Gram-negative bacteria- cell wall, examples, diseases, antibiotics

Bacteria are microscopic organisms that can be found in various environments and can cause different types of infections and diseases in humans and other animals. Bacteria can be classified into two major groups based on the structure and composition of their cell walls: gram-positive and gram-negative bacteria. This classification is based on a laboratory technique called gram staining, which was developed by a Danish bacteriologist named Hans Christian Gram in 1884 .

Gram staining is a simple and rapid method that uses a series of dyes to stain bacterial cells and differentiate them based on their ability to retain or lose the primary stain, which is crystal violet. Gram-positive bacteria have thick cell walls that consist mainly of peptidoglycan, a polymer of sugars and amino acids that forms a mesh-like layer around the cell membrane. Peptidoglycan can trap the crystal violet dye and retain it even after washing with alcohol, which is the decolorizing agent. Therefore, gram-positive bacteria appear purple or blue under a microscope after gram staining .

Gram-negative bacteria have thin cell walls that contain only a small amount of peptidoglycan, which is sandwiched between two membranes: the inner (cytoplasmic) membrane and the outer membrane. The outer membrane contains lipids and lipopolysaccharides, which are complex molecules that have both lipid and sugar components. The lipids and lipopolysaccharides make the outer membrane more resistant to certain chemicals, including alcohol. Therefore, when gram-negative bacteria are stained with crystal violet and washed with alcohol, they lose the primary stain and appear colorless under a microscope. To visualize them, a counterstain such as safranin or fuchsine is added, which stains them pink or red .

Gram staining is an important tool for identifying and characterizing bacteria, as it provides information about their cell wall structure, which can affect their physiology, pathogenicity, and susceptibility to antibiotics. However, gram staining is not always conclusive or reliable, as some bacteria may show variable or indeterminate results due to factors such as age, culture conditions, or staining technique. Moreover, gram staining does not provide enough information to distinguish between different species or strains of bacteria within the same group. Therefore, gram staining is usually followed by other tests such as culture, biochemical tests, serological tests, or molecular tests to confirm the diagnosis and guide the treatment of bacterial infections .

Gram-negative bacteria are a diverse group of microorganisms that share some common features in their cell structure and staining properties. One of the main characteristics of Gram-negative bacteria is their cell envelope, which consists of an inner cytoplasmic membrane, a thin peptidoglycan layer, and an outer membrane containing lipopolysaccharides (LPS) . The outer membrane acts as a barrier to many substances, including antibiotics, detergents, and lysozyme, and also contains porins that allow the passage of small molecules . The LPS is composed of three parts: lipid A, core polysaccharide, and O antigen. The lipid A is embedded in the outer membrane and is responsible for the endotoxic activity of Gram-negative bacteria, while the O antigen is a variable sugar chain that extends outward and determines the serological specificity of the bacteria .

Another characteristic of Gram-negative bacteria is their periplasmic space, which is a gel-like region between the inner and outer membranes that contains various proteins and enzymes involved in nutrient acquisition, peptidoglycan synthesis, and detoxification . The periplasmic space also contains the peptidoglycan layer, which is much thinner in Gram-negative bacteria than in Gram-positive bacteria. The peptidoglycan layer provides mechanical strength and shape to the bacterial cell wall and is composed of alternating units of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) cross-linked by peptide chains .

Gram-negative bacteria can have different shapes depending on their genus and species. Some of the common shapes are:

• Spherical or cocci: These are round-shaped bacteria that can be arranged in pairs (diplococci), chains (streptococci), clusters (staphylococci), or tetrads (sarcinae). Examples of Gram-negative cocci are Neisseria meningitidis, Neisseria gonorrhoeae, Moraxella catarrhalis, and Acinetobacter baumannii .
• Rod or bacillus: These are cylindrical-shaped bacteria that can be straight or curved. They can be arranged singly, in pairs (diplobacilli), chains (streptobacilli), or palisades (side-by-side). Examples of Gram-negative rods are Escherichia coli, Salmonella typhi, Shigella dysenteriae, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Haemophilus influenzae .
• Spiral or spirochete: These are helical-shaped bacteria that have a flexible cell wall and can move by rotating their axial filaments. Examples of Gram-negative spirochetes are Treponema pallidum, Borrelia burgdorferi, and Leptospira interrogans .
• Coccobacillus: These are oval-shaped bacteria that are intermediate between cocci and bacilli. Examples of Gram-negative coccobacilli are Brucella abortus, Bordetella pertussis, Francisella tularensis, and Helicobacter pylori .
• Vibrio: These are comma-shaped bacteria that have a single polar flagellum for motility. Examples of Gram-negative vibrios are Vibrio cholerae, Vibrio parahaemolyticus, and Vibrio vulnificus .

The shape of Gram-negative bacteria can be determined by microscopic observation after staining with the Gram stain technique. This technique involves four steps: applying a primary stain (crystal violet) to the bacterial cells, fixing the stain with an iodine solution, decolorizing with alcohol or acetone, and applying a counterstain (safranin) to the cells. Gram-negative bacteria lose the primary stain during the decolorization step and appear pink or red after the counterstain, whereas Gram-positive bacteria retain the primary stain and appear purple or blue . The shape and arrangement of the stained cells can then be observed under a light microscope.

The cell wall of Gram-negative bacteria is composed of three layers: the inner membrane, the peptidoglycan layer, and the outer membrane. The cell wall protects the bacteria from environmental stresses, maintains their shape and integrity, and contributes to their pathogenicity and resistance to antibiotics.

The inner membrane is also known as the cytoplasmic membrane or the plasma membrane. It is a phospholipid bilayer that encloses the cytoplasm and regulates the transport of molecules in and out of the cell. The inner membrane also contains various proteins that are involved in metabolic processes, such as respiration, photosynthesis, and chemotaxis.

The peptidoglycan layer is a thin layer of cross-linked sugar and amino acid molecules that provides mechanical strength and rigidity to the cell wall. The peptidoglycan layer is much thinner in Gram-negative bacteria than in Gram-positive bacteria, accounting for only 5-10% of the cell wall dry weight. The peptidoglycan layer is attached to the inner membrane by lipoproteins, such as Braun`s lipoprotein, which is the most abundant protein in the cell envelope.

The outer membrane is a unique feature of Gram-negative bacteria that distinguishes them from Gram-positive bacteria. The outer membrane is also a phospholipid bilayer, but it contains different types of lipids and proteins than the inner membrane. The most characteristic component of the outer membrane is lipopolysaccharide (LPS), which is a complex molecule composed of lipid A, core polysaccharide, and O antigen. LPS acts as an endotoxin that triggers inflammatory responses in host cells when released by bacterial lysis or shedding. LPS also confers resistance to some antibiotics and detergents by forming a barrier to their penetration.

The outer membrane also contains porins, which are proteins that form channels for the passage of small molecules, such as sugars, amino acids, and ions. Some porins are specific for certain substrates, while others are nonspecific. The outer membrane also contains surface proteins that mediate various functions, such as adhesion, invasion, secretion, and antigenicity. Some examples of surface proteins are pili, flagella, capsules, fimbriae, and secretion systems.

Between the inner and outer membranes lies the periplasmic space, which is filled with a gel-like substance called periplasm. The periplasm contains various enzymes and binding proteins that are involved in nutrient acquisition, peptidoglycan synthesis, detoxification, and defense. The periplasm also acts as a buffer zone that protects the inner membrane from harmful substances in the environment.

The cell wall of Gram-negative bacteria is a complex structure that plays a vital role in their survival and virulence. Understanding the structure and function of the cell wall can help us develop better strategies to combat bacterial infections.

The periplasmic space is the gap between the inner and outer membranes of gram-negative bacteria. It contains a gel-like substance called the periplasm, which is rich in proteins and other molecules that perform various functions for the bacterial cell.

One of the main functions of the periplasmic space is to provide a distinct environment for protein folding and quality control. The periplasm has a lower pH and a more oxidizing condition than the cytoplasm, which allows for the formation of disulfide bonds and the proper folding of proteins that are destined for the outer membrane or secretion. The periplasm also contains chaperones and proteases that help to fold and degrade misfolded proteins, preventing their accumulation and aggregation.

Another function of the periplasmic space is to house structural elements that support the cell envelope and maintain its shape and integrity. The most important of these elements is the peptidoglycan layer, which is a mesh-like polymer of sugars and amino acids that forms a rigid wall around the cell. The peptidoglycan layer is covalently linked to the outer membrane by Braun`s lipoprotein, which anchors the lipid bilayer to the sugar chains. The peptidoglycan layer also interacts with other proteins in the periplasm, such as adhesion sites and flagellar motors, that modulate the cell`s attachment and motility.

A third function of the periplasmic space is to facilitate the transport and sensing of molecules across the cell envelope. The periplasm contains various transporters and binding proteins that help to bring nutrients, ions, and signaling molecules into the cell or expel waste products and toxins out of the cell. Some of these transporters are part of complex systems that span both membranes, such as ATP-binding cassette (ABC) transporters and type III secretion systems. The periplasm also contains receptors and sensors that detect changes in the environment, such as pH, osmolarity, temperature, and oxidative stress, and transduce signals to the cytoplasm or the outer membrane.

In summary, the periplasmic space is a multifunctional compartment that plays a crucial role in protein processing, cell structure, and environmental adaptation for gram-negative bacteria.

The peptidoglycan layer is a thin layer of polysaccharide chains that are cross-linked by short peptides. It is located between the outer membrane and the cytoplasmic membrane of gram-negative bacteria. The peptidoglycan layer is much thinner (2-7 nm) and less dense in gram-negative bacteria than in gram-positive bacteria, where it forms a thick (20-80 nm) and rigid cell wall.

The peptidoglycan layer provides structural support and shape to the bacterial cell. It also protects the cell from osmotic lysis, which is the rupture of the cell due to a difference in water pressure across the membrane. The peptidoglycan layer is flexible and elastic, allowing the cell to withstand changes in osmotic pressure and environmental conditions.

The peptidoglycan layer is composed of alternating units of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM), which are linked by β-1,4 glycosidic bonds. Each NAM unit has a short peptide chain attached to it, which consists of four or five amino acids. The peptide chains can form cross-links between adjacent peptidoglycan strands, creating a mesh-like network. The cross-linking pattern varies among different gram-negative bacteria, but it usually involves a direct bond between D-alanine and Diaminopimelic acid (DAP) or a peptide interbridge between D-alanine and L-lysine.

The peptidoglycan layer is synthesized by a series of enzymes that are located in the cytoplasmic membrane and the periplasmic space. The synthesis involves three main steps: 1) the formation of NAG-NAM-pentapeptide precursors in the cytoplasm; 2) the transport of the precursors across the cytoplasmic membrane by a lipid carrier called bactoprenol; and 3) the incorporation of the precursors into the existing peptidoglycan layer by transglycosylases and transpeptidases in the periplasm. The synthesis of peptidoglycan is coordinated with the growth and division of the bacterial cell.

The peptidoglycan layer is also a target for many antibiotics that interfere with its synthesis or integrity. For example, penicillin inhibits the transpeptidase enzyme that forms the cross-links between peptide chains, weakening the peptidoglycan layer and making the cell susceptible to osmotic lysis. Other antibiotics, such as vancomycin and bacitracin, prevent the transport or incorporation of the peptidoglycan precursors, blocking the synthesis of new peptidoglycan. However, some gram-negative bacteria have developed resistance mechanisms against these antibiotics, such as modifying their peptidoglycan structure or producing enzymes that degrade or inactivate the antibiotics.

The outer membrane of gram-negative bacteria is a unique structure that distinguishes them from gram-positive bacteria. It is composed of a lipid bilayer, but unlike the inner membrane, it is asymmetrical, with phospholipids in the inner leaflet and lipopolysaccharides (LPS) in the outer leaflet. LPS are complex molecules that consist of three parts: lipid A, core polysaccharide, and O antigen. Lipid A is embedded in the outer membrane and anchors the LPS molecule to the surface. It also acts as an endotoxin that triggers a strong immune response when released from dead or damaged bacteria. The core polysaccharide is a short chain of sugars that connects lipid A to the O antigen. The O antigen is a long and variable chain of sugars that extends outward from the core and determines the serological specificity of different strains of bacteria.

The outer membrane has several functions that are essential for the survival and virulence of gram-negative bacteria. First, it acts as a permeability barrier that protects the bacteria from harmful substances such as antibiotics, bile salts, and detergents . The LPS molecules form a dense and rigid layer that prevents the entry of hydrophobic molecules, while the porin proteins allow the passage of small hydrophilic molecules such as sugars and amino acids . Second, it contains structures that help the bacteria adhere to host cells and tissues, such as pili, fimbriae, and adhesins . These structures are often involved in the pathogenesis of bacterial infections by facilitating colonization, invasion, and biofilm formation . Third, it modulates the cell shape and mechanical properties of the bacteria by interacting with the peptidoglycan layer and the periplasmic space. The outer membrane is connected to the peptidoglycan layer by Braun`s lipoprotein, which is covalently bound to both components . The outer membrane also forms adhesion sites that allow cell contact and membrane fusion . These interactions influence the curvature, elasticity, and stress-bearing capacity of the cell envelope.

The outer membrane of gram-negative bacteria is therefore a complex and dynamic structure that plays multiple roles in bacterial physiology and pathogenicity. It is a target for many antimicrobial agents that aim to disrupt its integrity or function. However, it also poses a challenge for drug delivery and diagnosis due to its low permeability and high variability. Understanding the molecular composition and physical properties of the outer membrane is crucial for developing new strategies to combat gram-negative bacterial infections.

Gram-negative bacteria are a diverse group of microorganisms that can cause various types of infections in humans and animals. Some of the most common and medically important gram-negative bacteria are listed below with their associated diseases and clinical features :

• Escherichia coli: This bacterium is normally found in the intestinal tract of humans and animals, where it helps with digestion and vitamin synthesis. However, some strains of E. coli can cause intestinal diseases such as enterotoxigenic (ETEC), enteropathogenic (EPEC), enterohemorrhagic (EHEC), enteroinvasive (EIEC), and enteroaggregative (EAEC) infections, which are characterized by diarrhea, abdominal cramps, nausea, vomiting, and sometimes bloody stools. E. coli can also cause extraintestinal diseases such as urinary tract infections, neonatal meningitis, septicemia, pneumonia, and wound infections .
• Salmonella: This bacterium is transmitted by contaminated food or water, especially poultry, eggs, and dairy products. It causes enteric fever (typhoid or paratyphoid fever), which is characterized by fever, headache, abdominal pain, constipation or diarrhea, and sometimes a rash. Salmonella can also cause gastroenteritis (salmonellosis), which is characterized by nausea, vomiting, and non-bloody diarrhea . Salmonella can invade the bloodstream and cause bacteremia, which can lead to complications such as osteomyelitis, septic arthritis, endocarditis, and meningitis.
• Shigella: This bacterium is transmitted by fecal-oral route or by contact with infected persons or objects. It causes shigellosis (bacillary dysentery), which is characterized by diarrhea with blood and mucus in stool, fever, abdominal cramps, and tenesmus (painful urge to defecate). Shigella can also cause bacteremia, septic shock, hemolytic uremic syndrome (HUS), and reactive arthritis .
• Vibrio cholerae: This bacterium is transmitted by contaminated water or food, especially seafood. It causes cholera, which is characterized by profuse watery diarrhea, vomiting, dehydration, electrolyte imbalance, and hypovolemic shock. Cholera can be fatal if not treated promptly with rehydration therapy and antibiotics .
• Helicobacter pylori: This bacterium is transmitted by oral-oral or fecal-oral route or by contact with contaminated objects. It colonizes the stomach and causes chronic gastritis, peptic ulcers, gastric adenocarcinoma, and mucosa-associated lymphoid tissue (MALT) lymphoma .
• Neisseria gonorrhoeae: This bacterium is transmitted by sexual contact or from mother to child during birth. It causes gonorrhea, which is a sexually transmitted infection that affects the mucous membranes of the genital tract, rectum, pharynx, and eyes. Gonorrhea can cause urethritis, cervicitis, pelvic inflammatory disease (PID), epididymitis, prostatitis, conjunctivitis, and disseminated gonococcal infection (DGI), which can manifest as arthritis, dermatitis, endocarditis, and meningitis .
• Neisseria meningitidis: This bacterium is transmitted by respiratory droplets or direct contact with infected persons or objects. It causes meningococcal disease, which can manifest as meningitis, septicemia, pneumonia, arthritis, or endophthalmitis. Meningococcal disease can be fatal or cause serious complications such as hearing loss, brain damage, or limb amputation .
• Haemophilus influenzae: This bacterium is transmitted by respiratory droplets or direct contact with infected persons or objects. It causes various types of infections such as otitis media, sinusitis, bronchitis, pneumonia, meningitis, epiglottitis, septic arthritis, cellulitis, and endocarditis. H. influenzae type b (Hib) is a major cause of invasive disease in children under 5 years of age, especially in developing countries .
• Pseudomonas aeruginosa: This bacterium is ubiquitous in the environment and can colonize various surfaces and medical devices. It causes opportunistic infections in immunocompromised or hospitalized patients, such as wound infections, burn infections, urinary tract infections, pneumonia, septicemia, endocarditis, osteomyelitis, and meningitis. P. aeruginosa can also cause infections in healthy individuals, such as otitis externa (swimmer`s ear), folliculitis (hot tub rash), and keratitis (corneal infection) .
• Klebsiella pneumoniae: This bacterium is normally found in the intestinal tract of humans and animals, but can cause infections when it spreads to other sites. It causes pneumonia, urinary tract infections, septicemia, wound infections, meningitis, and liver abscesses. K. pneumoniae can also cause a rare form of necrotizing pneumonia with bloody sputum, known as Friedländer`s pneumonia .
• Yersinia pestis: This bacterium is transmitted by fleas from infected rodents or by direct contact with infected animals or humans. It causes plague, which can manifest as bubonic plague (swollen and painful lymph nodes), septicemic plague (bacteria in the blood), or pneumonic plague (bacteria in the lungs). Plague can be fatal if not treated promptly with antibiotics .

Gram-negative bacteria are generally more resistant to antibiotics than gram-positive bacteria, because they have an outer membrane that prevents many drugs from reaching their target site. Some of the antibiotics that are effective against gram-negative bacteria are listed below :

• Aminoglycosides: These are bactericidal drugs that inhibit protein synthesis by binding to the bacterial ribosome. They include gentamicin, amikacin, tobramycin, and streptomycin. They are effective against many gram-negative bacteria, such as E. coli, Salmonella, Shigella, Pseudomonas, and Klebsiella. However, they have serious side effects such as nephrotoxicity and ototoxicity, and they require monitoring of blood levels.
• Carbapenems: These are broad-spectrum bactericidal drugs that inhibit cell wall synthesis by binding to penicillin-binding proteins. They include imipenem, meropenem, ertapenem, and doripenem. They are effective against many gram-negative bacteria, especially those that produce β-lactamases (enzymes that degrade β-lactam antibiotics). However, they are not active against some strains of Pseudomonas and Acinetobacter, and they can cause seizures and allergic reactions.
• Cephalosporins: These are bactericidal drugs that inhibit cell wall synthesis by binding to penicillin-binding proteins. They are classified into four generations based on their spectrum of activity and resistance to β-lactamases. The third- and fourth-generation cephalosporins, such as ceftriaxone, cefotaxime, ceftazidime, cefepime, and ceftaroline, are effective against many gram-negative bacteria, such as Neisseria, Haemophilus, E. coli, Klebsiella, Proteus, Salmonella, Shigella, and Pseudomonas. However, they are not active against some strains of Enterobacter and Acinetobacter, and they can cause hypersensitivity reactions and bleeding disorders.
• Fluoroquinolones: These are bactericidal drugs that inhibit DNA synthesis by interfering with bacterial topoisomerases. They include ciprofloxacin, levofloxacin, moxifloxacin, and norfloxacin. They are effective against many gram-negative bacteria, such as E. coli, Salmonella, Shigella, Campylobacter, Helicobacter, Neisseria, Haemophilus, Pseudomonas, and Yersinia. However, they are not active against some strains of Acinetobacter and Stenotrophomonas, and they can cause tendon rupture, cardiac arrhythmias, and central nervous system toxicity.
• Sulfonamides: These are bacteriostatic drugs that inhibit folic acid synthesis by competing with para-aminobenzoic acid (PABA). They include sulfamethoxazole, sulfisoxazole, and sulfadiazine. They are effective against some gram-negative bacteria, such as E. coli, Salmonella, Shigella, Chlamydia, and Nocardia. 
  
  
  

  Antimicrobial agents used against Gram-negative bacteria

Gram-negative bacteria are more resistant to antibiotics than gram-positive bacteria, because they have a complex cell wall that prevents many drugs from entering the cell. Therefore, finding effective antimicrobial agents against gram-negative bacteria is a major challenge for medicine and public health.

Antibiotics commonly used to treat gram-negative bacterial infections include:

• Penicillins: These are beta-lactam antibiotics that inhibit the synthesis of peptidoglycan, a major component of the bacterial cell wall. Penicillins are classified into different groups based on their spectrum of activity and resistance to beta-lactamases, enzymes that degrade beta-lactam antibiotics. Some examples of penicillins are ampicillin, amoxicillin, carbenicillin, and piperacillin .
• Cephalosporins: These are also beta-lactam antibiotics that have a similar mechanism of action as penicillins, but are more resistant to beta-lactamases and have a broader spectrum of activity. Cephalosporins are divided into four generations, with each generation having increased activity against gram-negative bacteria and decreased activity against gram-positive bacteria. Some examples of cephalosporins are cefazolin, cefuroxime, ceftriaxone, and cefepime .
• Monobactams: These are another type of beta-lactam antibiotics that have a monocyclic structure and are resistant to most beta-lactamases. Monobactams are effective against aerobic gram-negative bacteria, but not against gram-positive bacteria or anaerobic bacteria. The only monobactam available for clinical use is aztreonam .
• Aminoglycosides: These are antibiotics that bind to the 30S subunit of the bacterial ribosome and interfere with protein synthesis. Aminoglycosides are bactericidal and have a broad spectrum of activity against aerobic gram-negative bacteria and some gram-positive bacteria. However, they have serious side effects such as nephrotoxicity and ototoxicity, and they are inactivated by some enzymes produced by resistant bacteria. Some examples of aminoglycosides are gentamicin, streptomycin, and tobramycin .
• Quinolones: These are antibiotics that inhibit the bacterial DNA gyrase and topoisomerase IV enzymes, which are essential for DNA replication and transcription. Quinolones are bactericidal and have a broad spectrum of activity against both gram-positive and gram-negative bacteria. However, they have some adverse effects such as gastrointestinal disturbances, tendon rupture, and neurological disorders, and they may induce resistance by mutations in the target enzymes or efflux pumps. Some examples of quinolones are ciprofloxacin, levofloxacin, and moxifloxacin .
• Macrolides: These are antibiotics that bind to the 50S subunit of the bacterial ribosome and inhibit protein synthesis. Macrolides are bacteriostatic and have a narrow spectrum of activity against mainly gram-positive bacteria and some atypical gram-negative bacteria such as Legionella and Chlamydia. Macrolides may cause gastrointestinal disturbances, liver toxicity, and cardiac arrhythmias, and they may induce resistance by modifying the target site or by efflux pumps. Some examples of macrolides are erythromycin, azithromycin, and clarithromycin .
• Chloramphenicol: This is an antibiotic that also binds to the 50S subunit of the bacterial ribosome and inhibits protein synthesis. Chloramphenicol is bacteriostatic and has a broad spectrum of activity against both gram-positive and gram-negative bacteria. However, it has serious side effects such as bone marrow suppression, aplastic anemia, and gray baby syndrome in newborns, and it may induce resistance by acetylating enzymes or efflux pumps. Chloramphenicol is rarely used in clinical practice due to its toxicity .
• Folate antagonists: These are antibiotics that inhibit the bacterial synthesis of folic acid, which is required for DNA synthesis and cell division. Folate antagonists are bacteriostatic and have a broad spectrum of activity against both gram-positive and gram-negative bacteria. However, they may cause hypersensitivity reactions, hematological disorders, and renal toxicity, and they may induce resistance by mutations in the target enzymes or by plasmid-mediated resistance. Some examples of folate antagonists are sulfonamides and trimethoprim .
• Carbapenems: These are beta-lactam antibiotics that have the broadest spectrum of activity among all beta-lactams. They are resistant to most beta-lactamases and are effective against gram-positive, gram-negative, and anaerobic bacteria. However, they may cause allergic reactions, seizures, and gastrointestinal disturbances, and they may induce resistance by carbapenemases, enzymes that hydrolyze carbapenems. Some examples of carbapenems are imipenem, meropenem, and ertapenem .

In some cases, combination therapy with two or more antibiotics may be used to improve the efficacy, broaden the spectrum, prevent the emergence of resistance, or reduce the toxicity of antimicrobial agents. For example, beta-lactams may be combined with beta-lactamase inhibitors to overcome the resistance mediated by beta-lactamases. Some examples of such combinations are amoxicillin-clavulanic acid, piperacillin-tazobactam, and ampicillin-sulbactam.

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