What is Gram-Negative Bacteria?
Gram-negative bacteria (GNB), a type of bacteria highly resistant to antibiotics, pose one of the world’s biggest public health challenges. These bacteria are particularly dangerous in hospital settings, where they increase the risk of severe illness and death for patients in critical care units. Among these bacteria, two main groups, Enterobacteriaceae and non-fermenters, present the most clinical challenges, although others, such as Neisseria, Haemophilus spp., Helicobacter pylori, and Chlamydia trachomatis, are also worrisome.
Enterobacteriaceae is a widespread group of bacteria found in various environments. They account for about 80% of the gram-negative infections and can cause a range of diseases in humans, including urinary tract infections, pneumonia, diarrhea, meningitis, sepsis, endotoxic shock, and more. The most common of these bacteria that impact humans include Escherichia, Proteus, Enterobacter, Klebsiella, Citrobacter, Yersinia, Shigella, and Salmonella, among others. These bacteria are rod-shaped, don’t form spores, have variable movement, can grow with or without oxygen, convert glucose to energy, are cytochrome oxidase negative, and can convert nitrate to nitrite.
The non-fermenter, gram-negative bacteria occur less frequently than Enterobacteriaceae but are still crucial since they can cause severe and sometimes fatal infections, especially within hospitals. They’re often connected with diseases in ICU patients undergoing invasive procedures. These bacteria include Pseudomonas aeruginosa, Acinetobacter baumannii, Burkholderia cepacia, Burkholderia pseudomallei, Stenotrophomonas, Alcaligenes, and Moraxella. They stand out for being aerobic and non-sporulated; they cannot convert sugars, but use them through the oxidative route. These bacteria have unique resistance factors, given their ability to produce various genes capable of mitigating the effects of antibiotics.
These bacteria use several methods to resist the effects of most antibiotics used in medical treatments, including efflux pumps that remove drugs from the cell, alterations of the drug binding site and membrane permeability, production of enzymes that break down the drug, and the conformational change in the drug, leading to its inactivation. Gram-negative bacteria have two membranes—an external and an internal one. The external membrane can trigger a potent immune response, further complicating the treatment. Enterobacteriaceae have an added defense; they can spread their plasmids, DNA structures that carry antibiotic resistance genes, through a process called conjugation. This mechanism allows them to become resistant to almost all existing antibiotics, representing a severe health challenge.
What Causes Gram-Negative Bacteria?
Gram-negative bacteria, a type of harmful bacteria, can cause diseases in many areas of the human body including the digestive system, nervous system, urinary system, and blood. These can lead to conditions ranging from stomach problems to severe brain infections. These bacteria can live in places such as the intestines, airways, and skin, making it easy for them to spread to other parts of the body. This is especially dangerous for people with weakened immunity.
One of the challenges for healthcare workers is treating hospital-acquired infections of the lower respiratory tract, where these bacteria may be involved. That’s because these bacteria not only cause a significant portion of these infections, they also don’t respond well to antibiotics. This can be due to their high resistance to these drugs and the difficulty of the drugs reaching the lungs.
Another worrying issue is gastroenteritis, a stomach and bowel infection, caused by specific types of these bacteria (Shigella spp., Salmonella spp., and certain types of E. coli). Such infections affect millions of people globally, and are often linked to poor hygiene and sanitation. These bacteria can also cause meningitis, a severe and potentially fatal brain infection which can occur both in the community and in the hospital. Unfortunately, these bacteria have become more resistant to antibiotics, making urinary tract infections, particularly common in young women, harder to treat. A serious complication of these infections can be bacteremia, where bacteria enter the bloodstream, which is even more concerning given the bacteria resistance to antibiotics.
Risk Factors and Frequency for Gram-Negative Bacteria
Gram-negative bacteria are widespread and can cause infections in humans. The main worry for healthcare workers is these bacteria becoming resistant to multiple drugs, making them very difficult to treat. This is one of the biggest health challenges globally, considering these bacteria are not responding well to drugs. They have become resistant due to the production of certain enzymes. For instance, about twenty years ago, the first carbapenemase-resistant bacteria were found in the US, and such infections have now spread worldwide. Gram-negative bacteria producing ESBL enzymes, which also lead to drug resistance, have been reported since the 1980s, particularly in hospitals.
The Centers for Disease Control and Prevention (CDC) reports that these multi-drug resistant gram-negative bacteria are widespread in the United States, except in Maine and Idaho. In the US, studies have found infection rates ranging from 0.3 to 2.93 out of 100,000 people per year. Reports of these resistant bacteria have been found in almost all continents. In Europe, around 25,000 people die each year from such infections.
Extended-spectrum beta-lactamases (ESBLs) and carbapenemase are enzymes that resist types of antibiotic drugs. They’re the most common in the US and Europe. In the US, it’s found that 12% of E. coli bacteria produce ESBL. However, in Latin America and Asia, this figure could climb up to 27% and 38% respectively. Initially, such infections were associated with hospitals, but now they’re seen in people from the broader community as well.
The alarming feature of these bacteria is that they can transfer their drug-resisting genes to other bacteria, potentially making them resistant to nearly all types of antibiotics. On top of this, these harmful genes can spread between different species easily.
Patients with other health conditions, those staying in intensive care units, who have used antibiotics previously, or who have a central venous catheter for a long time, have higher chances of contracting a multi-drug resistant infection.
Signs and Symptoms of Gram-Negative Bacteria
Gram-negative infections can be difficult to identify based only on physical examination because the signs and symptoms are common to many infectious diseases. An example is pneumonia. Its typical symptoms include fever, chest pain, shortness of breath, and coughing up thick mucus. It might also come with rapid heart rate, fast breathing, low oxygen levels in the blood, and signs of lung consolidation (fluid buildup). However, these symptoms can also show up in other diseases. The only sure way to know the cause is to perform a culture test.
Similarly, bacterial meningitis has symptoms like fever, serious headache, nausea, vomiting, neck stiffness, extreme fatigue, and confusion, but these aren’t exclusive to it. Other evidence is needed to be sure about the type of organism causing the infection.
Testing for Gram-Negative Bacteria
If you have an infection caused by gram-negative bacteria, it may resemble infections caused by other germs. However, lab testing can identify the specific bacteria causing the infection and determine the most effective antibiotic to treat it. The most accurate test for these types of infections is culture testing. This is where a sample of the bacteria is grown in a lab to identify the type and its resistance to antibiotics. The downside to this test is it takes time to get results.
An important part of the lab testing is something called a Gram stain. It may sound complicated, but it’s a simple test that can quickly guide the treatment plan. Due to their diverse characteristics, Enterobacteria, a large family of gram-negative bacteria, require different biochemical tests. The results of these tests help determine the specific type of bacteria causing the infection.
For instance, E. coli, a type of Enterobacteria, can change the color of the lab testing medium to pink because of the specific acids they produce. Other bacteria, known as non-fermenters, can only grow in an oxygen-rich environment. They are identified using certain types of growth mediums like blood agar and MacConkey agar.
It’s also important to know that some bacterial strains are resistant to many antibiotics. Identifying these strains may need more advanced molecular methods, which are not available in all labs. In these cases, tests like the Modified Hodge test and the Combined Diffusion Disc test can be helpful. These tests check how well a type of bacteria can grow in the presence of certain antibiotics, providing information on what antibiotics the bacteria may be resistant to.
Treatment Options for Gram-Negative Bacteria
When treating infections caused by multi-drug resistant (MDR – bacteria that are immune to multiple types of antibiotics) gram-negative bacteria, options can be limited due to the bacteria’s ability to evolve and resist new drugs. As a result, doctors have sometimes had to resort to older drugs that were previously set aside due to their high toxicity (harmful effects), such as polymyxins and colistin. However, these drugs too now face a threat as bacteria resistant to them have emerged. One approach that has been found somewhat effective is combining these drugs with another class of antibiotics called carbapenems.
Tigecycline is another antibiotic that can fight MDR bacteria in the lab. However, its use in patients is often limited because it requires high doses and doesn’t penetrate tissues well, which impairs its effectiveness within the body. Fosfomycin, an older drug used in urinary tract infections, has also been reconsidered for treating MDR infections. But, like the others, it’s noted that the bacteria quickly develop resistance if fosfomycin is used alone. The most practical use for it is in combination therapy alongside other drugs.
Aminoglycosides, another class of antibiotics, were once rejected because of their harmful effects on the kidneys and ears. However, they have been reexamined for their effectiveness against gram-negative bacteria, providing yet another potential combination for treatment.
The use of carbapenems is effective against severe infections caused by ESBL-producing organisms (bacteria that produce an enzyme providing resistance to antibiotics). However, the emergence of bacteria that produce carbapenemase (an enzyme that destroys carbapenems) has posed challenges in treatments. The most effective use of carbapenems appears to be in combination with other drugs.
New drugs have been developed to combat this challenge, such as ceftazidime-avibactam and meropenem-vaborbactam. These drugs work by inhibiting an enzyme (beta-lactamase) that bacteria produce to resist certain types of antibiotics. The early results for these drugs are promising, but they don’t work against all types of MDR bacteria.
Cefiderocol, a new injectable drug, has shown a lot of promise because of its unique structure that gives it stability against numerous MDR bacteria. Other alternatives like Colistin are also used, but their use is often limited due to their harmful side effects and growing resistance among bacteria.
What else can Gram-Negative Bacteria be?
There are different types of infections that can occur, which are usually caused by various microorganisms. These include:
- Bacterial infections caused by Gram-positive bacteria such as Staphylococcus, Streptococcus, and Micrococcus species.
- Viral infections such as HIV, respiratory syncytial virus, and influenza.
- Infections caused by Mycobacterium and Nocardia species.
- Fungal infections due to microbes like Cryptococcus, Aspergillus species, and Candida albicans.
What to expect with Gram-Negative Bacteria
Infections caused by gram-negative bacteria can be hard to predict because there are many factors involved. In addition, some studies show different results compared to others. However, it is generally agreed that these types of infections often lead to poor health outcomes, particularly in elderly patients, individuals with a history of multiple medical conditions, those who have undergone solid organ transplantation, and those with cancer.
The success of treatment also relies on the specific type of bacteria causing the infection and where in the body the infection is located. Severe infections can lead to high death rates, especially if antibiotic treatment is delayed or not appropriate. On the flip side, timely and appropriate antibiotic treatment can greatly improve survival rates.
One challenge is that there isn’t a well-defined plan for treating these infections. This can lead to unsuccessful treatment if the antibiotics are not given at the right time or in the correct dosage. Lastly, treatment that involves only one type of medication, known as monotherapy, is often less successful than using a combination of different medications. This combination therapy approach is often linked to better health outcomes.
Possible Complications When Diagnosed with Gram-Negative Bacteria
Infections caused by gram-negative bacteria, particularly those that produce enzymes capable of breaking down carbapenems, can lead to a variety of complications. One of the problems that often arise is a recurrent urinary tract infection which is troublesome due to its easy acquisition. Unfortunately, we are now seeing more and more cases of multi-drug resistant bacteria in our communities. These infections can get very serious if not treated properly, potentially leading to kidney failure, a body-wide infection known as sepsis, and in severe cases, death.
Hospital-acquired infections are also a big concern, especially amongst patients with weakened immune systems, as well as other underlying health issues, or who are on medication that lowers their immune system. These scenarios pose a major challenge for health professionals.
Extra caution is necessary for burn patients, as their injuries create more entry points for bacteria to invade their bodies. Infections in burn patients can become quite severe and even deadly, depending on the number and type of bacteria involved.
Another risk comes in the form of respiratory tract infections, most commonly seen in patients on mechanical ventilation. Gram-negative bacteria, specifically Enterobacteriaceae and non-fermenting bacteria, are typically responsible for these infections, which carry a high risk of death.
Possible Complications:
- Recurrent urinary tract infection
- Kidney failure
- Sepsis
- Death
- Hospital-acquired infection
- Deadly infections in burn patients
- Respiratory tract infections for patients on mechanical ventilation
Preventing Gram-Negative Bacteria
A major challenge in treating infections caused by multiple drug-resistant ‘gram-negative’ bacteria is the overuse of antibiotics. This issue doesn’t just happen with antibiotics prescribed outside of hospitals, but also within them. As these drug-resistant bacteria became widespread, it became clear that the excessive use of these antibiotics needed urgent attention. So, efforts are being made to change how these drugs are used. These initiatives include educational campaigns and tackling inappropriate self-medication. Measures like monitoring drug use and recording them with pharmacies are important to change both the general public’s and health professionals’ habits with antibiotics.
