Current treatments for resistant infections

Enterobacteriaceae are a family of Gram negative rods, the medically important members of which can be found in the lower gastrointestinal tract of humans and animals as well as in soil and water (see Panel 1). These organisms can be involved in abdomino-pelvic sepsis, urosepsis, pneumonia (usually healthcare-associated) and complicated skin and soft tissue infection.

Enterobacteriaceae are inherently resistant to several antibiotics, including penicillin, macrolides (but not azithromycin), glycopeptides, linezolid, daptomycin, rifampicin, metronidazole and sodium fusidate. Over the past decade, particular attention has been paid to strains of Escherichia coli (see Panel 2) and klebsiella that produce extended spectrum beta lactamase (ESBL) enzymes.

In order to minimise the incidence of healthcare-associated infections and to maintain the effectiveness of antimicrobial agents, the UK Government receives advice from the Advisory Committee on Antimicrobial Resistance and Healthcare Associated Infection regarding trends in infections, resistance and prescribing, in addition to specific areas for surveillance.

Mechanisms of resistance

The mechanism of resistance most prevalent among enterobacteriaceae is degradation of ß-lactam antibiotics by ß-lactamase enzymes.

In the UK, only around 35 per cent of E coli isolates remain sensitive to amoxicillin. The first ß-lactamase enzyme was TEM-1 (described in 1965 and named after a patient called Temoneira, from whom the producing organisms were isolated). TEM-1 shows a substrate preference for penicillins, but is also active against first generation cephalosporins such as cefalexin and cefradine. Second generation cephalosporins, such as cefuroxime, stable against TEM-1, were introduced in the mid 1970s.

TEM-2, the second ß-lactamase discovered, can hydrolyse most penicillins (not temocillin) as well as both first and second generation cephalosporins. Today, around 78 per cent of E coli isolates in the UK remain susceptible to cefuroxime, which is commonly used both as surgical prophylaxis and as empirical treatment. The mid 1970s to early 1980s saw the introduction of third generation cephalosporins, such as cefotaxime, ceftriaxone and ceftazidime, which were not rendered inactive by either TEM-1 or TEM-2.

Extended-spectrum ß-lactamases

The first ß-lactamase that could hydrolyse third generation cephalosporins was SHV-2, described in Germany in 1983. The following year, in France, TEM-3 was identified. These enzymes had activity against all penicillins (except temocillin), aztreonam, and first, second, third and fourth generation cephalosporins. ESBLs have since diversified to more than 100 types. ESBL producers remained uncommon in the UK and were confined to Klebsiella spp in nosocomial settings until the early 21st century, when CTX-M-producing E coli emerged.

Several genotypes are described, the most prevalent in the UK being CTX-M-15. Mobile genetic elements (most commonly plasmids) allow rapid transmission and linkage to genes encoding resistance to other antimicrobials. In addition to being resistant to all penicillins (except temocillin), aztreonam and cephalosporins, enterobacteriaceae with the CTX-M-15 gene are usually cross-resistant to quinolones and trimethoprim.

AmpC ß-lactamases

In addition to the ß-lactamases already discussed, some enterobacteriaceae, in particular Enterobacter spp, Citrobacter freundii , Serratia spp and Morganella spp, often possess chromosomal, inducible genes that encode cephalosporinases. Up-regulation of ß-lactamase production can occur when the gene is induced by exposure to particular antibiotics, such as the newer cephalosporins and carbapenems. The ß-lactamase produced, termed AmpC, has the ability to hydrolyse all penicillins and first, second and third generation cephalosporins. Patients infected with these organisms might initially respond to therapy with penicillins or cephalosporins, but subsequently decline once gene induction takes effect.

Other mechanisms of resistance include inactivation of the antimicrobial by other enzymes, target site modification, efflux pumps, impermeability of bacterial outer membrane or bypass using alternate metabolic pathways to avoid enzyme inhibition.

What are the therapeutic options?

There are a number of options for ESBL or AmpC enterobacteriaceae infections, which are roughly listed in order of frequency of use:

Cephalosporins

Depending on the ESBL genotype, producers of these enzymes can exhibit varying levels of in vitro susceptibility to different cephalosporins. For example, strains that produce either TEM-6 or TEM-12 ESBLs are less efficient at hydrolysing ceftriaxone and cefotaxime, whereas CTX-M type ESBLs often spare ceftazidime. Bodies governing in vitro antimicrobial susceptibility testing such as the European Committee on Antimicrobial Susceptibility Testing (EUCAST), the British Society for Antimicrobial Chemotherapy and the Clinical and Laboratory Standards Institute (US) advise that in vitro susceptibility can be used to guide treatment.

Cephalosporins are generally avoided in the treatment of infections caused by AmpC producers.

Nitrofurantoin

Enterobacteriaceae (including ESBL and AmpC producers) are usually susceptible to nitrofurantoin with the exceptions of Proteus spp, Providencia spp and Serratia spp. Enterobacteriaceae are the predominant causes of UTI. However, nitrofurantoin is effective only for the treatment of lower UTI because therapeutic concentrations are only achieved in urine if the patient has adequate renal function. Due to rapid elimination, serum concentrations are insufficient for effective treatment of upper UTIs, which are frequently associated with bacteraemia.

Fosfomycin

Fosfomycin acts by inhibiting bacterial cell wall biosynthesis and is active against a wide-variety of both Gram positive and Gram negative bacteria, including most ESBL and/or AmpC-producing enterobacteriaceae.

Although currently unlicensed in the UK, oral fosfomycin has been used for the treatment of lower UTI with the convenience of a single dose (3g as trometamol salt), which is well tolerated and safe, even in pregnancy.

More recently, in the face of multiresistance, fosfomycin has been used for other infections. The good tissue penetration properties of this drug allow effective treatment of osteomyelitis, pneumonia and abdomino-pelvic sepsis although these infections require higher doses (up to 4g, six hourly) administered orally (as calcium salt) or intravenously (as disodium salt) for longer treatment courses.

Piperacillin-tazobactam

Piperacillin-tazobactam is a ß-lactam antibiotic/ß-lactamase inhibitor combination. Tazobactam is able to inhibit many ß-lactamases including CTX-M. Unfortunately, CTX-M-15 is associated with co-production of OXA-1, another ß-lactamase that is resistant to inactivation by tazobactam.

Recent studies of ESBL-producing urinary isolates have shown susceptibilities to piperacillin-tazobactam of 50–63 per cent, and clinical studies of infections caused by ESBL producers have demonstrated successful outcomes.

Piperacillin-tazobactam is not usually effective in the treatment of serious infections caused by AmpC cephalosporinase-producing enterobacteriaceae. Tazobactam is able to inhibit the AmpC enzymes of Morganella morganii, but there is little activity against other AmpC types.

Although this agent does have a role in carbapenem-sparing, the potential ecological impact of widespread use of an antipseudomonal drug must be considered. Narrower spectrum agents less likely to select for resistant strains of Pseudomonas aeruginosa (eg, temocillin, ertapenem) may be more appropriate, particularly in settings where co-infection with P aeruginosa is unlikely.

Carbapenems

The carbapenems have been regarded as the agents of choice for sepsis caused by ESBL-producing enterobacteriaceae. However, there are several reasons why it is timely to re-evaluate their role, notably changes in resistance patterns.

With rare exceptions, the carbapenems are active against all enterobacteriaceae regardless of ESBL or AmpC production. Ertapenem is distinct from the other carbapenems in clinical use (imipenem, meropenem and doripenem) in that it lacks significant activity against P aeruginosa, Acinetobacter baumanii and other important non-fermenters. As such, there is much less potential for selection of carbapenem resistance in these organisms. On this basis, ertapenem would seem the most appropriate carbapenem for infections caused by multiresistant enterobacteriaceae. It is also administered as a once daily regimen, which makes out-patient parenteral antibiotic therapy more feasible.

The past few years have seen a large increase in carbapenem resistance due to the emergence and worldwide spread of carbapenemase and metallo-protease producing organisms. In addition, other resistance mechanisms such as porin (OprD) deficiency and up-regulated efflux in P aeruginosa and hyperproduction of AmpC ß-lactamases/ESBLs combined with impermeability in enterobacteriaceae continue to contribute to resistance to this group of antimicrobials.

Temocillin

Temocillin is a 6-a-methoxy derivative of ticarcillin. This chemical modification has converted a ß-lactamase labile compound into one that is resilient to all TEM, SHV, CTX-M and AmpC ß-lactamases. Activity is exclusively against enterobacteriaceae and Burkholderia cepacia with no activity against Gram positive organisms, P aeruginosa or anaerobes. The cumulative urinary recovery of temocillin is around 70 per cent. This high urinary concentration produces efficacy against pathogens in the urinary tract with higher minimal inhibitory concentrations than in other sites.

The licensed indications for temocillin are UTI, lower respiratory tract infection and septicaemia where susceptible Gram negative bacilli are suspected or confirmed. Only intravenous administration is possible.

Tigecycline

Tigecycline is the first glycylcyline to be marketed. It is a synthetic derivative of minocycline, produced by addition of an N-N dimethylglycylamido group. Tigecycline binds ribosomes with higher affinity than tetracycline, and has the added advantage of being a poor substrate for most bacterial efflux pumps.

Tigecycline is a relatively broad spectrum agent, with activity against multiresistant Gram positive (eg, meticillin-resistant Staphylococcus aureus , vancomycin-resistant enterococci) Gram negative (ESBL- and AmpC-producing enterobacteriaceae) and anaerobic bacteria. This spectrum of activity makes it an attractive agent for polymicrobial infection, particularly in patients unable to tolerate ß-lactams. Tigecycline has no activity against P aeruginosa, minimising selection pressure for resistance.

In the UK, the licensed indications for tigecycline are limited to complicated intra-abdominal infections and complicated skin and skin structure infections. It is not licensed for the treatment of healthcare-associated pneumonia, and, as the urinary recovery of tigecycline is only 22–33 per cent, is unsuitable for use in urosepsis.

Increased mortality has been observed in patients treated with tigecycline for complicated intra-abdominal infections and complicated skin and skin structure infections compared with a variety of other drugs so alternatives should be considered for serious infections.

Aminoglycosides

The aminoglycosides are active against a wide variety of Gram negative organisms including enterobacteriaceae and P aeruginosa. They are also active against Staphyloccus aureus (including MRSA) but lack anaerobic activity. Gentamicin resistance rates among ESBL producers can be as high as 50 per cent in some parts of the UK. Amikacin susceptibility, however, is much better preserved. Most AmpC producers (>90 per cent) remain susceptible to gentamicin and amikacin.

The place of aminoglycosides is strongest in treating upper UTI and bacteraemia. Relatively poor penetration makes them less suitable for other infections such as intra-abdominal sepsis (including biliary sepsis), skin and skin structure infection, osteomyelitis and pneumonia. Their propensity to cause ototoxicity and nephrotoxicity, and the need for serum level monitoring, are other disadvantages with these agents.

Colistin

Colistin belongs to the polymyxin group — it is a multicomponent polypeptide antibiotic, the major constituents being colistin A and B. This drug is rapidly bactericidal against most medically significant enterobacteriaceae (with the exceptions of Proteus spp and Serratia marcescens ) and environmental non-fermenters. The mode of action of colistin relies on producing a change in the permeability of the outer membrane — activity is preserved in ESBL producers.

Although there are several studies reporting the efficacy of colistin in the management of infections with P aeruginosa and A baumanii , clinical experience of colistin in the treatment of infections caused by multiresistant enterobacteriaceae remains scarce. However, in vitro studies are encouraging and the successful use of colistin in the management of bacteraemia, septic shock and multi-organ failure caused by a strain of K pneumoniae that was resistant to all other available antibiotics has been reported.

The optimisation of colistin dosage is essential in order to maximise efficacy and minimise the development of resistance and toxicity. Earlier reports of nephrotoxicity and neurotoxicity deterred clinical use of colistin for many years, but it is now becoming evident that when used within recommended doses, neurotoxicity is rare and nephrotoxicity is not only less frequent than originally feared but also reversible.