certain bacteria, an important mechanism of resistance is active removal of antibiotics from the bacterial cell so that intracellular concentrations of antibiotics never reach a sufficiently high level to exert antimicrobial activity. This efflux mechanism is energy dependent. This is a prime defense for bacteria against tetracyclines and macrolides. Also is responsible for Pseudomonas being resistance to meropenem.
 
Molecular Genetics of Antibiotic Resistance
Genetic variability that helps in evolution of microbes is the result of mutations. Point mutations result in a change in a nucleotide base pair, which is referred to as micro-evolutionary change. For example, point mutations at critical locations on old β lactamase genes are responsible for the newly recognized extended spectrum β lactamases (ESBL).
A macroevolutionary change is a whole scale rearrangement of large DNA segments at a single event. This includes inversion, duplication, insertion, deletion or transposition of large sequences of DNA from one location of a bacterial chromosome or plasmid to another.
Plasmids are extrachromosomal circular double stranded DNA pieces that act independently of the chromosome. Chromosomal DNA is relatively stable whereas plasmid DNA is easily mobilized from one strain to another. They are adapted to serve as agents of genetic evolution and resistance genes dissemination. The linking of resistance genes for multiple antibiotics on a plasmid allows bulk transfer of resistance characterizing many newly resistant organisms.
Transposons translocate from one area of a chromosome to another or between chromosome and plasmid or bacteriophage DNA. They are not capable of autonomous replication and hence exist on a replicon like chromosome, plasmid or bacteriophage. For example, transposon is responsible for tetracycline resistance in N. gonorrhoeae, Mycoplasma hominis and Ureaplasma urealyticum.
Some transposons or plasmids have genetic elements termed integrons that enable them to capture exogenous genes. A number of genes may, therefore, be inserted into a given integron, resulting in resistance to multiple antimicrobial drugs or possibly allowing the accumulation of both regulatory and structural genes in the same transposon. Insertion elements as integrons specialize in picking up “gene resistant cassettes” for rapid and efficient transfer of resistance.
Foreign DNA is acquired and carried by plasmids, bacteriophges, naked DNA sequences or transposable genetic elements. The resistance genes can then spread to other bacteria by processes like transformation (parts of DNA acquired by bacteria from external environment), transduction (bacteriophages which are bacteria specific viruses that help transfer DNA between bacteria) or conjugation (transfer via direct cell to cell contact).
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Bacterial resistance is somewhat different in the hospital and the community. Though interchangeable, each of these 2 environments represents different bacterial flora, different reservoirs, and different selective pressures.
 
Resistance in Gram-Positive Organisms
 
Streptococcus Pneumoniae
Pneumococcal resistance to β lactams has been increasing over the last decade. In 1999, the Invasive Bacterial Infection Surveillance (IBIS) group reported penicillin resistance in 1.3%, chloramphenicol resistance in 56% and resistance to cotrimoxazole in 17% of isolates respectively. At our center in Mumbai in the year 2003, we detected penicillin resistance in 12% of invasive and noninvasive isolates of S. pneumoniae, compared to 0% in 1992. Today, however, most nonmeningeal pneumococcal infections can be treated by standard doses of amoxicillin/ampicillin as the new CLSI breakpoints for penicillin have different breakpoints for meningeal and nonmeningeal sites. This change was prompted by the fact was no difference noted in the clinical outcome of nonmeningeal infections in patients who were drug resistant by the earlier breakpoints.
 
Mechanism
Pneumococcal resistance to β lactam antibiotics is a function of altered PBP (1a, 1b, 2a, 2b, 2c), transpeptidases involved in cell wall synthesis.
Pneumococcal serotypes most commonly associated with drug resistance are those most often responsible for infection and carriage in children, 6, 14, 19 and 23.
Risk factors for acquisition of drug resistant S. pneumoniae (DRSP) include:
  1. Previous antimicrobial therapy
  2. Day care center attendance
  3. Prior hospitalization
 
Identification in the laboratory
The use of oxacillin disk (1 μg) is required to screen for beta lactam resistance. If oxacillin is resistant, for meningitis, Pen MIC > 0.12 mg/mL regarded as R, however, for pneumonia, Pen MIC > 8 mg/mL regarded as R.
 
Management
Penicillin susceptible Pneumococci are susceptible to all commonly used cephalosporins. Penicillin intermediate strains are resistant to all first and many second-generation cephalosporins but are susceptible to some third-generation cephalosporins including cefotaxime and ceftriaxone as well as high doses of amoxicillin (80–100 mg/kg/day). One half of highly penicillin resistant Pneumococci are also resistant to cefotaxime and ceftriaxone, a higher proportion are resistant to cefepime and nearly all are resistant to cefpodoxime. They are, however, susceptible to other drugs such as vancomycin and linezolid.
 
Resistance in Enterococcus Species
Enterococci are naturally tolerant to penicillins and resistant to cephalosporins, clindamycin and achievable serum levels of aminoglycoside. Cephalosporin resistance is due to poor 6affinity of the antibiotic for enterococcal PBP. Natural low level aminoglycoside resistance is the result of inability of aminoglycosides to penetrate the cell wall; but in the presence of cell wall active drugs such as ampicillin or vancomycin, aminoglycosides are able to penetrate and work. High-level gentamicin resistance in enterococci has rapidly spread worldwide. This also is strongly associated with nosocomial acquisition. Such strains do not demonstrate synergistic killing when aminoglycosides are combined with penicillin or vancomycin. Most of such resistance is carried on transposons and is plasmid mediated. Detection of high-level gentamicin resistance requires testing with a disk with high concentration of gentamicin or streptomycin (e.g. > 500 μg/mL). Chromosomal high level penicillin resistance is a species-specific characteristic of E. faecium. Such strains are likely to be nosocomially acquired. High-level penicillin resistant E. faecium are also resistant to imipenem and lactam-β lactamase inhibitors and are often glycopeptide resistant. Since ampicillin or penicillin resistance among enterococci due to β lactamase production are not reliably detected using routine disk diffusion or dilution methods, a direct nitrocefin based beta lactamase test is recommended for the isolates of enterococci from blood and CSF. A positive beta lactamase test indicates resistance to penicillins, aminopenicillins, carboxypenicillins as well as ureidopenicillins.
 
Vancomycin-Resistant Enterococci (VRE)
Glycopeptides are large complex molecules that do not enter the bacterial cell. Vancomycin resistance mechanisms involve a complex series of reactions that ultimately result in the building of the cell wall by bypassing the D-alanine-D-alanine containing pentapeptide intermediate structure, thus eliminating the glycopeptide target.
 
Risk factors for VRE colonization/infection
  • Exposure to antibiotics such as broad-spectrum cephalosporins, fluoroquinolones, vancomycin
  • Longer length of hospital and ICU stay
  • Intra-hospital transfers
  • Liver transplant requiring surgical re-exploration.
Vancomycin-resistant enterococci are characterized phenotypically as van A, van B, and van C strains based on levels of resistance to vancomycin, cross-resistance to teicoplanin and inducible or constitutive nature of resistance. Strains exhibiting the Van A phenotype show an acquired inducible high level resistance to vancomycin and teicoplanin. Van B phenotype is associated with moderate to high level resistance to vancomycin but the isolates remain sensitive to teicoplanin. The Van C phenotype can be inducible or constitutive chromosomally mediated but rarely seen in Enterococci causing human infection. A fourth vancomycin resistant genotype Van D, described in a strain of E. faecium exhibits moderate levels of resistance to vancomycin and teicoplanin. A fifth Van E genotype has also been described in E. faecalis. Strict adherence to infection control measures to limit the spread of such isolates in the hospital setting is of critical importance.
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Management
Most strains of VRE. faecalis retain susceptibility to ampicillin and penicillin, which can be used for therapy. VRE. faecium isolates are usually highly resistant to ampicillin and may have high-level aminoglycoside resistance. Linezolid has excellent in vitro activity against E. faecium and E. faecalis and is effective in treating infections caused by VRE. Resistance to oxazolidinone antibiotics like linezolid is rare but can occur in Enterococci and Staphylococci. It is usually mutational and can be selected during treatment, especially long courses of the antibiotic. Plasmid mediated resistance occurs by the cfr gene which modifies the ribosomal RNA blocking the binding of linezolid. E. faecium isolates resistant to linezolid have been recently encountered in UK, the index case being a patient who fell ill on arrival to a hospital in UK from India. The concerned isolates were cfr gene positive.
Quinupristin – dalfopristin demonstrates bacteriostatic activity against most VRE faecium but has no activity against E. faecalis. Daptomycin is a relatively newer drug that can be used to treat VRE.
 
Resistance in Staphylococcus Aureus
 
Methicillin-Resistant Staphylococcus Aureus (MRSA)
Methicillin resistance in Staphylococci is mostly mediated by the mec A gene encoding for a single additional PBP, PBP 2a with low affinity for all β lactams. This gene is widely distributed in both coagulase positive and coagulase negative staphylococci and is carried on a transposon. Expression of this gene can be constitutive or inducible. MRSA isolates containing mec A are resistant to all β lactam antibiotics. Most nosocomial and health care associated isolates frequently carry other multiple resistance determinants. However, most community acquired MRSA strains are susceptible to multiple classes of antibiotics other than β lactams, including trimethoprim-sulphamethoxazole, clindamycin, aminoglycosides, tetracyclines.
Risk factors for nosocomial bacteremia caused by MRSA include:
  • Presence of severe systemic disease
  • Presence of indwelling central venous catheters or other devices
  • Increased length of stay in the hospital
  • Prior antimicrobial exposure.
The spread of MRSA from nosocomial to health care associated settings and the emergence of community acquired MRSA (CA-MRSA) are concerning developments. The occurrence of true CA-MRSA infections in otherwise healthy individuals without risk factors is increasing in incidence, particularly in pediatric populations. The methicillin resistance mechanism in CA-MRSA is predominantly associated with the SSC mec type IV variant of the mec gene. The Panton-Valentine leukocidin is a potent virulence factor of CA-MRSA.
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Management
Methicillin-resistant Staphylococcus aureus resistance rates across India vary but seem to increase over time. Community acquired (CA) MRSA in India may not conform strictly to the conventional case definition of CA-MRSA infection with no history of surgery, hospitalization, presence of a percutaneous device or indwelling catheter, dialysis within the previous year, previous MRSA infection or colonization, hospitalization > 48 hr before culture. The epidemiology includes SCC mec IV, V with far fewer antibiotic resistance genes and positive for PVL (Panton Valentine leukocidin) genes. In India, CA-MRSA is likely to expand its resistance profile as it is fit, rapidly evolving and probably may displace hospital acquired MRSA. We are seeing increasingly more resistance to ciprofloxacin in CA-MRSA and increasing prevalence in the health care setting without apparent risk factors.
For CA-MRSA infections, clindamycin is often effective (should be restricted to erythromycin susceptible isolates). Other options include trimethoprim-sulphamethoxazole, fluoroquinolones (never used on its own), tetracycline and linezolid. Vancomycin, an option, must be given intravenously which complicates outpatient therapy. The treatment of choice for nosocomial and healthcare associated MRSA infections is intravenous vancomycin or teicoplanin. Interestingly, vancomycin is a less active anti-staphylococcal agent than a beta lactam against methicillin susceptible strains. Gentamicin is synergistic with vancomycin in vitro and can be used for bacteremia and endovascular infections. Rifampicin plus vancomycin combination may be particularly useful in the CSF and with infections of foreign bodies. Rifampicin resistance emerges quickly when the drug is used alone. Linezolid which has good in vitro activity against both MSSA and MRSA is effective in the treatment of skin and soft tissue infection and nosocomial pneumonia caused by MRSA.
 
Vancomycin-Resistant Staphylococcus Aureus (VRSA)
Since 1996, reports of infections caused by MRSA with intermediate susceptibility to vancomycin (MIC 8–16 μg/mL) termed as vancomycin intermediate S. aureus (VISA/GISA or glycopeptide intermediate S. aureus) began to emerge. Independent risk factors for infections caused by VISA include prior infection caused by MRSA and antecedent vancomycin use within 3 months of VISA infection. In Mumbai, we are seeing creeping MICs to vancomycin with a mean of 1,33 μg/mL. In S. aureus, vancomycin resistance is known to be conferred by the van A resistance cluster which also mediates glycopeptide resistance in some enterococcal species. The breakpoints for glycopeptides have now been modified as serious infections with VISA/GISA are not treatable with increased doses of glycopeptides. In fact, with infections caused by S. aureus isolates with MIC to vancomycin of 2 μg/mL, clinical response may be impaired when glycopeptides are used for treatment. S. aureus isolates with MIC to glycopeptides >2 μg/mL are now reported resistant (GRSA or glycopeptide resistant S. aureus).
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Resistance in Gram-Negative Organisms
 
Haemophilus Influenzae
This is a common community pathogen implicated in the acute exacerbation of chronic bronchitis in adults and meningitis/bacteremia/pneumonia in young children. Beta lactam resistance among clinical isolates of H. influenzae arises by β lactamase production and, to a lesser extent, by PBP modifications and outer membrane permeability. Among these diverse mechanism, TEM-1 beta lactamases is by far the most prevalent, accounting for > 90% of ampicillin resistance encountered in this organism, especially among the capsular type, serotype b. H. influenzae also produces another enzyme, ROB-1, with a similar substrate profile as TEM-1.
Resistance to ampicillin, chloramphenicol and cotrimoxazole was reported in 46%, 60% and 55% of isolates in 2002 (IBIS study).
 
Management
H. influenzae that produces β lactamase is best treated with a β lactam-β lactamase inhibitor combination or in more serious infections with an intravenous third generation cephalosporin such as ceftriaxone.
 
Salmonella Typhi and Salmonella Paratyphi A
Enteric fever is the most important etiology of fever of unknown origin in the community in developing countries. For decades, chloramphenicol, cotrimoxazole and amoxicillin were the mainstay drugs in the treatment of typhoid. Plasmid-mediated resistance to these three drugs necessitated the search for other options. Fluoroquinolones introduced at that time seemed to be an ideal option when introduced. There has been a gradual increase in the MIC of ciprofloxacin from 0.0004 in 1990 to 1 μg/mL in 2002. Since these levels and the disk diffusion diameters are still within the susceptible range as per CLSI standards, laboratories continue to report the strains as sensitive to ciprofloxacin. The new CLSI guidelines 2012 have addressed this issue and lowered the MIC of ciprofloxacin to <0,25 μg/mL and increased to zone diameter to >31 for susceptibility. Clinical failure is common today with the use of quinolones to treat enteric fever. Nalidixic acid resistance in vitro correlates with high ciprofloxacin MIC and reliably predicts poor clinical outcome with quinolone usage in the usual doses and thus can be used to guide the choice of therapy. At our center in Mumbai, nalidixic acid resistance has increased from 0% in 1990 to 90% in 2003. Also seen with increasing quinolone resistance is return in susceptibility to older drugs such as cotrimoxazole, chloramphenicol and amoxicillin. The % susceptibility across 15 centers in India to ampicillin, chloramphenicol and cotrimoxazole was found to be 89,95 and 94.5 respectively in 2010.
Treatment depends on the susceptibility to nalidixic acid. In the case of NARST (Nalidixic acid resistant Salmonella typhi), it is prudent to give a third generation cephalosporin such as ceftriaxone in a sick patient. Other options for out-patient therapy include the use of azithromycin, cefixime and if susceptible cotrimoxazole or amoxicillin.
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Resistance in other Gram-Negative Bacilli
 
Extended Spectrum β Lactamase (ESBL)
ESBLs are enzymes produced by gram-negative bacilli that have the ability to inactivate β lactams containing an oxyimino group (i.e. third-generation cephalosporins and aztreonam). They are known as “extended spectrum” because they are able to hydrolyze a broader spectrum of β lactams than the simple parent β lactamases from which they are derived. ESBLs are plasmid-mediated enzymes, most commonly found in Klebsiella pneumoniae but also in Escherichia coli, Proteus mirabilis, Salmonella and other gram-negative bacilli. Treatment of infections by ESBL producers is a growing challenge. These organisms display in vitro susceptibility to third-generation cephalosporins but treatment failures occur in vivo. Such organisms are also more resistant to other classes of antibiotics like aminoglycosides and quinolones. It is important for the clinical laboratory to employ methods to detect the presence of an ESBL. Carbapenems (imipenem and meropenem) are effective in the treatment of these isolates. Cefepime and beta lactam-beta lactamase inhibitor antibiotics possess good in vitro activity against some ESBL expressing organisms but should not be used for treating serious infections. Many strains producing ESBLs demonstrate an inoculum effect in that the MIC of the expanded spectrum cephalosporins rises as the inoculums of the organism increases. In India ESBLs rates are high and in E. coli and Klebsiella spps vary from from 58–87%.
 
Amp C β Lactamase
Amp C β–lactamases can be chromosomal or plasmid mediated, the presence of which is a species specific characteristic of some organisms such as Enterobacter, Serratia, Citrobacter, Proteus vulgaris, Morganella, Acinetobacter, Pseudomonas, etc. Exposure to particular β lactams like cephalosporins, cephamycins, monobactams and extended spectrum penicillins causes induction of Amp C production to high levels in these bacteria, thus the organism can become resistant on treatment. Mutations can lead to hyperinduction or constitutive hyperproduction of Amp C.
Beta lactam-beta lactamase inhibitor combinations are ineffective against Amp C producing isolates. Cefepime, a fourth generation cephalosporin that is a much weaker inducer of Amp C production and carbapenems are usually the only available treatment options.
Laboratory detection of Amp C producing isolates poses a unique challenge. Up to 30% Amp C genes have been detected in E. coli and Klebsiella pneumoniae with a majority of strains co-producing ESBLs.
 
Carbapenemases
Carbapenem resistance is mediated through 2 types of carbapenem hydrolyzing enzymes, namely serine carbapenemases and metallo β lactamases (MBLs). The MBL like all β lactamases can be divided into those that are normally chromosomally mediated (Stenotrophomonas maltophilia) and those that are encoded by transferable genes. Carbapenem resistance in Pseudomonas aeruginosa (also in Enterobacter spp and other 11chromosomal Amp C producing organisms as Serratia, Citrobacter) can also occur by mutational loss of porin channels or by the efflux mechanism. Today the 5 commonest carbapenemases in Enterobacteriaceae are KPC, IMP-1, VIM, NDM and OXA-48.
Risk factors for acquisition of imipenem resistant P. aeruginosa:
  • ICU stay
  • Prolonged hospital stay
  • Exposure to imipenem, piperacillin tazobactam and aminoglycosides.
In case of multidrug resistant P. aeruginosa infection, intravenous colistin/polymyxin B is a therapeutic option although renal toxicity is often a limiting factor. Due to high prevalence of antibiotic resistance and the potential for emergence of resistance, deep seated Pseudomonas infections may be treated with two active agents demonstrating additive or synergistic activity, such as a β lactam in combination with either an aminoglycoside or fluoroquinolone during the initial stages of therapy. After the burden of infection is decreased, de-escalation to a single antibiotic is appropriate.
New Delhi Metallo β lactamases (NDM-1) is an enzyme capable of destroying carbapenems, most often seen in K. pneumoniae and E. coli. This type of resistance has been circulating in India since 2007 and has now been reported in Australia, USA, Holland, France, Canada, Sweden and UK. The characteristic risk factor is health-care contact in the Indian subcontinent. It is a plasmid encoded enzyme that can be transferred between bacteria. The emergence of this enzyme has become a major public health concern globally.
 
Strategies to Combat AMR
Antimicrobial resistance is the result of inappropriate and irrational use of antimicrobials in not only human medicine but also in animal husbandry. Sound surveillance systems are key in identifying the problem in the first place. The antimicrobial armamentarium to combat resistant bacteria is dwindling. The following will be crucial in the control of AMR:
  • Physician education and awareness to prevent misuse of antibiotics
  • Strict antimicrobial policies in hospitals based on local antimicrobial resistance patterns
  • Rigorous adherence to infection control guidelines
  • Reducing the use of antibiotics with high potential for resistance and rotating them with low potential resistance drugs
  • Good antibiotic stewardship with antibiotic policies that work
  • Eliminating inappropriate therapy for “look alike” non-infectious clinical syndromes that mimic sepsis and for colonizing flora
  • De-escalation of broad-spectrum antibiotic therapy once sensitivities are available
  • Optimizing adequate antibiotic dosing for different groups of drugs keeping pharmacokinetic and pharmacodynamic principles in mind.
Despite ongoing efforts to curtail antibiotic use and implement aggressive infection control efforts, emergence of new resistant pathogens continues to bring more challenges to the clinician and the clinical microbiology laboratory.
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