The worldwide prevalence of multidrug-resistant Gram-negative bacteria in particular Pseudomonas aeruginosa, Acinetobacterbaumanniiand Klebsiella pneumonia is escalating at an alarming rate(1)(3) with polymyxins being the only active antibiotics(6). In the Unites States of America, up to 16% of Pseudomonas aeruginosa isolates in the time period between 1997 and 2000 were resistant to at least three principal anti-pseudomonas medications(7). Pseudomonas aeruginosa has proved to be resistant to a number of antibiotics, including aminoglycosides, quinolones and β-lactams(10). The absence of new antibiotics against resistant bacteria due to the decline of the antibiotic discovery pipeline, has led to renewed interest in reviving the use of older antibiotics that were considered too toxic for clinical use, in particularpolymyxins (B and E), to be the only salvage arsenal in the antibiotics armory in multi-resistant gram negative bacterial infections in particular Pseudomonas aeruginosa(1).
P. aeruginosa is a perilous and feared ubiquitous Gram-negative, opportunistic nosocomial acquired bacterium(5), responsible for 10% of all hospital-acquired infections(11), in immunocompromised hosts, culprit in ventilator-associated pneumonia, resistant to anti-microbials due to its ability to produce a variety of toxins, resisting phagocytosis, encoding large percentage of controlling enzymes important for metabolism and transportation with its high level of intrinsic resistance to most anti-microbials through restricted outer membrane permeability, efflux systems that pump anti-microbials out of the cell and production of antibiotic-inactivating enzymes such as β-lactamases giving it great metabolic versality and high adaptability to resist ecological changes thus its ability to colonize a wide variety of settings (12)(10). It is mostly isolated from patients with burns injuries, cystic fibrosis, and neutropenia(5)(12).
The use of old antibiotics resembles the antibiotic rotation scheme where some antibiotics are intentionally withheld from use to reduce chances of developing resistance to certain pathogens(7). Old antibiotics have a major advantage to the currently used antibiotics by the fact that their use has been greatly limited in recent years(7). It’s well known that emergence of resistance to antimicrobials is from the misuse of the antimicrobial itself(7). Challenge posed by many old discarded antibiotics is their toxicity and adverse effects, however their efficacy can be improved by chemically modifying their compounds to enable better tissue penetration and extend half-livestherefor increasing potency to certain pathogens.(7).
Colistin (polymyxin E) is a multicomponent polypeptide antibiotic comprised mainly of colistin A and Bantibiotic discovered in 1949(3) and has been available since 1959 for the treatment of infectious diseases caused by Gram-negative bacteria used throughout in the 1960s and 1970s, discarded due to reports of nephrotoxicity for the potentially less-toxic aminoglycosides(1)(6)(7)(4).The clinical picture of colistin nephrotoxicity include a decrease in clearance of creatinine, proteinuria, cylindruria or oliguria(4).This led to decline in its use from the 1970s to the early 2000s(6). However it has been observed that the nephrotoxicity is dose dependent, usually but not always reversible and end organ kidney damage rarely reported(4).
After the emergence of multi-resistant Gram negative bacteria, its re-use re-emerged with fewer reported side effects compared to aminoglycosides which had replaced it more than 3 decades ago(7). The toxicity previous reported could be owed to higher colistin doses administered, the administration of the more toxic form of colistin sulphate or the co-administration of nephrotoxic drugs(7).
However a concerning and scary reality exist as there have been studies were isolates showed resistance to both colistin and carbapenems(2). Colistin resistance have been reported in UK, were resistant strains of P.aeruginosain cystic fibrosis have been observed, colistin resistant carbapenemase-producing K.Pneumoniae,resistant strains of A.baumannii and polymyxin resistant Escherichia coli(2). A study in India identified resistant strains of Escherinchia coli, K.pneumoniae, P.aeruginosa, and Acinetobacterbaumanniito bothmeropenem and colistin(2). These are frightening reports to clinicians who face multi-resistant strains of Gram-negative bacteria, with colistin as there only single salvage antibiotic losing its potency. However the advent of colistin resistance has been described in high-use settings(9).
A new hope exists as colistin can be used with combination with rifampicin or sulbactam antibiotics to increase efficacy for the treatment of multi-drug resistant Gram negative bacteria(1)(6)(8)despite the increased risk in toxicity(8).Animal studies have shown combination of colistin with either rifampicin, carbenicillin, piperacillin and imipenem for treatment of P.aeruginosa, A.baumannii or E. coli infections there were significant reduced mortality rates(8).However, there is a need for clinicians to share their experience on the efficacy and safety of single therapy colistin use versus colistin combination therapy.Best approach to this is randomized controlled trials comparing and contrasting effectiveness and safety of colistin monotherapy versus colistin combination therapy(8).
A new surge of antibiotic discovery research is needed in these desperate times of increasing AMR. Contrary to this need, nearly half of all major antimicrobial producers in Japan and USA have halted or decreased antimicrobial production almost 30 decades ago(3)(7)(13).The absence of alternative antibiotics to treat the ever increasing rate of AMR among even common bacteria is likely to end up in a clinical scenario where colistin will be the only last line salvage therapeutic drug against multidrug-resistant Gram-negative pathogens in the 21st century(6).In clinical scenarios where β-lactam, aminoglycoside or quinolone is rendered ineffective, the polymyxins, especially colistin, serve as the final alternative arsenal(6).
It is understood that resistance is acquired through a number of mechanisms including selection pressure mainly due to miss use of the drugs. It is an open issue whether restricting antimicrobial usage contributes to the elimination of multidrug-resistant bacteria. Resistance mutations frequently have associated fitness costs. However, such costs may decline subsequently through the accumulation of compensatory mutations(14). It has previously been demonstrated that drug-resistance declines in an antibiotic-free laboratory environment in as few as 480 generations(15) where 64.7% of drug-resistant E. coli strains showed elevated susceptibilities to at least one antibiotic investigated. Reductions in antimicrobial prescription have been reported to achieve specific, localized decreases in antimicrobial resistance in many parts of the world(16). Although antibiotic withdrawal has not been a formal strategy for managing AMR, our finding underscores the possibility of antibiotic withdrawal strategy as a promising approach to contain AMR.
In this case, our patient was a chronic kidney diseased diabetic and hypertensive. She developed carbapenem resistant Pseudomonas aeruginosa diabetic foot ulcer infection. She was instituted on the nephrotoxic antibiotic molecule colistin. Her renal blood work during treatment were monitored and were within normal acceptable ranges. This gives new hope for the safe and efficacious re-introduction of colistin even in renal comprised patients.
In this current clinical scenario of increasing AMR, old and current active antimicrobials should be engaged in combating severe infections due to multi-drug resistant strains of Gram-negative bacteria. Individual countries drugs and food agencies should review the old discarded antibiotics as their potential new armory in the fight against current resistant bacterial strains.However, this should be viewed as potential dangerous last step towards re-entering the same clinical scenario of the pre-antibiotic era were clinicians had virtually no antibiotic molecules to treat infections. Strict laws should be put to place to enforce the rational use of current active antibiotics.Colistin can be safely used as a last reserve antibiotic for multi-resistant strains of Pseudomonas aeruginosa infection even in patients with renal impairment. Dose adjustments are needed in patients with renal impairment. In severe multi-resistant bacterial strains, it can be combined with rifampicin or a carbapenems to increase efficacy. Its use should be restricted only as a last resort to avoid re-emergence of colistin resistance.