CLINICAL MATTERS

Recently, a paper in the prestigious scientific journal Lancet highlighted the growing threat of drug-resistant microorganisms to humanity. It has gotten to a point where it can be described as a global emergency with no easy fix. The paper emphasized that even with proper treatment, people were at higher risk for dying from drug-resistant infections due to the delay in recognition of a resistant organism. It also stated that resource-limited settings like our country were even more at risk for this threat since the diagnostics and antibiotics required for the treatment of multi-drug resistant (MDR) organisms is out of reach for their healthcare systems. The inability to afford appropriate treatment even if a resistant organism is properly identified means that millions more will die from drug-resistant infections. 

The discovery of effective and safe antibiotics such as penicillin and erythromycin ushered in a golden age of medicine in the mid-1900s. Many people used to die from common bacterial diseases like pneumococcal pneumonia or staphylococcal skin infection. Even with the emergence of penicillin-resistant bacteria, the pharmaceutical industry seemed to be quickly producing new and more potent antibiotics for a wide variety of indications. In the 1970s, this led some doctors to predict that humanity could soon “close the book” on infectious diseases since there seemed to be a good antibiotic for every single organism. This naïve assessment was eventually shown to be inaccurate as MDR organisms started to emerge. A combination of improper use of antibiotics and the prodigious ability of bacteria to adapt to their environment led to acceleration in the incidence drug-resistant infection.

In the Philippines, historically poor regulation of antibiotic dispensing has been identified as one of the factors contributing to the rise of MDR infections. When I was growing up, people could buy antibiotics without a prescription. Some sari-sari stores sold amoxicillin along with typical over-the-counter drugs such as paracetamol. Amoxicillin was taken habitually for any kind of upper respiratory infection (URTI) without consulting a doctor. URTIs are usually caused by viruses so this practice is not only useless but can expose people needlessly to side effects from the antibiotic and also increase the risk of resistance. Amoxicillin capsules were also frequently misused for topical treatment of infected wounds by opening the capsule and pouring the powdered contents over the wound. This misuse among other reasons has now led to an unprecedented 80 percent resistance to amoxicillin for common bacteria like Escherichia coli (E. coli). E. coli is among the most common causes of urinary tract infections and intraabdominal infections, and so losing a cheap and safe drug like amoxicillin is a major blow to affordable and effective care.

Over the past decade, the three bacterial groups that have contributed to an outsized increase in resistance in the Philippines are Methicillin-resistant Staphylococcus aureus (MRSA), Extended spectrum B-lactamase (ESBL) producing Enterobacterales (which includes Klebsiella pneumoniaeand E. coli), and Carbapenem-resistant Enterobacterales (typically carbapenemase-producing Klebsiella pneumoniae. There are other scary bacteria such as Pseudomonas aeruginosa and Acinetobacter baumaniithat have increased their resistance to antibiotics, but the three groups described are the ones that are giving us doctors nightmares.

Staphylococcus aureus is a ubiquitous bacteria that can normally be found on our skin and inside the nose.Most of the time, S. aureuslives in harmony with the rest of the bacterial flora on our skin. Occasionally, it can cause infection when there are skin breaks or if the host immune system is weakened. People who develop moderate to severe S. aureus infections will require antibiotics. In the recent past, the antibiotic of choice for S. aureus infections were a class of penicillins called anti-staphylococcal penicillins. These include cloxacillin, dicloxacillin and oxacillin.These used to work very well. In the past two decades, more and more resistance has emerged. The original drug used to test for anti-staphylococcal penicillin resistance was an antibiotic called methicillin, and so the original resistant S. aureus was called methicillin-resistant Staphylococcus aureus or MRSA. MRSA is resistant to all penicillins, most of the cephalosporins (a class of antibiotics related to the penicillins), and carbapenems (a very strong class of antibiotics also related to penicillins usually used as last-line treatment). While there are alternatives like vancomycin, linezolid and clindamycin, these medications have their own set of drawbacks such as higher risk of kidney dysfunction (vancomycin), higher cost (linezolid and vancomycin) and increasing resistance (clindamycin). Rates of MRSA in the Philippines have soared to as high as 60 percent in the last two decades and currently hover at 40 percent, which is still quite high.

ESBL-producing Enterobacterales (or ESBLs for short) are intrinsically resistant to most cephalosporins. Cephalosporins such as ceftriaxone and cefuroxime have become mainstays of treatment of intra-abdominal infections, pneumonias, and urinary tract infections. Unfortunately, resistance has been rising since the early 2000s and ESBL rates in the Philippines have gone as high as 56 percent. It has improved to about 30% in 2023. ESBLs are problematic because the drug of choice for treatment is the carbapenem class, which are typically our last-line antibiotics. Carbapenems are also much more expensive than cephalosporins and penicillins. We have had to use more and more carbapenems due to the high numbers of ESBLs, and thus the number of carbapenem-resistant bacteria has also grown due to the increased drug pressure. People with ESBL infections are up to two times more likely to die compared with non-ESBL infections. 

Among the scariest MDR organisms are the carbapenem-resistant Enterobacterales (CRE for short), specifically carbapenem-resistant (CR)-Klebsiella pneumoniae for which very limited treatment options exist. Since carbapenems are typically considered last-resort antibiotics, treatment for CREs is complicated and very expensive. To make matters worse, there are different types of bacterial enzymes that confer carbapenem resistance and the treatment options for each are different. Expensive molecular tests are needed to differentiate these so-called carbapenemase types and these may not be as readily available. For example, a carbapenemase named KPC can be treated with a new type of antibiotic called ceftazidime-avibactam alone, but a different carbapenemase called NDM requires addition of a second antibiotic called aztreonam. Combination ceftazidime-avibactam plus aztreonam costs more than ₱30,000 a day in the hospital, and is not affordable to most people. CRE infections, like ESBLs are two times more likely to cause death than non-CRE infections. CR-Klebsiella rates in the Philippines continue to increase every year, and are currently sitting at around 16 percent.

The global emergency of antimicrobial drug resistance means that everyone should contribute to its prevention and its mitigation if we hope to retain meaningful use of antibiotics in the near future. For the general public, this means taking antibiotics only when prescribed by a doctor, and following your doctor’s instructions on the dose, frequency and duration of the medication. Governments should adopt policies that prevent the exacerbation of antimicrobial resistance, including proper regulation of use of antibiotics in agriculture and in medical practice. The pharmaceutical industry should prioritize innovative research to find more antibiotics that can be used to treat MDR infections and make these available and affordable to all especially in resource-limited settings. Professional medical societies should educate their members and the public in antimicrobial stewardship. We should all work together to preserve one of the most important and life-saving discoveries of modern medicine.