Colistin–Meropenem Synergy in Carbapenem Resistant Gram-Negative Infections: A Practical Clinical Guide

The combination therapy involving colistin-meropenem has emerged as a possible treatment choice for severe infections resistant to antibiotics. Such infections, usually occurring in hospitalized patients in ICU setting, include pneumonia among mechanically ventilated patients and bacteremia among those with infected central lines, all of which are due to CR-GN bacteria. Due to the rise of difficult infections associated with such organisms, many medical teams consider employing a combined therapy based on colistin (polymyxin antibiotic) and meropenem (carbapenem). Laboratory data confirm that in some cases, the combination of both medicines shows a synergic effect when dealing with the growth of bacteria. It is important to note the possibility of this effect in clinical conditions.

Why It Matters

The carbapenem-resistant organisms pose a significant threat because they are resistant to carbapenem antibiotics, once used as the “Big Gun” of antibiotics in hospital settings. The rapid resistance of infected patients, their organ failure or prolonged length of stay as well as mortality are the outcomes associated with infection caused by such germs. In some regions of the world, colistin remains among the few drugs effective against certain CR-GN strains. Often, doctors administer meropenem along with colistin to obtain an additive effect from these two antibiotics.

The concept of antibiotic synergy is quite known for professionals in the field of infectious diseases. In vitro experiments often reveal the synergistic interaction of colistin and meropenem.But results are not accurate 100% all the time due to some physiological factors. Indeed medical decisions have an impact on whether the person survives, what organs are recovered, the adverse reactions to colistin (kidney toxicity, for example), and the consumption of healthcare resources. In addition, the administration of meropenem might prolong the duration of therapy, while colistin’s toxicity might necessitate prolonged ICU stay.

Beyond the level of individual patients, there is also the healthcare system as a whole. The hospital administration needs to determine whether this medication combination should be included in the treatment protocol of severely ill patients. This will depend on whether the laboratories are willing to develop additional synergy assays or use fast diagnostic methods to detect resistance genes. At the same time the cost and availability of these medications is something that health systems and insurance companies consider. As an older drug, colistin has difficult supply issues and additional requirements for monitoring. If the combination therapy will help to reduce relapses or repeat ICU admissions, it will be economically viable although expensive initially. However using two powerful drugs in large amounts will contribute to increased resistance to the drugs.

Who It Affects

Patient Population: This involves critically ill patients who are suffering from CR-GN infections. Patients with ICU admission, those using ventilator support who have pneumonia infection, and central line patients with bloodstream infection. The aforementioned population consists of comorbid patients with depleted reserves. They need to receive quick and effective treatment. Clinicians from infectious disease, critical care, pulmonology, and hospital medicine specialties make the key decisions in this scenario. This is because they will need to assess the severity of the condition, its origin, and the different approaches that exist. When dealing with pneumonia, issues such as inability of drugs to penetrate the lungs and bacteria biofilm are major concerns, hence some clinicians believe combination therapy should prove more effective. On the contrary, for bloodstream infections, the control of the origin of infection assumes as much importance as the antibiotic use itself. Pharmacists have an important role in the process of dosing and monitoring. Dosing colistin is complicated by the fact that the drug exists in an inactive form and requires dosing according to weight and renal function. The pharmacists need to assess drug interactions and dose modification due to kidney damage. They also need to manage the intravenous infusion of these drugs.

The microbiologists and laboratory scientists have a significant impact on treatment due to the timely provision of information. Susceptibility tests will show whether any antibiotics can be used. Sometimes laboratories can conduct more complex procedures such as synergy testing or PCR for quick identification of resistance genes. Such information changes the risk/benefit analysis of meropenem combined with colistin.

Hospitals and Health Systems: Administration of colistin-metapenem combination therapy affects the finances and policies of hospitals. Combination therapies are generally costly due to high drug expenses and increased monitoring needs. If the patients under the therapy require additional laboratory monitoring such as measuring creatinine levels on a daily basis or extended ICUs admissions due to adverse effects, the hospitals have to plan their finances. However, if the combination therapy decreases the rate of failures or reduces hospital stay, it may prove to be financially sound. Hospitals have to consider several aspects such as ensuring that old antibiotics (colistin) and novel antibiotics (ceftazidime, avibactam, meropenem, vaborbactam, or cefiderocol) are readily available.

What Changes

• Clinical application: Doctors can begin colistin along with meropenem as the treatment regimen for patients suffering from serious cases of CR-GN pneumonia or CR-GN sepsis if there are no other available options or if all other regimens are expected to fail. Patients who have serious infections of bacteria that are not responsive to any other antibiotics (such as A. baumanii, K. pneumoniae, or MDR Pseudomonas) could benefit from this combination. On the other hand, doctors can refrain from using this combination if the patients are stable or if the quick diagnostic test indicates a bacteria that can be cured with one antibiotic.
• Monitoring and Safety Considerations Hospitals are recommended to increase their monitoring activities in order to detect the adverse effects of colistin. One adverse effect that colistin poses is nephrotoxicity. Hence patients who take colistin are required to have regular tests regarding their kidney functions, including serum creatinine and urine output. There is a need for nursing and pharmacy personnel to be knowledgeable about the complicated dosage regimen of colistin (i.e. loading dose followed by maintenance dose). It is also essential for nurses to watch out for potential neurologic adverse effects, since rarely does colistin cause peripheral neuropathy. Meropenem is well-tolerated except when taken for extended periods.
• Laboratory assistance Microbiology laboratories should give facility of quick reporting of antibiotic susceptibility testing, preferably within 24–48 hours of isolation of the organism. The tests may involve not only conventional antibiotic sensitivity tests but may also include screening for mechanisms associated with resistance (carbapenemases). It will be advantageous if laboratories have systems for identifying synergistic combinations of drugs, such as checkerboard and time-kill studies of colistin and meropenem combination is synergistic against a certain isolate. Rapid PCR panel testing for resistant genes such as NDM, KPC and OXA can be helpful for better treatment.
• System And Policy Implications There must be defined strategies regarding when combination therapy is to be used. It will cover what needs to happen if empirical therapy (what do when cultures take time before being available) and when to consider a switch from combination to monotherapy depending on the type of organism isolated. For this purpose, a stewardship program may stipulate that “for X risk population in ICU use colistin+meropenem and narrow later on after sensitivities come back.” Such a program should ensure that there is documented evidence justifying the use of the combination therapy and follow up to prevent unnecessary use of the combination. Patient Experience And Practical Challenges As far as the experience of patients is concerned, treatment involving colistin and meropenem normally involves taking more medication and more testing. The patient has additional intravenous lines or infusion pumps for both medications and will need regular blood draws (to determine drug concentrations and renal function). Monitoring, blood draws and other aspects of treatment may prove exhausting and limit one’s movement. Should kidney dysfunction occur, the dosage may be lowered or treatment paused altogether, potentially extending the duration of the disease or length of the hospital stay. However on the positive side treatment may lead to survival from a highly lethal condition or prevent any relapses. It is essential that medical professionals inform patients about their condition, why the therapy is required and what side effects to look out for. Looking Ahead Hospitals and decision-makers must plan for the future by funding diagnostics, development of new antimicrobial agents and educational programs. Point-of-care diagnostics such as rapid PCR or sequencing of the bacteria will allow for the detection of pathogens and their resistance in hours, not in days meaning that clinicians will not have to give combinations of agents empirically anymore. The research to identify patients in whom the synergism between antibiotics works best is essential. Also hospitals should provide a sufficient supply of colistin in an adequate dosage form (there are areas using colistimethate sodium while others prefer colistin sulfate). Furthermore the health care institutions should encourage patients’ access to new and safer antibiotics to use in case of CRE or CRAB (such as ceftazidime-avibactam for the former and sulbactam-durlobactam for the latter if they are available). Antibiotic pathways in hospitals may be updated stating implementation of circumstances when the empiric combination of colistin and meropenem indicates the duration of treatment in case the causative organism is meropenem-sensitive. Educating medical staff about combination therapy is of vital importance here.

References

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