What are the main categories of antibiotics. How do different antibiotics work. Which antibiotics are most commonly prescribed. What factors influence antibiotic selection. How do bacteria develop resistance to antibiotics. What are the emerging trends in antibiotic development.

The Evolution of Antibiotic Classes: From Penicillin to Modern Therapeutics

The discovery of antibiotics revolutionized medicine, transforming once-deadly infections into treatable conditions. Since Alexander Fleming’s serendipitous discovery of penicillin in 1928, numerous antibiotic classes have been developed, each with unique mechanisms of action and spectra of activity.

Understanding the various antibiotic categories is crucial for healthcare professionals and patients alike. This knowledge enables more informed decisions about treatment options, helps combat antibiotic resistance, and sheds light on the ongoing development of new antimicrobial agents.

The Birth of Antibiotics: A Brief History

The antibiotic era began with the development of sulfonamides in the 1930s, followed by the mass production of penicillin in the 1940s. Since then, numerous antibiotic classes have been discovered and synthesized, each offering new ways to combat bacterial infections.

• 1932: Prontosil (first sulfonamide) developed
• 1928: Penicillin discovered by Alexander Fleming
• 1940s: Mass production of penicillin begins
• 1950s-1970s: Golden age of antibiotic discovery
• 1980s-present: Focus on modifying existing antibiotics and combating resistance

Beta-Lactams: The Cornerstone of Antibiotic Therapy

Beta-lactam antibiotics, including penicillins and cephalosporins, remain the most widely prescribed class of antibiotics. Their effectiveness against a broad range of bacteria and relatively low toxicity make them a cornerstone of modern antibiotic therapy.

How Do Beta-Lactams Work?

Beta-lactams interfere with bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs). This disruption weakens the cell wall, ultimately leading to bacterial cell lysis and death.

What makes beta-lactams so effective against Gram-positive bacteria? The answer lies in their ability to penetrate the thicker peptidoglycan layer of these organisms, which is a critical component of their cell wall structure.

Types of Beta-Lactam Antibiotics

1. Penicillins (e.g., amoxicillin, ampicillin)
2. Cephalosporins (1st to 5th generation)
3. Carbapenems (e.g., meropenem, imipenem)
4. Monobactams (e.g., aztreonam)

Among these, amoxicillin stands out as the most commonly prescribed antibiotic in many healthcare systems, including the UK’s National Health Service (NHS).

Sulfonamides: Pioneers in Synthetic Antibiotics

Sulfonamides hold a special place in antibiotic history as the first commercially available antibiotics. Developed in 1932, they paved the way for the antibiotic revolution.

Mechanism of Action and Spectrum of Activity

Unlike beta-lactams, sulfonamides do not directly kill bacteria. Instead, they inhibit bacterial growth by interfering with folate synthesis, a crucial process for bacterial DNA replication and cell division. This bacteriostatic action makes sulfonamides effective against both Gram-positive and Gram-negative bacteria.

Why have sulfonamides fallen out of favor in modern medicine? Two primary factors contribute to their decreased use:

• Development of widespread bacterial resistance
• Concerns about potential side effects and toxicity

Despite these challenges, sulfonamides still find use in specific clinical scenarios, particularly in combination with other antibiotics for synergistic effects.

Tetracyclines: Broad-Spectrum Workhorses

Tetracyclines, discovered in the 1940s, quickly became popular due to their broad-spectrum activity against a wide range of bacteria, including some atypical pathogens like Chlamydia and Mycoplasma.

How Tetracyclines Combat Bacteria

Tetracyclines work by inhibiting bacterial protein synthesis. They bind to the 30S subunit of bacterial ribosomes, preventing the attachment of aminoacyl-tRNA to the mRNA-ribosome complex. This action effectively halts the growth and reproduction of bacteria.

What makes tetracyclines unique among antibiotics? Their ability to accumulate within bacterial cells at concentrations much higher than in the surrounding environment, enhancing their effectiveness.

Common Tetracycline Antibiotics

• Doxycycline
• Minocycline
• Tetracycline
• Tigecycline (a glycylcycline derivative)

Tetracyclines remain valuable in treating a variety of infections, including respiratory tract infections, acne, and certain sexually transmitted diseases.

Macrolides: Fighting Intracellular Pathogens

Macrolide antibiotics, characterized by a large lactone ring in their chemical structure, are particularly effective against intracellular pathogens and respiratory tract infections.

Mechanism of Action

Like tetracyclines, macrolides inhibit bacterial protein synthesis. They bind to the 50S subunit of the bacterial ribosome, blocking the exit of the growing peptide chain. This action prevents the bacteria from producing essential proteins needed for survival and reproduction.

What gives macrolides an edge in treating certain infections? Their ability to concentrate in host cells makes them particularly effective against intracellular pathogens like Legionella and Chlamydia.

Commonly Prescribed Macrolides

1. Erythromycin
2. Azithromycin
3. Clarithromycin
4. Telithromycin (a ketolide derivative)

Macrolides are often used as alternatives for patients allergic to penicillin and in treating atypical pneumonia and certain sexually transmitted infections.

Fluoroquinolones: Synthetic Broad-Spectrum Agents

Fluoroquinolones represent a class of synthetic broad-spectrum antibiotics that have become increasingly important in treating a wide range of bacterial infections.

How Fluoroquinolones Target Bacteria

Fluoroquinolones work by inhibiting bacterial DNA gyrase and topoisomerase IV, enzymes crucial for DNA replication and cell division. This unique mechanism of action makes them effective against both Gram-positive and Gram-negative bacteria.

What sets fluoroquinolones apart from other antibiotic classes? Their ability to penetrate difficult-to-reach tissues, including the central nervous system and prostate, makes them valuable for treating complex infections.

Common Fluoroquinolone Antibiotics

• Ciprofloxacin
• Levofloxacin
• Moxifloxacin
• Ofloxacin

While highly effective, fluoroquinolones are often reserved as second-line agents due to concerns about potential side effects and the development of resistance.

Aminoglycosides: Potent but Potentially Toxic

Aminoglycosides are a class of antibiotics known for their potency against Gram-negative bacteria and their synergistic effects when combined with other antibiotics.

Mechanism of Action and Unique Properties

Aminoglycosides bind to the 30S subunit of bacterial ribosomes, disrupting protein synthesis. They also have a unique ability to disrupt bacterial cell membrane integrity, enhancing their bactericidal activity.

Why are aminoglycosides often used in combination with other antibiotics? Their synergistic effects, particularly with beta-lactams, can enhance overall efficacy and help prevent the development of resistance.

Commonly Used Aminoglycosides

1. Gentamicin
2. Tobramycin
3. Amikacin
4. Streptomycin

Despite their effectiveness, the use of aminoglycosides is limited by their potential for ototoxicity and nephrotoxicity, requiring careful monitoring during treatment.

Emerging Trends and Future Directions in Antibiotic Development

As antibiotic resistance continues to pose a significant global health threat, researchers are exploring new avenues for antibiotic development and alternative approaches to combat bacterial infections.

Novel Antibiotic Classes and Approaches

What new strategies are scientists employing to develop effective antibiotics? Several innovative approaches are being explored:

• Teixobactin and other naturally derived compounds
• CRISPR-Cas9 based antimicrobials
• Bacteriophage therapy
• Antivirulence strategies targeting bacterial pathogenicity
• Immunomodulatory approaches to enhance host defenses

These emerging technologies and approaches offer hope for overcoming antibiotic resistance and developing more targeted, effective treatments for bacterial infections.

Combating Antibiotic Resistance

How can we preserve the effectiveness of existing antibiotics? Several strategies are being implemented:

1. Antibiotic stewardship programs in healthcare settings
2. Development of rapid diagnostic tests to guide appropriate antibiotic use
3. Exploration of combination therapies to prevent resistance
4. Research into bacterial resistance mechanisms to inform drug design
5. Public education initiatives on proper antibiotic use

By understanding the mechanisms of antibiotic action and resistance, researchers and clinicians can work together to develop more effective treatment strategies and preserve the power of these life-saving drugs for future generations.

As we continue to unravel the complexities of bacterial infections and antibiotic resistance, the field of antimicrobial therapy remains dynamic and ever-evolving. The ongoing development of new antibiotic classes, combined with innovative approaches to combat resistance, offers hope for addressing the challenges posed by emerging and resistant pathogens. By staying informed about these advancements and practicing responsible antibiotic use, we can all play a role in preserving the efficacy of these crucial medicines.

Overview of Antibiotics – Infections

Usually, antibiotics are given by mouth, and the length of treatment does not cause hardship. However, some infections—such as many of those involving bone (osteomyelitis Osteomyelitis Osteomyelitis is a bone infection usually caused by bacteria, mycobacteria, or fungi. Bacteria, mycobacteria, or fungi can infect bones by spreading through the bloodstream or, more often, by… read more ) or the heart (endocarditis Infective Endocarditis Infective endocarditis is an infection of the lining of the heart (endocardium) and usually also of the heart valves. Infective endocarditis occurs when bacteria enter the bloodstream and travel… read more )—may require antibiotics to be given by vein (intravenously) for a long time, often 4 to 6 weeks. If people have no other conditions that need treatment in the hospital and are feeling relatively well, intravenous (IV) antibiotics may be given at home.

When antibiotics have to be given a long time, the short IV catheters that are inserted into a small vein in the arm or hand (such as those used in most routine hospital procedures) may not be desirable. These catheters last only up to 3 days. Instead, a special type of IV catheter is used. It may be inserted either

• Directly into a large central vein, usually in the neck or chest (called a central catheter)

• Into a small vein in the arm and threaded into a large central vein (called a peripherally inserted central catheter, or a PICC)

Some devices for giving antibiotics IV are simple enough that people and their family members can learn to operate them on their own. In other cases, a visiting nurse must come to the home to give each dose. In either situation, people are carefully supervised to make sure the antibiotic is being given correctly and to watch for possible complications and side effects.

If antibiotics are given at home through an IV catheter, the risk of developing an infection at the site where the catheter is inserted and in the bloodstream is increased. The following may indicate a catheter-related infection:

• Pain, redness, and pus at the catheter insertion site

• Chills and fever (even without problems at the insertion site)

A Brief Overview of Classes of Antibiotics – Compound Interest

Click to enlarge

When we’re suffering from a bacterial infection, a trip to the doctors to be prescribed antibiotics is commonplace.  However, there are a wide range of antibiotics available, and they vary both in their usage and their mechanism of action. This graphic summarises the major classes, and also gives a brief insight into the manner in which they combat bacterial infections; we’ll also consider each of the groups in turn, as well as bacterial resistance to each.

Bacteria themselves can be divided into two broad classes – Gram-positive and Gram-negative. The classes derive these names from the Gram test, which involves the addition of a violet dye to the bacteria. Gram-positive bacteria retain the colour of the dye, whilst Gram-negative bacteria do not, and are instead coloured red or pink. Gram-negative bacteria are more resistant to antibodies and antibiotics than Gram-positive bacteria, because they have a largely impermeable cell wall. The bacteria responsible for MRSA and acne are examples of Gram-positive bacteria, whilst those responsible for Lyme disease and pneumonia are examples of Gram-negative bacteria.

Beta-Lactams

Beta-lactams are a wide range of antibiotics, the first of which to be discovered was penicillin, which Alexander Fleming identified in 1928. All beta-lactam antibiotics contain a beta-lactam ring; they include penicillins, such as amoxicillin, and cephalosporins. They work by interfering with the synthesis of peptidoglycan, an important component of the bacterial cell wall, and are mostly used against gram-positive bacteria. Bacteria can, however, develop resistance to beta-lactams via several routes, including the production of enzymes that break down the beta-lactam ring. In the NHS, penicillins are the most commonly prescribed antibiotics, with amoxicillin being the most common in the class.

Sulfonamides

Prontosil, a sulfonamide, was the first commercially available antibiotic, developed in 1932. A significant number of sulfonamide antibiotics were subsequently developed, defined as broad-spectrum antibiotics capable of acting on both Gram-positive and Gram-negative bacteria. Unlike the beta-lactams, they do not act by directly killing the bacteria, but by inhibiting bacterial synthesis of the B vitamin folate, thus preventing growth and reproduction of the bacteria. In the present day, sulfonamides are rarely used, partially due to the development of bacterial resistance, but also due to concern about unwanted effects such as hepatotoxicity.

Aminoglycosides

Aminoglycosides inhibit the synthesis of proteins in bacteria, eventually leading to cell death. They are only effective against certain Gram-negative bacteria, as well as some Gram-positive bacteria, but are not absorbed during digestion, so must be injected. In the treatment of tuberculosis, streptomycin was the first drug found to be effective; however, due to issues with toxicity of aminoglycosides, their present day use is limited.

Tetracyclines

Tetracyclines are broad-spectrum antibiotics, active against both Gram-positive and Gram-negative bacteria. Like the sulfonamides, they inhibit protein synthesis, inhibiting growth and reproduction of bacteria. Their use is decreasing due to increasing instances of bacterial resistance; however, they still find use in treatment of acne, urinary tract, and respiratory tract infections, as well as chlamydia infections. They must be taken in isolation, often two hours before or after eating, as they can easily bind with food, reducing their absorption.

Chloramphenicol

Another broad-spectrum antibiotic, chloramphenicol also acts by inhibiting protein synthesis, and thus growth and reproduction of bacteria. However, it is also bactericidal against a limited number of bacteria. Due to the possibility of serious toxic effects, in developed countries it is generally only used in cases where infections are deemed to be life-threatening, although it is also occasionally used in the treatment of eye infections. Despite this, it is a much more common antibiotic in developing countries due to its low cost and availability, and is recommended by the World Health Organisation as an effective first line treatment for meningitis in those countries with a low income.

Macrolides

Much like the beta-lactams, the macrolides are mainly effective against Gram-positive bacteria; however, they act in a bacteriostatic manner, preventing growth and reproduction by inhibiting protein synthesis. Their effectiveness is marginally broader than that of penicillins, and they have been shown to be effective against several species of bacteria that penicillins are not. Whilst some bacterial species have developed resistance to macrolides, they are still the second most commonly prescribed antibiotics in the NHS, with erythromycin being the most commonly prescribed in the class.

Glycopeptides

Glycopeptides include the drug vancomycin – commonly used as a ‘drug of last resort’, when other antibiotics have failed. Whilst this used to be the last line of defence against infections, particularly MRSA, the more recent development of newer antibiotics in other classes has provided other options. Nonetheless, there remain strict guidelines on the circumstances in which vancomycin can be used to treat infections, in order to delay the development of resistance. The bacteria against which glycopeptides are active are otherwise somewhat limited, and in most they inhibit growth and reproduction rather than killing bacteria directly.

Oxazolidinones

Oxazolidinones are active against Gram-positive bacteria, and act by inhibiting protein synthesis, and hence growth and reproduction. Linezolid, approved for use in 2000, was the first marketed antibiotic in the class, although the compound cycloserine has been used as a second line tuberculosis treatment since 1956. Whilst linezolid is expensive, resistance seems to be developing relatively slowly since its introduction.

Ansamycins

This class of antibiotics are effective against Gram-positive bacteria, as well as some Gram-negative bacteria. They inhibit the production of RNA, which has important biological roles inside the cells of the bacteria, and as such leads to the death of the bacterial cells. A subclass of antibiotics, rifamycins, are used to treat tuberculosis and leprosy. Uncommonly, ansamycins can also demonstrate anti-viral activity.

Quinolones

Quinolones are bactericidal compounds that interfere with the replication and transcription of DNA in bacteria cells. They are broad-spectrum antibiotics, and are widely used for urinary tract infections, as well as other hospital-acquired infections where resistance to older classes of antibiotics is suspected. Additionally, their use for veterinary purposes is widespread; a use that has been criticised in some quarters for hastening the development of resistance. Resistance to quinolones can be particularly rapid in its development; in the US, they were the most commonly prescribed antibiotics in 2002, and their prescription for unrecommended conditions or viral infections is also thought to be a significant contributor to the development of resistance.

Streptogramins

Streptogramins are unusual in that they are usually administered as a combination of two antibiotic drugs from the different groups within the class: streptogramin A and streptogramin B. On their own, these compounds only show growth-inhibiting activity, but combined they have a synergistic effect and are capable of directly killing bacteria cells, by inhibiting the synthesis of proteins. They are often used to treat resistant infections, although resistance to the streptogramins themselves has also developed.

Lipopeptides

Discovered in 1987, lipopeptides are the most recent class of antibiotics, and are bactericidal against Gram-positive bacteria. Daptomycin is the most commonly used member of the class; it has a unique mechanism of action, disrupting several aspects of cell membrane function in bacteria. This unique mechanism of action also seems to be advantageous in that, currently, incidences of resistance to the drug seem to be rare – though they have been reported. It is given via injection, and commonly used to treat infections in the skin and tissue.

Antibiotic Resistance

Bacterial resistance to antibiotics is on the rise, to the extent that it has been made the focus of this year’s Longitude Prize. The prize is offering a £10 million prize fund for the development of a cheap and easy to use bacterial infection test kit, in the hope that this will allow doctors to prescribe the correct antibiotics at the correct time for patients, and also prevent the prescribing of antibiotics in the cases of viral infections. It’s hoped both of these measures will help slow the development of antibiotic resistance in bacteria.

The graphic in this article is licensed under a  Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. See the site’s content usage guidelines.

References & Further Reading

Overview of antibiotic therapy – Knowledge @ AMBOSS

Last updated: September 14, 2021

Summary

Antibiotics are a class of drugs employed mainly against bacterial infections. Some antibiotics are also used against parasitic infections. Antibiotics can have bacteriostatic (i.e., stopping bacterial reproduction), bactericidal (i. e., killing bacteria), or both mechanisms of action. Antibiotics are effective against either a small group of bacteria (narrow-spectrum) or a wide range of pathogens (broad-spectrum). Most antibiotics work by inhibiting cell wall synthesis, protein synthesis, or certain enzymes (e.g., THF, RNA-polymerase) in bacteria. Common side effects of antibiotic treatment include hypersensitivity reactions, as well as nephrotoxic and hepatotoxic effects. Many antibiotics are contraindicated in certain patient groups (e.g., children, pregnant and/or breastfeeding women). In the case of severe infection, one or more antibiotics may be initiated without waiting for a microbiological confirmation (empirical antibiotic therapy) to target the most likely pathogens. Antibiotics are widely used because they are instrumental in the management of infectious diseases; however, use of antibiotics without valid indications and with inappropriate dosages and timing has led to the emergence of antibiotic-resistant pathogens (e. g., MRSA, Pseudomonas).

Overview

Definitions

As a general rule, agents that inhibit cell wall synthesis are bactericidal (except ethambutol), while those that inhibit protein synthesis are bacteriostatic (except tigecycline, rifamycins, and aminoglycosides).

Overview

^[1][2]

AcTions at 30, CELebrationS at 50: Aminoglycosides and Tetracyclines are 30S inhibitors; Chloramphenicol/Clindamycin, macrolides (e.g., Erythromycin), Linezolid, and Streptogramin are 50S inhibitors.

All protein synthesis inhibitors are bacteriostatic, except aminoglycosides (bactericidal) and linezolid (can be either bactericidal or bacteriostatic depending on concentration).

Beta-lactam antibiotics

Beta-lactamase inhibitors

CATS: Clavulanate, Avibactam, Tazobactam, Sulbactam are β-lactamase inhibitors.

Penicillins

• Examples
• Clinical use
• Adverse effects
• Mechanisms of resistance

Penicillinase-resistant penicillins

• Examples (oral or IV)
  • Nafcillin
  • Dicloxacillin
  • Oxacillin
  • Floxacillin
  • Methicillin
• Special characteristics: intrinsically β-lactamase resistant through the addition of bulky side chains (e.g., isoxazolyl), which prevent bacterial β-lactamase from hydrolyzing the β-lactam ring
• Clinical use: narrow spectrum
• Adverse effects
• Mechanism of resistance: alteration of PBP binding site; → reduced affinity → pathogen is not bound or inactivated by β-lactam; (an altered PBP target site is one of the main virulence factors of MRSA)

Use NAF (nafcillin) for STAPH (S. aureus).

• Examples
  • Oral or IV: amoxicillin (combined with clavulanate )
  • IV or IM: ampicillin (with or without sulbactam)
• Special characteristics
• Clinical use: broader spectrum of activity than penicillin (extended-spectrum penicillin)
  • Gram-positive aerobes
  • Gram-negative rods (not effective against Enterobacter spp. )
  • Most effective against:
• Adverse effects
• Mechanisms of resistance: cleavage of the β-lactam ring by penicillinases

AmOxicillin is administered Orally, while amPicillin is administered by a Prick!

Aminopenicillin therapy HHEELPSSS against H. influenzae, H. pylori, E. coli, Enterococci, Listeria monocytogenes, Proteus mirabilis, Salmonella, Shigella, Spirochetes.

Antipseudomonal penicillins

The PIPER in his CAR full of TICks ran over Pseudomonas: PIPERacillin, CARbenicillin, and TICarcillin are antipseudomonals.

Carbapenems

• Examples
  • IV imipenem (combined with cilastatin)
  • IV meropenem
  • IV ertapenem
  • IV doripenem
• Special characteristics
  • Imipenem is always given with cilastatin, which inhibits human dehydropeptidase I (a renal tubular enzyme that breaks down imipenem).
  • Meropenem is stable to dehydropeptidase I.
• Clinical use
  • Last-resort drugs (used only in life-threatening infections or after other antibiotics have failed) because of the significant adverse effects
  • Broad-spectrum antibiotics with intrinsic beta-lactamase resistance
• Adverse effects
  • Secondary fungal infections ^[11]
  • CNS toxicity: can lower seizure threshold at high serum concentrations
  • Gastrointestinal upset
  • Rash
  • Thrombophlebitis ^[12]
• Mechanism of resistance: inactivation by carbapenemase

Get a kill that is lastin’ with imipenem plus cilastatin.

don’t DIe on ME: Doripenem, lmipenem, Meropenem, and Ertapenem are carbapenems and used in life-threatening infections.

Monobactams

• Examples: : IV aztreonam
• Special characteristics:
• Clinical use
• Adverse effects: rare
  • GI upset
  • Injection reactions
  • Rash

Cephalosporins

• Special characteristics: less susceptible to penicillinases
• Adverse effects
• Mechanisms of resistance
  • Inactivation by cephalosporinase (a type of β-lactamase)
  • Change in transpeptidase (PBP) structure

1 PEcK: 1^st generation cephalosporins cover Proteus mirabilis, E. coli, Klebsiella pneumoniae.
2 HENS PEcK: 2^nd generation cephalosporins cover H. influenzae, Enterobacter aerogenes (now Klebsiella aerogenes), Neisseria, Serratia marcescens, Proteus mirabilis, E. coli, Klebsiella pneumoniae.

2^nd graders wear fake fox fur to tea parties: 2^nd generation cephalosporins include cefaclor, cefoxitin, cefuroxime, and cefotetan.

Cephalosporins are LAME: 1^st–4^th generation cephalosporins do not act against Listeria, Atypical organisms (e.g., Chlamydia, Mycoplasma), MRSA, and Enterococci (with the exception of ceftaroline, which does act against MRSA).

Glycopeptides

• Examples
  • Oral or IV vancomycin, teicoplanin
  • Topical bacitracin
• Mechanism of action
• CNS penetration: only when there is increased permeability of the meningeal vessels (i.e., with meningeal inflammation)
• Route of elimination: renal (via glomerular filtration)
• Clinical use: especially effective against multidrug-resistant organisms
• Adverse effects
  • Intravenous administration
  • Oral administration: predominantly dysgeusia and gastrointestinal side effects
• Contraindications: Consider use in pregnant women only if the benefits outweigh the risks. ^[21]
• Mechanisms of resistance

The vancomycin van carries a TON of red DRESSes: the side effects of vancomycin are Thrombophlebitis, Ototoxicity, Nephrotoxicity, red man syndrome, and DRESS syndrome.

The fine for VANdalism is one DALlAr in LACjac: VANcomycin resistance is caused by amino acid modification (D-Ala-D-Ala to D-Ala-D-Lac).

Epoxides

Lipopeptides

• Examples: daptomycin
• Mechanism of action: incorporate K⁺ channels into the cell membrane of gram-positive bacteria → rapid membrane depolarization; → loss of membrane potential → inhibition of synthesis of DNA, RNA, and proteins → cell death (bactericidal effect) ^[24]
• Route of elimination: renal
• Clinical use
• Adverse effects
• Contraindications: hypersensitivity
• Mechanisms of resistance: repulsion of daptomycin molecules due to the change in the bacterial surface charge ^[26]

Dap-to-my-cin is good to my skin: daptomycin is used to treat skin infections.

Polymyxins

• Examples
• Mechanism of action
• CNS penetration: poor
• Route of elimination: mostly renal
• Clinical use: severe infections caused by multidrug-resistant gram-negative bacteria
• Adverse effects
• Contraindications:
  • Hypersensitivity to polymyxins
  • Cautious use in patients with renal dysfunction

Aminoglycosides

• Examples
  • IV or IM gentamicin
  • IV or IM amikacin
  • IV or IM tobramycin
  • IV or IM streptomycin
  • Oral neomycin
• Mechanism of action
• CNS penetration: poor
• Route of elimination: renal (via glomerular filtration)
• Clinical use ^[29]
• Adverse effects
• Contraindications
• Mechanisms of resistance: inactivation via acetylation, phosphorylation, and/or adenylation by secreted bacterial transferase enzymes

Me and my NEw AMIgA are taking GENeral STEPs to AMeliorate our TOBacco intake but are still unsuccessful: NEomycin, AMIkAcin, GENtamicin, STrEPtomycin AMinoglycosides, and TOBramycin are unsuccessful in killing anaerobes.

Ah, MI(y) NEPHew’s OTter keeps TERrorizing our block: the side effects of AMInoglycosides include NEPHrotoxicity, OTotoxicity, TERatogenicity, and neuromuscular blockade.

Tetracyclines

• Examples
  • Oral or IV minocycline
  • Oral or IV tetracycline
  • Oral doxycycline
  • Oral demeclocycline
• Mechanism of action: bind 30S subunit → aminoacyl-tRNA is blocked from binding to ribosome acceptor site → inhibition of bacterial protein synthesis (bacteriostatic effect)
• CNS penetration: poor
• Route of elimination
• Clinical use
• Special considerations
  • Oral tetracyclines should not be taken with substances that contain large amounts of Ca²⁺, Mg²⁺, or Fe²⁺ (e.g., milk, antacids, iron supplements, respectively) because divalent cations inhibit the intestinal absorption of tetracyclines.
  • CNS penetration is limited
• Adverse effects
• Contraindications
• Mechanisms of resistance: Plasmid-encoded transport pumps increase efflux out of the bacterial cell and decrease uptake of tetracyclines.

Teethracyclines: teeth discoloration is a side effect of tetracyclines.

Glycylcyclines

• Examples: tigecycline
• Mechanism of action ^[35]
• CNS penetration: poor
• Route of elimination: mostly biliary
• Clinical use
• Special considerations
• Adverse effects ^[4]
• Contraindications ^[38]
  • Children of age
  • Pregnant women
  • Breastfeeding women
  • Cautious use in patients with hepatic dysfunction

Macrolides

Macroslides: macrolides inhibit translocation during protein synthesis, in which ribosomes slide along mRNA.

The adverse effects of MACROlides include gastrointestinal Motility issues, Arrhythmia (due to prolonged QT interval), acute Cholestatic hepatitis, Rash, and eOsinophilia.

Lincosamides

• Examples: clindamycin
• Mechanism of action: binds to 50S subunit → blockage of peptide translocation (transpeptidation) → inhibition of peptide chain elongation →inhibition of bacterial protein synthesis (bacteriostatic effect)
• CNS penetration: poor
• Route of elimination: both renal and biliary
• Clinical use
• Special considerations: cross-resistance with macrolides
• Adverse effects
• Contraindications: In pregnant women during the 1^st trimester and breastfeeding women, clindamycin should be used only if benefits outweigh the risks.

Streptogramin

• Examples: IV quinupristin-dalfopristin
• Mechanism of action ^[46]
• Route of elimination: biliary and renal ^[48]
• Clinical use
• Special considerations: inhibits CYP3A4 ^[50]
• Adverse effects
• Contraindications: consider use in the following populations only if benefits outweigh the risks, as safety in these has not been established ^[50]
• Mechanisms of resistance

Oxazolidinones

• Examples: linezolid
• Mechanism of action
• CNS penetration: good
• Route of elimination: both biliary and renal elimination after hepatic metabolism
• Clinical use: multidrug-resistant gram-positive bacteria (VRE, MRSA)
• Adverse effects
• Contraindications
• Mechanism of resistance: point mutation of 23S rRNA ^[52]

Amphenicols

• Examples: chloramphenicol
• Mechanism of action: bind 50S subunit → blockage of peptidyltransferase → inhibition of bacterial protein synthesis (bacteriostatic effect) ^[53]
• CNS penetration: good
• Route of elimination: renal elimination after hepatic metabolism
• Clinical use
• Special considerations
  • Potent inhibitory effect on cytochrome P450 isoforms CYP2C19 and CYP3A4 ^[53]
  • Rare in the US due to adverse effects
  • Most commonly used in resource-limited countries due to low drug costs
• Adverse effects
• Contraindications
  • Infancy
  • Pregnancy
  • Cautious use in patients with renal and/or hepatic dysfunction
• Mechanisms of resistance: drug inactivation via plasmid-encoded acetyltransferase

Fluoroquinolones

Fluoroquinolones hurt the attachments to your bones.

Nitroimidazoles

• Examples
  • Oral or IV: metronidazole
  • Oral or IV tinidazole
• Mechanism of action: creates free radicals within the bacterial cell → DNA-strand breaks; → cell death (bactericidal and antiprotozoal effect)
• CNS penetration: good
• Route of elimination: renal
• Clinical use
• Adverse effects
• Contraindications
  • Consider use in the following populations if benefits outweigh the risks, as safety in this populations has not been established
  • Cautious use in patients with hepatic dysfunction

Take the Metro To lonG BEaCH: Metronidazole treats Trichomonas, Giardia/Gardnerella, Bacteroides, Entamoeba, Clostridium, and H. pylori.

Sulfonamides and diaminopyrimidine

• Drug classes
• Examples
• Mechanism of action
• CNS penetration: good
• Route of elimination: primarily renal (via tubular secretion)
• Clinical use: Common indications include UTIs and acute otitis media.
• Adverse effects
• Contraindications
  • Children of age
  • Pregnant women
  • Breastfeeding women
  • Cautious use in people with
• Mechanisms of resistance

TMP Treats Marrow Poorly.

ROCk, PAper, SCiSSors: the most important sulfa drugs are fuROsemide, (hydro)Chlorthalidone, Probenecid, Acetazolamide, Sulfamethoxazole/Sulfadiazine, Celecoxib, Sulfasalazine, and Sulfonylureas).

Nitrofurans

• Examples: nitrofurantoin
• Mechanism of action: : reduced by bacterial nitroreductases to reactive metabolites → bind to bacterial ribosomes → impaired metabolism, impaired synthesis of protein, DNA, and RNA → cell death (bactericidal effect)^[7][8]
• Route of elimination: : primarily renal , small amounts in feces
• Clinical use
  • Urinary tract pathogens
    • Gram-positive: Enterococci, Staphylococcus saprophyticus, group B streptococcus, Staphylococcus aureus, Staphylococcus epidermidis
    • Gram-negative: E. coli, Enterobacter spp., Shigella spp., Salmonella spp., Citrobacter spp, Neisseria spp, Bacteroides spp., Klebsiella spp.
  • Not effective against Pseudomonas and/or Proteus
  • Clinical indications include:
• Adverse effects
• Contraindications

Antimycobacterial drugs

See “Treatment” in “Tuberculosis.”

Rifamycins

• Examples
• Mechanism of action: inhibits bacterial DNA-dependent RNA-polymerase → prevention of transcription (mRNA synthesis) → inhibition of bacterial protein synthesis → cell death (bactericidal effect)
• Route of elimination: biliary
• Clinical use ^[35]
• Adverse effects
• Contraindications
  • Breastfeeding women
  • Should be used during pregnancy only if clearly needed
  • Cautious use in patients with hepatic dysfunction
• Mechanisms of resistance

The 6Rs of Rifampin: Red or orange urine, RNA polymerase Repression, Ramping up of cytochrome P450 activity, and Rapid Resistance development if used alone.

Rifampin really amplifies (induces) cytochrome P450, but rifabutin does not.

Isoniazid (INH)

• Mechanism of action
• CNS penetration: variable
• Metabolization: primarily hepatic
  • INH is converted into various metabolites (e.g., via acetylation), some of which are hepatotoxic (e.g., hydrazine, acetylhydrazine).
  • Main metabolic enzyme: N-acetyltransferase (NAT): involved in metabolite formation and subsequent neutralization
  • The rate of NAT acetylation is genetically determined.
    • Individuals with slow acetylation: higher half-life due to lack of hepatic NAT → increased risk of drug-induced toxicity
    • Individuals with fast acetylation: lower half-life of active drug → administration of a higher dose is required for reaching the same blood concentration compared to individuals with slow acetylation ^[74][75]
  • Inhibits cytochrome P450 isoforms (CYP1A2, CYP2A6, CYP2C19, and CYP3A4) ^[75]
• Route of elimination: renal elimination after hepatic metabolism
• Clinical use: ^[76]
• Adverse effects
• Contraindications
  • Should be used during pregnancy only if clearly needed
  • Cautious use in patients with renal and/or hepatic dysfunction
• Mechanisms of resistance: mutations causing decreased KatG → decreased expression of catalase-peroxidase → less/no biologically active INH

INH Is Not Healthy In Neurons and Hepatocytes.

Neurotoxicity may be prevented by supplementing with pyridoxine (vitamin B6).

Pyrazinamide

• Mechanism of action
  • Not completely understood
    • Prodrug: converted into active form pyrazinoic acid
    • Most effective at acidic pH (e.g., in acidic phagolysosomes)
  • Bactericidal effect
• CNS penetration: only when meninges are inflamed
• Route of elimination: renal elimination after hepatic metabolism
• Clinical use: M. tuberculosis
• Adverse effects
• Contraindications
  • Consider use in pregnant and breastfeeding women only if benefits outweigh the risks ^[77]
  • Hepatic failure ^[78]
  • Acute gout
• Mechanisms of resistance: mutations in RpsA gene coding for ribosomal protein S1 ^[79]

Ethambutol

• Mechanism of action: inhibits arabinosyltransferase → ↓ carbohydrate polymerization → prevention of mycobacterial cell wall synthesis (bacteriostatic effect)
• CNS penetration: only when meninges are inflamed
• Route of elimination: primarily renal
• Clinical use
• Adverse effects
• Contraindications
  • Contraindicated in patients who are unable to report visual changes
  • Contraindicated in patients with optic neuritis
  • Consider use in the following populations only if benefits outweigh the risks, as safety in these has not been established
• Mechanisms of resistance: mutations of EmbCAB gene coding for arabinosyltransferase ^[81]

EYEthambutol: Ethambutol causes optic neuropathy.

Dapsone

• Mechanism of action
• Route of elimination: mostly renal
• Clinical use
• Adverse effects
• Contraindications
  • G6PD deficiency
  • Consider use in pregnant and breastfeeding women only if benefits outweigh the risks
  • Cautious use in patients with renal and/or hepatic dysfunction
• Mechanism of resistance: mutations of folP1 gene coding for dihydropteroate synthase ^[84]

Contraindications

For SAFe Children, these Tablets are Contraindicated: Sulfonamides, Aminoglycosides, Fluoroquinolones, Clarithromycin, Tetracyclines, and Chloramphenicol are contraindicated in children.

Cut the Tablets for your Child’s SAFety: Chloramphenicol, Tetracyclines, Clarithromycin, Sulfonamides, Aminoglycosides, and Fluoroquinolones are contraindicated in pregnancy.

We list the most important contraindications. The selection is not exhaustive.

Additional considerations

Empiric antibiotic therapy

Empiric antibiotic therapy covers the most probable causative organism(s) before the pattern of resistance and/or causative organism are known.

Indications

• A bacterial infection that is potentially life-threatening (e.g., meningitis, sepsis) and/or may result in severe morbidity (e.g., septic arthritis) if treatment is delayed until the causative organism is definitively identified.
• Infections that are commonly treated empirically
  • Brain: meningitis, brain abscess
  • Lung: pneumonia, lung abscess
  • Skin: cellulitis, necrotizing fasciitis, surgical site infections
  • Bones and/or joints: osteomyelitis, septic arthritis
  • Respiratory tract: bacterial rhinosinusitis, tonsillitis, pharyngitis
  • Heart: infective endocarditis
  • GI tract: dysentery, spontaneous bacterial peritonitis
  • Kidney and genital region: urinary tract infections (e. g., pyelonephritis, prostatitis, genital discharge)
  • Any cause of sepsis

Choosing empiric antibiotic therapy

Target the most probable causative organism(s) but consider factors which might affect the success of usage of the chosen agent:

• Host factors
  • Circumstances of infection
  • Site of infection
    • Specific infections are more commonly caused by certain organisms (e.g., UTIs are most commonly caused by E. coli
    • Certain sites are difficult to reach by antibiotics and require the use of higher/more frequent doses, longer duration of therapy, combinations of antibiotics, and/or the use of antibiotics that cross the blood-brain barrier.
  • Relative contraindications (see “Contraindications” above)
    • Children, pregnant women, breastfeeding women
    • Individuals with pre-existing illnesses and/or comorbidities
  • Previous antibiotic therapy
• Drug factors

Other guiding principles

• Escalation of antibiotic therapy
• De-escalation of antibiotic therapy: A more specific narrow-spectrum antibiotic regimen is initiated after the causative organism, as well as its patterns of resistance and sensitivity, are known.

Blood cultures should be taken before initiating empiric antibiotic therapy.

Targeted antibiotic therapy

• Targeted antibiotic therapy is chosen based on the results of culture and antibacterial sensitivity testing.
• Aims to decrease the risk of treatment toxicity, prevent the development of antimicrobial resistance, and reduce the cost of the treatment
• Usually employs narrow-spectrum agents to maximize efficacy and reduce the risk of side effects

Antibiotic prophylaxis

• Antibiotics are commonly used for prophylaxis against infections in the following situations:

Antibiotics and pregnancy: What’s safe?

Is it safe to take antibiotics during pregnancy?

Answer From Mary Marnach, M.D.

Antibiotics are commonly prescribed during pregnancy. However, the specific type of medication must be chosen carefully. Some antibiotics are OK to take during pregnancy, while others are not. Safety depends on various factors, including the type of antibiotic, when in your pregnancy you take the antibiotic and for how long, how much you take, and the possible effects it might have on your pregnancy.

Here’s a sampling of antibiotics generally considered safe during pregnancy:

• Penicillins, including amoxicillin (Amoxil, Larotid) and ampicillin
• Cephalosporins, including cefaclor and cephalexin (Keflex)
• Clindamycin (Cleocin, Clinda-Derm, Clindagel)

Certain other antibiotics are believed to pose risks during pregnancy. For example, tetracyclines can affect bone development and discolor a developing baby’s teeth. Tetracyclines aren’t recommended for use after the fifth week of pregnancy. Sulfonamides might pose a small risk of heart conditions, cleft lip or palate, and jaundice. Sulfonamides are generally avoided during the first trimester of pregnancy and near the time of delivery.

If an antibiotic is the best way to treat your condition, your doctor will prescribe the safest antibiotic and dosage. If you have questions or concerns about the use of an antibiotic during pregnancy, talk to your doctor.

• Ankle swelling during pregnancy
• Aspirin during pregnancy

July 02, 2021

Show references

1. Landon MB, et al., eds. Drugs and environmental agents in pregnancy and lactation: Teratology, epidemiology, and patient management. In: Gabbe’s Obstetrics: Normal and Problem Pregnancies. 8th ed. Elsevier; 2021. https://www.clinicalkey.com. Accessed June 6, 2021.
2. Fan H, et al. Associations between macrolide antibiotics prescribing during pregnancy and adverse child outcomes in the UK: Population-based cohort study. The BMJ. 2020; doi:10.1136/bmj.m331.
3. Lockwood CJ, et al. Prenatal care: Patient education, health promotion, and safety of commonly used drugs. https://www.uptodate.com/contents/search. Accessed June 6, 2021.
4. Chestnut DH, et al., eds. Pharmacology during pregnancy and lactation. In: Chestnut’s Obstetric Anesthesia: Principles and Practice. 6th ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed June 6, 2021.
5. Clindamycin. MotherToBaby. https://mothertobaby.org/fact-sheets/clindamycin-pregnancy/. Accessed June 6, 2021.
6. Tetracycline. MotherToBaby. https://mothertobaby.org/fact-sheets/tetracycline-pregnancy/. Accessed June 12, 2021.
7. Sulfamethozole trimethoprim (Bactrim or Septra). MotherToBaby. https://mothertobaby.org/fact-sheets/sulfamethoxazoletrimethoprim-bactrim-septra-pregnancy/. Accessed June 12, 2021.
8. Marnach ML (expert opinion). Mayo Clinic. June 12, 2021.

See more Expert Answers

Products and Services

1. Book: Obstetricks
2. Book: Mayo Clinic Guide to a Healthy Pregnancy

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The distribution of antibiotic use and its association with antibiotic resistance

Essential revisions:

This is a useful and important analysis of antibiotic usage and resistance patterns across US states. The authors pose a specific question as to whether first use is more closely correlated with resistance than repeat use. A strength is that they are able to explore this for a large number of drug-bug combinations.

One obvious difficulty is the definition of first and repeat use. First use per calendar year immediately looks problematic. In the Discussion section, mention is made of first use in a four-year period giving similar results, but there remains the possibility that there was previous usage prior to the observation period. It is likely that some repeat use is misclassified as first use but not vice versa. The scale of the problem could be assessed for, say, years 2, 3 and 4 by checking for usage in the previous calendar year, but this is not done.

We agree that the definitions of “first” and “repeat” present difficulty. Each person has only one truly first use of an antibiotic in their whole lifetime. Any other definition of “first” and “repeat” must be defined with respect to some ad hoc time window.

That being said, our goal was to measure the association between the distribution of antibiotic use, at the population level, and antibiotic resistance, at the population level. Our results do not state that individuals who had a recent first use of antibiotics had a higher risk of an antibiotic resistance than individuals with recent non-first use. We only claim that population-level first and repeat use rates have associations with population-level resistance.

Our first-in-that-year and repeat-in-that-year use metrics were intended to characterize the distribution of antibiotic use across a population. We used those metrics because we found them easier to interpret than other measures of the distribution of antibiotic use, say, the Gini coefficient or Shannon entropy.

To clarify this point, we amended the Discussion section to point out that reasoning from the population level to the individual level is difficult because of possible ecological fallacies (subsection “Distribution of antibiotic use and antibiotic resistance”) and because the first-in-a-year and repeat-in-a-year metrics are not obviously sensible at the individual level (subsection “Distribution of antibiotic use and antibiotic resistance”).

Another obvious problem is that the usage data are for outpatients, but the resistance data are (mainly) from hospitals, and that the latter data was only a small sample of the levels of resistance. It’s likely that the antibiotics used in hospitals are very different to those used in the outpatient setting and hence the resistances selected may vary. This concern is addressed well in the Discussion section, however, and we don’t think there is further work that could be done apart from looking at the subset of community associated infections if those data were available. But this is a major caveat.

We agree that measuring antibiotic resistance at hospitals is a key limitation, and we hope that the caveats in the Results section and Discussion section address this concern. To further emphasize this point, we expanded the note in the Discussion section and included another citation which compares the roles of the hospital and the community in the acquisition of resistant infections.

The key result (subsection “Lack of evidence for more positive association with repeat use”) is that usage-resistance correlations across states tended to be positive for first use and negative for repeat use. The latter result appears to be unexpected and so post hoc explanations are invoked. Care is needed here. It is clearly reasonable to suggest that first use might generate resistance. Presumably subsequent use can then only generate resistance in still susceptible cases (see Introduction). And so on. But it is not clear how that process plays out in terms of generating the correlations explored here. It would have been good to have seen the authors’ expectations set out and justified (possibly using a mathematical model). That would help with interpreting the results. Certainly, the Discussion section might benefit from including something about what these conclusions mean for the modelling of resistance. For instance, from a within-host perspective, do the conclusions imply that one dose is enough to generate a resistant dominant population in a host? And that the clearance rate is low?

We heartily agree that these results generate many interesting questions for follow-up. Developing causal explanations that unify the within-host and population-level and explain the observed associations is certainly one of them. However, as we are wary of including more material in a manuscript that introduces a new approach to studying the relationship between antibiotic use and resistance, new metrics, and new datasets, we followed the alternative recommendation and included some points about how these conclusions suggest modeling questions in the Discussion section.

We also do not suspect that repeat use somehow selects for susceptibility. We therefore made revisions that we hope clarify that repeat use tends to have negative regression coefficients only within a multiple regression that also includes first use as a predictor. In other words, repeat use has a negative association with resistance only when first use is controlled for. It is not the case that repeat use has a negative correlation with resistance. This is a subtle but important distinction that we tried to clarify (Results section, Discussion section).

We appreciate the cautionary note about invoking post hoc explanations, which, as we understand, refers to the section of the Discussion section that point outs the possibility of “reverse causality” (subsection “Distribution of antibiotic use and antibiotic resistance”). We temper this point by noting that studies with ecological designs are of limited value for distinguishing between different potential causal pathways (subsection “Distribution of antibiotic use and antibiotic resistance”).

More generally, the statistical analyses presented are very simple. This aids transparency, but a lot more could have been looked at with more sophisticated regression modelling (never mind dynamical models). For instance, multivariable, multivariate regression applied to all bug-drug combinations simultaneously could look at drug, extensive/intensive use, bug and geographic (i.e. states) which might be resolvable by combining the data. Such an approach would have also allowed formal model selection/comparison to resolve statistically significant effects. The authors should at least comment on the potential of more advanced analyses and why they chose not to pursue these here.

We agree that this data presents many opportunities for developing and testing more complex methodology to address more sophisticated questions about antibiotic use and resistance. For example, we suspect that use of antibiotic A will select for resistance B in an organism for which resistance to A and B are correlated. Methodology to address these kinds of questions is developing (see citations subsection “Landscape of use-resistance relationships”). Models with more predictors may be more accurate, but we do not have a way to verify them with the available data, and it is not clear they will directly address our central question about the association of the distribution of use with resistance.

That being said, we appreciate this suggestion and amended a section of the Discussion section to propose this more careful approach as a fruitful direction for future work.

In doing more to explain/unravel the trends seen, the route to resistance (e.g. mutation vs. mobile genetic element) might be considered, e.g. exploring if those with a mutational based resistance (e.g. fluoroquinolones) had stronger correlations with use – repeat use in particular.

We agree that this is an interesting idea, but we have two concerns.

First, we expect that the strength of the use-resistance relationship, whether measured by correlation or by regression, will depend on many factors related to the biology and epidemiology of the organism. The resistance mechanism is certainly one of those factors, but it could be that the relationship between quinolone use rates and quinolone resistance among E. coli is strong because of factors that have to do with E. coli alone or with quinolone use alone, rather than the mechanism of quinolone resistance in E. coli. In this sense, we feel the more appropriate hypothesis is that the use-resistance association for a mutational-based resistance to a drug in an organism will be stronger than the association for an HGT-based resistance for the same drug and pathogen. This strikes us as a difficult question that deserves more careful attention and a different data source. In our data sets, resistance is measured phenotypically, not genotypically, so mutational and HGT-based resistance mechanisms cannot be separated for a given drug-organism combination.

Second, we are not entirely sure that our results are consistent with this hypothesis, even when broadly stated. We found macrolides, quinolones, and cephalosporins had systematically more positive use-resistance correlations than nitrofurantoin and TMP/SMX. However, resistance mechanisms do not obviously fall along these lines. Macrolide and nitrofurantoin resistance come from a mix of mutational and HGT-based mechanisms, while cephalosporin resistance is probably plasmid-based. In some cases, quinolone resistance can be HGT-based (Jacoby, 2005). Thus, these distinctions would require a careful review of the dominant resistance mechanisms present in each organism, which is outside the scope of this manuscript.

We would appreciate further suggestions on this point if we have misconstrued the suggestion.

Obviously, this is an analysis of trends in the US. In a few places it would be good to compare the US situation to other countries (e.g. in the percentage of antibiotics used in outpatient vs. healthcare settings, perhaps the distribution of antibiotics used) and to explain more in detail the population (e. g. what percentage of the population is included and what is the Medicare population?).

We thank the reviewers for reminding us to address a global audience. We therefore included:

i) A note with a citation comparing the palette of antibiotics used in the US with those used in other countries (Discussion section), and noting the effect that this might have on the generalizability of our results,

ii) clarified that the statistic about the ratio of outpatient to inpatient antibiotic use is from the UK and Sweden and is merely presumed to also apply to the US (Introduction), and

iii) added an explanation about Medicare when it is first mentioned in the Introduction.

[Editors’ note: further revisions were requested prior to acceptance, as described below.]

The manuscript has been improved but we would still like a more effort put into addressing reviewer #2’s concerns below regarding hospital vs. outpatient antibiotic use. For instance, presentation of datasets showing some geographic correlation between usage in outpatient and hospital settings.

[…]

Reviewer #2:

I do not think this manuscript has been improved. The authors have responded to the reviewers’ comments, but have made only minor changes to the manuscript, even in response to the “essential” revisions. Those changes are largely confined to explanations, caveats and discussion; as far as I can see, they have not revised their analyses in any way.

In particular they have not been able to address in any meaningful way the mis-match between scoring antibiotic usage in outpatients but resistance in hospital patients. This seems to me to be a fundamental flaw in the analysis.

With regret, I cannot recommend this paper for publication. I do not have complete confidence in the findings.

As we understand, the principal concern is that the antibiotic use data, measured at pharmacies in the community, may not be causally linked to the resistance data, which was collected by hospitals.

To address this concern, in this revision, we also included sensitivity analyses considering changes in the resistance data, as was suggested in the previous round of review: “We don’t think there is further work that could be done apart from looking at the subset of community associated infections if those data were available.”

(Sensitivity analyses included in previous revisions only considered the sensitivity of the results to changes in the antibiotic use data.) In a minority of cases, the antibiogram records include annotations indicating whether the isolates whose susceptibility are reported in those records were collected from patients in outpatient facilities, emergency room patients, or inpatients:

67% of records in the ResistanceOpen data are not specific about the origin of the isolates, while the annotations on 20% of records indicate that they refer exclusively to inpatients, and 14% of records indicate that they refer specifically to outpatients and emergency room patients.

In the first new sensitivity analysis, we excluded resistance data from exclusively-inpatient antibiogram records. In the second analyses, we used only data from exclusively-outpatient/emergency room patients. The outpatient-only data is insufficient to achieve statistical significance for the landscape of use-resistance correlations, having at most 21 states per pathogen-drug combination, while our power calculation suggests that at least 33 states are required.

The results of these analyses are shown in

i) Figure 3—figure supplement 1, a new figure showing the correlation landscape for these two sensitivity analyses,

ii) Supplementary file 2 (correlation coefficients for all pathogen-antibiotic-dataset combinations),

iii) Supplementary file 3 (comparison of the sensitivity analyses for the correlation landscape),

iv) Supplementary file 5 (comparison of the sensitivity analyses for the multiple regressions),

v) a new paragraph in subsection “Landscape of correlations between total use and resistance across pathogens and antibiotics”, and

vi) edits to subsection “Lack of evidence for more positive association with repeat use”.

The main conclusions of the paper still hold when using these two subsets of the resistance: use-resistance correlations are more often positive than negative (and not systematically stronger or weaker than the correlations from the complete dataset), and first use regression coefficients are more often positive than repeat use coefficients.

We welcome suggestions for other kinds of analysis that improve the internal validity of these results.

We also wanted to ensure the manuscript is clear about a few points.

First, as mentioned in the previous revision, although most organizations contributing antibiotic susceptibility reports were hospitals, hospital antibiotic susceptibility reports are biased toward community-acquired organisms. The resistance data are “from hospitals”, but this does not mean that the isolates are mostly from hospital-acquired infections (subsection “Landscape of correlations between total use and resistance across pathogens and antibiotics”).

Second, antibiotic resistance in the hospital is not exclusively determined by hospital antibiotic use. The previous revision included a citation for a theoretical study (Knight et al.,2018) about how resistance measured in hospitals, even among inpatients, can be driven by outpatient antibiotic use (subsection “Landscape of correlations between total use and resistance across pathogens and antibiotics”). We supplement that reference with a recently-published one (MacFadden et al., 2018) about how outpatient antibiotic is a driver of ESBL production among E. coli in hospitals.

Third, as discussed in subsection “Landscape of use-resistance relationships”, to whatever degree community use is not a determinant of antibiotic resistance as measured by hospitals, this mismatch should bias our results toward null conclusions (e.g., correlations not significantly different from zero). In other words, this weakens the power of the study to detect a relationship, rather than increasing the probability that it will discover a false relationship.

We heartily agree with reviewer #2 that there is some mismatch between the use and resistance data, and we do expect this is a limitation to our findings, as laid out in the Introduction, Materials and methods section and Discussion section. As per the above points, we do not consider this mismatch a “fundamental” flaw, but we do invite critiques of the logic laid out above.

References:

Jacoby GA. (2005) Mechanisms of Resistance to Quinolones. Clinical Infectious Diseases, Volume 41, Issue Supplement_2, 15 July 2005, Pages S120–S126, doi: 10.1086/428052

https://doi.org/10.7554/eLife.39435.018

Antibiotic Prophylaxis Prior to Dental Procedures

With input from the ADA, the American Heart Association (AHA) released guidelines for the prevention of infective endocarditis in 2007,⁷ which were approved by the CSA as they relate to dentistry in 2008.⁸ These guidelines were updated by a 2021 scientific statement by the AHA that recommended no changes to the 2007 guideline recommendations. ⁹ The AHA continues to recommend infective endocarditis prophylaxis “only for categories of patients at highest risk for adverse outcome while emphasizing the critical role of good oral health and regular access to dental care for all.”⁹ In 2017, the AHA and American College of Cardiology (ACC) published a focused update¹⁰ to their 2014 guidelines on the management of valvular heart disease that also reinforced the previous recommendations.

These current guidelines support infective endocarditis premedication for a relatively small subset of patients. This is based on a review of scientific evidence, which showed that the risk of adverse reactions to antibiotics generally outweigh the benefits of prophylaxis for many patients who would have been considered eligible for prophylaxis in previous versions of the guidelines. Concern about the development of drug-resistant bacteria also was a factor.

In addition, the data are mixed as to whether prophylactic antibiotics taken before a dental procedure prevent infective endocarditis. The guidelines note that people who are at risk for infective endocarditis are regularly exposed to oral bacteria during basic daily activities such as brushing or flossing.  The valvular disease management guidelines¹⁰ recommend that persons at risk of developing bacterial infective endocarditis (see “Patient Selection”) establish and maintain the best possible oral health to reduce potential sources of bacterial seeding.  They state, “Optimal oral health is maintained through regular professional dental care and the use of appropriate dental products, such as manual, powered, and ultrasonic toothbrushes; dental floss; and other plaque-removal devices.”

Patient Selection

The current infective endocarditis/valvular heart disease guidelines^{7, 8, 10} state that use of preventive antibiotics before certain dental procedures is reasonable for patients with:

• prosthetic cardiac valves, including transcatheter-implanted prostheses and homografts;
• prosthetic material used for cardiac valve repair, such as annuloplasty rings and chords;
• a history of infective endocarditis;
• a cardiac transplant^a with valve regurgitation due to a structurally abnormal valve;
• the following congenital (present from birth) heart disease:^b
• unrepaired cyanotic congenital heart disease, including palliative shunts and conduits
• any repaired congenital heart defect with residual shunts or valvular regurgitation at the site of or adjacent to the site of a prosthetic patch or a prosthetic device

^a According to limited data, infective endocarditis appears to be more common in heart transplant recipients than in the general population; the risk of infective endocarditis is highest in the first 6 months after transplant because of endothelial disruption, high-intensity immunosuppressive therapy, frequent central venous catheter access, and frequent endomyocardial biopsies. ^9
b Except for the conditions listed above, antibiotic prophylaxis is no longer recommended for any other form of congenital heart disease.

Pediatric Patients
Congenital heart disease can indicate that prescription of prophylactic antibiotics may be appropriate for children. It is important to note, however, that when antibiotic prophylaxis is called for due to congenital heart concerns, they should only be considered when the patient has:

• Cyanotic congenital heart disease (birth defects with oxygen levels lower than normal), that has not been fully repaired, including children who have had a surgical shunts and conduits.
• A congenital heart defect that’s been completely repaired with prosthetic material or a device for the first six months after the repair procedure.
• Repaired congenital heart disease with residual defects, such as persisting leaks or abnormal flow at or adjacent to a prosthetic patch or prosthetic device.

Antibiotic prophylaxis is not recommended for any other form of congenital heart disease.

Beyond identifying the specific patient population for whom antibiotic prophylaxis is appropriate, special consideration should be given to the antibiotic dose prescribed to children, as it will vary according to the child’s weight. Weight-based regimens for children are outlined in Table 2 of the 2007 American Heart Association guidelines and Table 5 of the 2021 AHA scientific statement.^7-9 As with any medication, check with the primary caregiver to determine whether the child has an allergy to antibiotics or other antibiotic-related concerns before prescribing.

Dental Procedures
Prophylaxis is recommended for the patients identified in the previous section for all dental procedures that involve manipulation of gingival tissue or the periapical region of the teeth, or perforation of the oral mucosa.

Additional Considerations About Infective Endocarditis Antibiotic Prophylaxis (When Indicated)

The 2021 AHA scientific statement on prevention of infective endocarditis no longer recommends use of clindamycin as an oral or parenteral alternative to amoxicillin or ampicillin in individuals with allergies to these drugs because clindamycin “may cause more frequent and severe reactions than other antibiotics used for [antibiotic prophylaxis]” (including C. difficile infection).⁹ The AHA recommends that in individuals who are allergic to penicillin or ampicillin and who can take oral medication, cephalexin (or other first- or second-generation cephalosporins), azithromycin, clarithromycin, or doxycycline be used as alternatives.⁹ In individuals who are penicillin or ampicillin allergic and who cannot take oral medication, the AHA recommends cefazolin or ceftriaxone as alternatives.⁹ However, the AHA also recommends that cephalosporins should not be used in an individual with a history of anaphylaxis, angioedema, or urticaria with penicillin or ampicillin.⁹ The current medication regimens recommended (when indicated) are listed in Table 5 of the 2021 AHA scientific statement. 

Sometimes, patients forget to premedicate before their appointments. The recommendation is that for patients with an indication for antibiotic prophylaxis, the antibiotic be given before the procedure. This is important because it allows the antibiotic to reach adequate blood levels. However, the guidelines to prevent infective endocarditis^{7, 8} state, “If the dosage of antibiotic is inadvertently not administered before the procedure, the dosage may be administered up to 2 hours after the procedure.” If a patient with an indication for prophylaxis who appropriately received antibiotic premedication prior to a dental procedure one day and who is then scheduled the following day for a dental procedure also warranting premedication (e.g., dental prophylaxis), the antibiotic prophylaxis regimen should be repeated prior to the second appointment. Because of the nature of the pharmacokinetics of an antibiotic prophylaxis regimen, a single loading dose is given in order to cover the period of potential bacteremia produced by a single procedure.^11-13

Another concern that dentists have expressed involves patients who require prophylaxis but are already taking antibiotics for another condition. In these cases, the AHA guidelines and 2021 AHA scientific statement for infective endocarditis^{7, 9} recommend that the dentist select an antibiotic from a different class than the one the patient is already taking. For example, if the patient is taking amoxicillin, the dentist should select azithromycin or clarithromycin for prophylaxis.

Other patient groups also may merit special consideration, which is discussed more fully in the AHA guidelines.

In 2015, The Lancet published a study out of the United Kingdom that reported a correlation between institution of more limited antibiotic prophylaxis guidelines by the National Institute for Health and Clinical Evidence (NICE) in 2008 and an increase in cases of infective endocarditis.¹³ Because of the retrospective and observational nature of the study, the authors acknowledged that their “data do not establish a causal association.” At this time, the ADA recommends that dentists continue to use the AHA/ACC guidelines discussed above. Dental professionals should periodically visit the ADA website for updates on this issue.

Cheap analogues of expensive antibiotics: analogues of expensive drugs

Antibiotics are one of the most expensive groups of drugs. And if the cost of the “old” antibiotics is even more or less acceptable, then the new broad-spectrum antibiotics actions are incredibly expensive, which is not surprising, since about 1 billion US dollars are spent on the development of one new antibiotic.

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If you think about this topic, then you can understand that there are not so many new antibiotics, because not only do development and clinical research take decades, but also the cost of the project is equal to the cost of a flight into space.In this regard, only very few pharmaceutical companies in the US and Europe can conduct such expensive research.

Thus, the latest antibiotic to be launched on the market is Linezolid (trade name Zyvox), patented by Pfizer. At the same time, it was synthesized back in 1990, and only in 2000 was it first used in practice.

And what are the rest of the pharmaceutical companies doing, including domestic ones, which cannot afford such expenses? The answer is simple – they produce generics, that is, analogs of long-known antibiotics, with the same active ingredient as the original drug, but under a different trade name. The cost of such drugs is often lower than the cost of the original drug, but there are also opposite cases.

When prescribing a therapy that includes an antibiotic, doctors can prescribe both the original drug – an expensive antibiotic (which happens less often), and its analogue – a cheap antibiotic (in most cases). The reason for this is the work of medical representatives of pharmaceutical companies and distributor firms. So if your doctor has prescribed you an expensive antibiotic, do not rush to purchase it to the detriment of your budget.Most likely, he has a cheaper analogue, which can be advised by the pharmacist at the pharmacy, if you ask him about it.

In this article, we have provided a list of analogues of the most famous and widely used antibiotics.

Antibiotics for colds list Ukraine

Penicillin antibiotics

Flemoxin Solutab , Ospamox (amoxicillin) is a broad spectrum antibiotic used to treat lung and uncomplicated cases of bronchitis, sinusitis, pneumonia, peptic ulcer, cystitis, etc.

The average cost of Flemoxin Solutab and Ospamoks is 80-150 UAH. Its analogue is Amoxil (amoxicillin analogs, amoxiclav analogs). The average cost is 50-70 UAH (inexpensive antibiotics for colds).

Antibiotics of the group of inhibitor-protected aminopenicillins

Flemoklav Solutab , Augmentin (amoxicillin and clavulanic acid).

This antibiotic is used to treat lung and uncomplicated cases of bronchitis, sinusitis, pneumonia, peptic ulcer, cystitis, etc.caused by bacteria producing b-lactamase.

Average cost of Flemoklav Solutab – 100-150 UAH, Augmentin – 130 – 190 UAH.

Flemoklav Solutab analogs, Augmentin analogs ( cheap broad-spectrum antibiotics):

Baktoklav – the cheapest antibiotic, the average price is 60 – 70 UAH.

Amoxil K, Medoklav, Abiklav, Amoxiclav 2x, Betaklav, are also inexpensive antibiotics for colds.

Antibiotics of the cephalosporin group

Emssef , Rotacef , Blicef , Diacef , Denicef ​​ (ceftriaxone analogs in tablets) – Loraxon, Medaxon (ceftriaxone analogue in tablets), Zeftriaxone-Daraxone tablets -KMP, Ceftriaxone-Lekhim.

Antibiotics treat diseases such as sepsis, meningitis, disseminated Lyme borreliosis (early and late stages of the disease), infections of the abdominal organs, etc.

Cefuroxime-Sandoz , Cefutil (cefuroxime) – Axetin, Aksef, Auroxetil.

Antibiotics treat urinary tract infections – cystitis, pyelonephritis, urethritis; skin and soft tissues – furunculosis, pyoderma, impetigo, etc.

Quadrocef , Roxipim , Abipim , Denipim , Exipime , Septipime (cefepime) – Cefepim-Lekhim, Acefine.

Antibiotics treat diseases of the respiratory tract (pneumonia and bronchitis), urinary tract infections, as well as skin and soft tissues.

Eurosidime , Ceftazidim-Vista (ceftazidime) – Ceftazidim Yuria-farm, Ceftum, Zatsef, Ceftazidim-BHFZ.

These antibiotics are prescribed for the treatment of meningitis, sepsis and other diseases.

Sorcef , Cefinak , Suprax Solutab (cefixime) – Loprax, Opticef, Cefix.

Antibiotics treat diseases such as pharyngitis, tonsillitis, sinusitis, acute and chronic bronchitis, otitis media, and urinary tract infections.

Antibiotics of the macrolide group

Sumamed , Azax , Azitrox , Aztek , Hemomycin , Zybax (azithromycin analogs are expensive, sumamed analogs) – Azibiot, Az , Ormax, Azimed (the best analogue of sumamed) Azicin, Zoxy, Azithromycin-Astrafarm, Azithromycin-Health, Azithromycin-BHFZ, Azithromycin-Krasnaya Zvezda, Ziomycin (azithromycin analogs of the drug).

These antibiotic names are used to treat pharyngitis, tonsillitis, sinusitis, otitis media, as well as acute bronchitis, pneumonia.

Klacid , Fromilid , Klabel , Clerimed , Oradro (clarithromycin analogues) – Aziklar, Clarithromycin-Health, Clarithromycin-Astrapharm, Clarithromycin-Dar …

Antibiotics treat diseases such as infections of the upper respiratory tract and ENT organs: tonsillopharyngitis, otitis media, acute sinusitis, as well as infections of the lower respiratory tract: acute bronchitis, exacerbation of chronic bronchitis and others.

Antibiotics of the tetracyclines group

Unidox Solutab (doxycycline) – its inexpensive antibiotics – analogues: Doxycycline-Teva, Doxycycline-Darnitsa, Doxycycline-BHFZ (inexpensive antibiotic).

Antibiotics are used to treat pharyngitis, bronchitis, tracheitis, bronchopneumonia, as well as otitis media, tonsillitis, sinusitis and others.

Antibacterial drugs of the fluoroquinolone group

Ofloxin (ofloxacin) – Ofloxacin-Darnitsa, Ofloxacin-Lekhim (inexpensive antibiotic).

Antibiotics treat infectious and inflammatory diseases of bones and joints, abdominal cavity, kidney (pyelonephritis) and urinary tract diseases (cystitis, urethritis.

Abiflox , Glevo , Levaksela, Lebel , Levoximed, Levomak , Tigeron (Levofloxacin) – Levokils, Levofloxofloxacin-Lexcin-Lexin Floxium, Leflok.

Antibiotics are used to treat acute sinusitis, exacerbation of chronic bronchitis, community-acquired pneumonia, complicated urinary tract infections.

Avelox , Moxicum, Timoksi, Moxifloxacin-Sandoz (moxifloxacin) – Moxifloxacin-Lekhim, Moflaxa, Moxifloxacin-Pharmex, Atovax.

Antibiotics are used to treat acute sinusitis, exacerbation of chronic bronchitis, community-acquired pneumonia.

Cifran , Ciprinol , Ciprolet analogs , Flaprox, Ciprobel (ciprofloxacin analogs are expensive) – Ciprofloxacin-Euro, Ciprofloxacin-Lekhim.

The antibiotic is used for the treatment of sepsis and peritonitis, as well as for the prevention and treatment of infections in immunocompromised patients.

Antibacterial drugs of the nitroimidazole group

Strong antibiotics in tablets

Trichopol , Efloran (metronidazole) – Metrogyl, Metressa, Metronidazole-Health, Metronidazole-Darnitsa, Metronidazole-Infusion, Metronidazole-Yuria farm, Metronidazole Lubnypharm.

Antibiotics treat protozoal infections: extraintestinal amebiasis, including amoebic liver abscess, intestinal amebiasis (amoebic dysentery), trichomoniasis, giardiasis, balantidiasis, cutaneous leishmaniasis, trichomonas vaginitis, trichomonas urethritis and others.

Ornigil , Ornizol, Ornimak (Ornidazole) – Ornidazol-Darnitsa, Ornidazole-Novopharm, Ornidazole-Infusion.

Antibiotics are used to treat trichomoniasis, amebiasis, giardiasis, and a mild antibiotic is used to prevent postoperative complications.

Antibiotic analogs table

Penicillins and inhibitor-protected aminopenicillins Flemoxin Solutab, Ospamox (amoxicillin) Flemoklav Solutab, Augmentin (amoxicillin and clavulanic acid)	Penicillins and inhibitor-protected aminopenicillins Amoxil Amoxil-K, Medoklav, Abiklav, Amoxiclav 2x, Betaklav, Bactoklav.
Cephalosporins Emssef, Rotacef, Blicef, Diacef, Denicef ​​(ceftriaxone) Cefuroxime-Sandoz, Cefutil (cefuroxime) Quadrocef, Roxipim, Abipim, Denipim, Exipim, Septipim (cefepime) Eurosidime, Ceftazidim-Vista (ceftazidime) Sorcef, Cefinak, Suprax Solutab (cefixime)	Cephalosporins Loraxon, Medaxon, Ceftriaxone-Darnitsa, Ceftriaxone-KMP, Ceftriaxone-Lekhim. Aksetin, Aksef, Auroxetil. Cefepim-Lekhim, Cefepim Abryl, Cefepim Aurobindo. Ceftazidim Yuria-farm, Ceftum, Zatsef, Ceftazidim-BHFZ. Loprax, Opticef, Cefix.
Fluoroquinolones Ofloxin (ofloxacin) Abiflox, Glevo, Levaksela, Lebel, Levoximed, Levomak, Tigeron (levofloxacin) Avelox, Moxicum, Timoksi, Moxifloxacin-Sandoz (moxifloxacin) Tsifran, Tsiprinol, Tsiprolet, Flaprox, Tsiprobel (ciprofloxacin)	Fluoroquinolones Ofloxacin-Darnitsa, Ofloxacin-Lekhim. Levokils, Levofloxacin-Lekhim, Levofloxacin-Health, Floxium, Leflok. Moxifloxacin-Lekhim, Moflaxa, Moxifloxacin-Pharmex, Atovax. Ciprofloxacin-Euro, Ciprofloxacin-Lekhim, Ciprofloxacin-Astrapharm, Citeral.
Nitroimidazoles	Nitroimidazoles
Trichopolum, Efloran (metronidazole) Ornigil, Ornizol, Ornimak (Ornidazole)	Metrogyl, Metressa, Metronidazole-Health, Metronidazole-Darnitsa, Metronidazole-Infusion, Metronidazole-Yuria farm, Metronidazole Lubnyfarm. Ornidazol-Darnitsa, Ornidazole-Novopharm, Ornidazole-Infusion.
Macrolides Sumamed, Azax, Azitrox, Aztek, Hemomycin, Zybax (azithromycin) Klacid, Fromilid, Klabel, Clerimede, Oradro (clarithromycin)	Macrolides Azibiot, Azipol, Zitrox, Ormax, Azimed, Azicin, Zoxi, Azithromycin-Astrafarm, Azithromycin-Health, Azithromycin-BCPZ, Azithromycin-Red Star, Ziomycin. Aziklar, Clarithromycin-Health, Clarithromycin-Astrafarm, Clarithromycin-Darnitsa, Clarithromycin-Arterium, Klabax.
Tetracyclines Unidox Solutab (doxycycline)	Tetracyclines Doxycycline-Teva, Doxycycline-Darnitsa, Doxycycline-BHFZ.

90,000 WHO reformed antibiotic treatment

WHO has recently undertaken major reforms in antibiotic treatment. What
the essence of the new changes? What lessons should be learned from them practical
doctors? New antibiotic recommendations included in the Model List
essential medicines WHO.

Over the past 40 years, this is the most
a big and serious revision of these drugs. If we talk
very briefly about the reform, then it explains to doctors in detail what
antibiotics should be used in the treatment of common infections, and which should
leave for the most severe cases.

An expert’s view

About why the need for such a reform is ripe and what the current situation with antibiotic therapy is, tells us
Chief Freelance Clinical Specialist of the Ministry of Health of the Russian Federation
Microbiology and Antimicrobial Resistance, and President
Interregional Association for Clinical Microbiology and Antimicrobial
chemotherapy (IACMAC), Corresponding Member of the Russian Academy of Sciences, leading specialist in
this problem in the country Roman Kozlov .As a leader
WHO Collaborating Center for Strengthening Oversight Capacity
research on antimicrobial resistance, he took the most direct
participation in the development of antibiotic reform.

“Russia, like many other countries, considers the sustainability of
microbes to antibiotics as a threat to national security, and WHO –
as a threat to global stability, says Roman Sergeevich. – Today
there are already some types of bacteria that are effective against
one or two drugs, they are called “antibiotics of last resort.”But also to
they can develop resistance, which leads to large
difficulties in treating infections, and sometimes death of patients.

Alternative approaches to antibiotics for the treatment of dangerous infectious
diseases will definitely not help. It is about nosocomial infections – in
departments where antibiotics are often used, the most resistant
bacteria. We urgently need new drugs against them. Important
aspect: WHO calls for uniting efforts of states and pharmaceutical
companies to create such antibiotics.Fortunately, in our country it is
understand and motivate businesses to develop them.

We are doing a lot of work among doctors so that they correctly
antibiotics were prescribed. But it is extremely important to apply them correctly and by yourself.
patients. If the drug is prescribed for 7 days, you need to drink so much, neither
less during the day, even if you feel that you are already cured. On one’s own
a shortened course of treatment is a classic way of screening bacteria that does not
sensitive to antibiotics: in such conditions, the most
drug resistant bacteria and they impart these properties to the following
generations of microbes.When they cause infection again in the same
a person or his relatives, it will be much more difficult to treat it. Highly
it is important to strictly observe the frequency and conditions of taking antibiotics indicated
in the instructions. It is written to drink the drug before meals, after or with food,
execute, it affects its effectiveness. Strongly do not recommend
take antibiotics on your own or online. I AM
against the recommendations of pharmacists, only a doctor should do this – very
there are many subtleties and complexities that only he can take into account.No way
do not use drugs left over from previous treatment with
expired date “.

Blacklist

The reform of antibiotic therapy took a long time, and its release
preceded by the publication of a list of 12 bacteria, to combat which
new antibiotics are urgently needed. According to WHO experts, it is they who
represent today the main threat to human health. The list contains
bacteria that are resistant to the action of several antibiotics at once.
They are able to develop more and more new ways and mechanisms of resistance.
against such drugs.And secondly, they can, together with their genes
transfer these qualities to other bacteria. Thanks to this interchange
the number of antibiotic-resistant microorganisms will increase
fan-shaped. 12 dangerous bacteria were divided into three groups, in
depending on the degree of threat they pose.

According to WHO, the most dangerous bacteria against which antibiotics may soon stop working

Helicobacter pylori 91

90-31 medium risk of bacterial resistance

to penicillin

Name	Resistance
1st priority group – the highest risk of developing resistant bacteria
Acinetobacter baumannii	to carbapenems
Pseudomonas aeruginosa	to carbapenems
Enterobacteriaceae	to develop high bacterial Bacteria	to produce high bacterial B3
Enterococcus faecium	to vancomycin
Staphylococcus aureus	to methicillin, moderately sensitive or resistant to vancomycin
	Campylobacter spp.	to fluoroquinolones
Salmonellae	to fluoroquinolones
Neisseria gonorrhoeae	to cephalosporins, fluoroquinolones
Haemophilus influenzae	to ampicillin
Shigella spp.	to fluoroquinolones

The essence of antibiotic reform

For the first time, WHO experts have divided all antibiotics into three categories.V
in accordance with the practice accepted in the West, each category is given a vivid
a symbolic name in capital letters. In Russian
it looks like this – access, surveillance and reserve. Honestly, the titles
for us it turned out not very successful, not very speaking, especially for
the first two categories. Why? This will become clear later.

Key to antibiotic use reform is to ensure
the availability of the necessary drugs and, perhaps most importantly, to facilitate
the correct prescription of these drugs for the treatment of one or another
specific infection.

This is exactly what experts expect
will improve the results of therapy, slow down the development of bacteria resistant to
drugs, and will maintain the effectiveness of antibiotics “last resort”,
necessary when all other drugs no longer work. Bye
this only applies to antibiotics used to treat 21 of the most
common common infection. If the reform works, it will
will spread to other infectious diseases.

Pay for the 1st, 2nd, 3rd!

The first category, called ACCESS, includes antibiotics
first line – they should be used for treatment widely
common infections in the first place (see.table 1). If they
will be ineffective, then you can prescribe other drugs from the same or
second category. However, if drugs from the group do not work either
observation (this is the second category), the role of drugs from the third
categories – from the reserve.

Table 1. First category

9 0292 Doxycycline

Access antibiotics	For example
Beta – lactams (Beta-lactam medicines) 9027 03 903 amoxicillin		Cefotaxime *
benzathine penicillin G (benzathine benzylpenicillin)	Phenoxymethylpenicillin (phenoxymethylpenicillin)
benzylpenicillin (benzylpenicillin)	piperacillin + tazobactam (piperacillin + tazobactam) *
Cephalexin (cefalexin)	Procaine-benzilpenitsil Lin (procaine benzyl penicillin)
Cefazolin	Meropenem (meropenem) *
Cefixime (cefixime) *	Antibiotics 9029 (amikacin)	Gentamicin (gentamicin)
Azithromycin (azithromycin)	Metronidazole (metronidazole)
Chloramphenicol (chloramphenicol)	nitrofurantoin (nitrofurantoin)
ciprofloxacin (ciprofloxacin) *	Streptomycin (spectinomycin) (EML only)
Clarithromycin (clarithromycin) *	Sulfamethoxazole + trimethoprim (sulfamethoxazole + trimethoprim)
Clindamycin 9000 (clindamycin)
Clindamycin ) *
Vancomycin, parenteral (vancomycin, parenteral) *

* Antibiotics restricted to specific infectious diseases or pathogens.

Antibiotics from the observation group (see table 2) can be used in
as first choice drugs only for the treatment of limited
the number of infections. For example, it is recommended to drastically reduce the use of
ciprofloxacin, now widely used by doctors to treat cystitis
and upper respiratory tract infections such as bacterial sinusitis
or bronchitis. Their use for such diseases is regarded as
error. This is necessary in order to prevent further development.
resistance to ciprofloxacin.But it will not affect the quality of treatment, so
as there are very good antibiotics for these infections from the first group
access.

Table 2. Second category

-lactamase or without it)

902 Reserves of the third group.table 3) should
regarded as “antibiotics of last resort”, and use them
is possible only in the most difficult cases, when all other methods
cures are exhausted. This is especially important for the treatment of life-threatening
infections that are caused by bacteria with multidrug
stability.

Table 3. Third category

Antibiotics OBSERVATIONS	For example
Quinolones and fluoroquinolones	ciprofloxacin,
cefixime, ceftriaxone, cefotaxime, ceftazidime
Macrolides	azithromycin, clarithromycin, erythromycin
antibiotics 93 antibiotics 93 lactamase	piperacillin + tazobactam
Carbapenems	meropenem, imipenem + cilastatin
Penems	faropenem

Antibiotics RESERVE	For example
Aztreonam
	Cephalosporins Cephalosporins 9029 9029 9029 9029 generation	ceftaroline
polymyxin	polymyxin B, colistin
fosfomycin (IV)
oxazolidinones	linezolid
Tigecycline
Daptomycin

These recommendations are so important for doctors that we advise you to cut them out and
hang in the office, as well as add to the smartphone so that they are always
at hand.

Alexander Melnikov

Intermedical | Determination of antibiotic susceptibility

Antibiotic therapy is the most widely used method of treating a wide range of diseases. This is due to the high efficiency and relative harmlessness of the method. However, it is not always possible to immediately select the necessary drugs.

Modern pharmaceuticals have provided medical specialists with an extensive selection of antibacterial drugs.Often, more than 3 different drugs are found to treat the same pathogen. The antibiotic susceptibility test will help you choose the most effective in each case.

Antibiotic susceptibility testing is used in the treatment of not only STDs, but also many other infectious diseases. It is better to start the treatment of any disease in which antibiotic therapy is used with determining the sensitivity of pathogenic microorganisms to antibiotics.

Why is antibiotic susceptibility testing necessary?

Such analyzes are necessary for several reasons:

• Determination of the most effective drug;
• Elimination of “addiction” of pathogenic microorganisms to therapy;
• Substitution of the drug due to ineffectiveness or allergic reactions;
• Reducing the duration of treatment.

Like any type of laboratory test, antibiotic susceptibility testing is completely safe and does not cause discomfort or pain.A biomaterial sample is taken from the patient, then studies are carried out in laboratory conditions.

Methods for determining antibiotic susceptibility

Methods for determining the sensitivity of bacteria to antibiotics are divided into 2 groups: diffusion and dilution methods.

Determination of the sensitivity of bacteria to antibiotics: diffusion methods using antibiotic discs using E-tests Breeding methods dilution in liquid nutrient medium (broth) Agar dilution

When determining the sensitivity by the disk diffusion method, a bacterial suspension of a certain density (usually equivalent to the McFarland 0.5 turbidity standard) is applied to the agar surface in a Petri dish and then discs containing a certain amount of antibiotic are placed.Diffusion of the antibiotic into agar leads to the formation of a zone of suppression of the growth of microorganisms around the discs. After incubation of plates in a thermostat at a temperature of 35 ^about -37 ^about C overnight, take into account the result by measuring the diameter of the zone around the disc in millimeters. Disk method – qualitative and allows you to assess whether a microbe is sensitive or resistant to a drug.

Based on the obtained quantitative data (diameter of the zone of inhibition of the growth of the antibiotic or the value of the MIC), microorganisms are divided into sensitive, moderately resistant and resistant.To distinguish between these three categories of sensitivity (or resistance), the so-called breakpoint concentrations of (breakpoint) antibiotic (or cutoff values ​​of the diameter of the zone of inhibition of the growth of a microorganism) are used.

Cut-off concentrations are not constant values. They can be revised, depending on changes in the sensitivity of the population of microorganisms. The development and revision of the interpretation criteria are carried out by leading specialists (chemotherapists and microbiologists) who are members of special committees.One of them is the US National Committee for Clinical Laboratory Standards (NCCLS). Currently, NCCLS standards are recognized in the world and are used internationally to assess the results of determining the sensitivity of bacteria in multicenter microbiological and clinical studies.

There are two approaches to the interpretation of the results of determining the sensitivity: microbiological and clinical. Microbiological interpretation is based on an analysis of the distribution of antibiotic concentrations that suppress the viability of bacteria.Clinical interpretation is based on evaluating the effectiveness of antibiotic therapy.

Susceptible organisms

Bacteria are clinically classified as susceptible (taking into account the parameters obtained by in vitro ) if, when treating infections caused by these microorganisms with standard doses of an antibiotic, a good therapeutic effect is observed.

In the absence of reliable clinical information, the division into categories of sensitivity is based on the joint consideration of data obtained in vitro , and pharmacokinetics, i.e.e. at the concentrations of antibiotic attainable at the site of infection (or in the blood serum).

Resistant microorganisms

Resistant (resistant) bacteria are bacteria when, in the treatment of an infection caused by these microorganisms, there is no effect of therapy even when using the maximum doses of the antibiotic. Such microorganisms have resistance mechanisms.

Microorganisms with intermediate resistance

Clinically, intermediate resistance in bacteria is understood if the infection caused by such strains can have different therapeutic outcomes.However, treatment can be successful if the antibiotic is used in excess of the standard dosage, or the infection is localized at a site where the antibiotic accumulates in high concentrations.

From a microbiological point of view, bacteria with intermediate resistance include a subpopulation that is in accordance with the values ​​of the MIC or the diameter of the zones, between susceptible and resistant microorganisms. Sometimes strains with intermediate resistance and resistant bacteria are combined into one category of resistant microorganisms.

It should be noted that the clinical interpretation of the sensitivity of bacteria to antibiotics is conditional, since the outcome of therapy does not always depend only on the activity of the antibacterial drug against the pathogen. Clinicians are aware of cases when, with the resistance of microorganisms, according to the study in vitro , a good clinical effect was obtained. Conversely, with the sensitivity of the pathogen, therapy may be ineffective.

In certain clinical situations, when there are insufficient results of a susceptibility test by conventional methods, the minimum bactericidal concentration is determined.

Minimum bactericidal concentration (MBC) – the lowest concentration of an antibiotic (mg / l or μg / ml), which, when tested in vitro , causes the death of 99.9% of microorganisms from the initial level within a certain period of time.

Minimum bactericidal concentration (MBC) is the lowest concentration of an antibiotic (mg / L or μg / ml) that, when tested in vitro , causes the death of 99.9% of microorganisms from the initial level within a certain period of time

The MBC value is used for therapy with antibiotics with bacteriostatic action, or in the absence of the effect of antibiotic therapy in a special category of patients.Particular cases for determining MBC can be, for example, bacterial endocarditis, osteomyelitis, or generalized infections in patients with immunodeficiency states.

In conclusion, I would like to note that today there are no methods that would make it possible to predict with absolute certainty the clinical effect of antibiotics in the treatment of infectious diseases. However, the data of the results of determining the sensitivity can serve as a good guideline for clinicians in the choice and correction of antibiotic therapy.

Table 1. Criteria for interpreting the sensitivity of bacteria

Microorganism susceptibility category Microbiological characteristics Clinical characteristics Sensitive No resistance mechanisms Therapy is successful with usual doses With intermediate resistance Subpopulation between susceptible and resistant Therapy is successful when the maximum dose is used or when the infection is localized in places where the antibiotic accumulates in high concentrations Resistant Has resistance mechanisms No effect from therapy when using maximum doses

What can serve as a model for research?

A sample of biomaterial is determined depending on the causative agent of the disease.Can be used:

• Saliva;
• Urine;
• Scraping;
• Breast milk;
• Prostate secret;
• Cervical swab;
• Urethral swab;
• Smear from the back of the pharynx;
• Nasal swab;
• Sperm.

How do I prepare for the test?

No special training required. You just need to follow a few rules to get the most effective result.

Antibiotic susceptibility testing will help you determine the antibacterial drugs that are right for you. They will provide effective treatment, exclude cases of relapse, and reduce the duration of treatment.

Please do not self-medicate!

Remember, only a doctor can determine the diagnosis and correctly prescribe the treatment.

90,000 The government supports a bill to tighten control over antibiotics in the agro-industrial complex – Economy and Business

MOSCOW, 17 August./ TASS /. The Russian government has supported a bill to tighten control over the use of antibiotics in agriculture. This was reported by the press service of the Deputy Prime Minister of the Russian Federation Victoria Abramchenko.

“At the government meeting, a package of amendments to the law” on veterinary medicine “and” on the circulation of medicines “prepared by the Rosselkhoznadzor was supported. The bill introduces a ban on the addition of antimicrobial drugs to feed without a prescription,” the message says.

As explained in the office of the Deputy Prime Minister, the draft law will soon be sent to the State Duma.

“The amendments are aimed at strengthening control over the use of antibacterial drugs in livestock and poultry farming. According to expert estimates, uncontrolled use of antibiotics is one of the reasons for antibiotic resistance – the resistance of infectious agents to drugs. The bill introduces rules on prescription drugs, which will reduce the cases of their unjustified use and will improve the quality and safety of finished products, “said Abramchenko, whose words are quoted in the message.

According to the bill, it is proposed to establish a ban on the addition of antimicrobial drugs to feed and the sale of such feed in the absence of a requirement or prescription.

It is necessary to establish the categories of persons who require a pharmaceutical license to add antimicrobial drugs to feed during their production and sale.

Registration of a prescription for a medicinal product for veterinary use will be possible in the federal state information system in the field of veterinary medicine.

Rosselkhoznadzor is empowered to approve the list of medicines for veterinary use, including antimicrobial drugs dispensed by prescription or requirements, the form of requirements, the procedure for their registration, accounting and storage.

The entry into force of the federal law is provided from September 1, 2022.

Expert opinion

“There are studies from the World Health Organization where they say that more than 70% of the antibiotics produced in the world are used primarily in animal husbandry.And it is not necessarily the veterinary service that does it, most often such drugs are used by farmers when feeding animals in order to increase profitability. And as soon as we start to penetrate the world of bacteria in this way, bacteria respond to us accordingly, very quickly. It takes years and millions of dollars to develop new antibiotics, and bacteria need a few days or weeks to develop resistance mechanisms, “says Aleksey Ermakov, head of the Department of Biology and General Pathology, Don State Technical University, whose words are also quoted in the message.

“The unconscious use of antibacterial feed is a serious problem. Control is paramount here, but before we take action, we could first raise awareness among people and explain the existence of such a problem. Also, this problem should be controlled at the legislative level, therefore The OIE has developed appropriate recommendations for countries, which must be included in national legislation so that no one can go and buy antibiotics without a doctor’s recommendation – we must change this routine practice for people in all countries, “said the head of the Regional Office for International Epizootic Bureau (OIE) for Europe in Moscow Budimir Plavsic.

Rosselkhoznadzor Position

According to the Rosselkhoznadzor, its representatives positively assess the development and approval of the bill by the government. “The department has repeatedly focused on the problems arising from the uncontrolled and intensive use of antibiotics in agriculture, as well as the use of such drugs to stimulate the growth and increase the productivity of livestock. The uncontrolled use of antimicrobial drugs leads to the formation of drug resistance in microbes,” message.

In institutions subordinate to the Rosselkhoznadzor, there is a set of methods for determining the main groups of antimicrobial drugs used in veterinary medicine, including those of particular importance for medicine. In particular, a national collection of antibiotic-resistant strains of microorganisms has been created in the subordinate service of the FSBI “VGNKI”. In addition, the institution conducts research work “Veterinary monitoring of bacterial resistance to antimicrobial agents and identification of genetic determinants of resistance from environmental objects.”

“Such measures serve as the basis for organizing activities aimed at preventing and limiting the spread of resistance of microorganisms to antimicrobial agents,” added the Rosselkhoznadzor.

90,000 Can antibiotics be given to a dog?

Antibiotics are medicines that are needed to fight fungi and disease-causing bacteria in dogs. In no case should you treat your pet with antibiotics intended for humans: dog antibiotics are produced according to a special formula, human drugs will become poison for the animal!

WHAT ANTIBIOTICS DO DOGS TREAT?

There are two categories of antibiotics that can be given to dogs: bacteriostatic (stops the growth and reproduction of bacteria, but does not kill them) and bactericidal (completely destroys bacteria).

The most commonly prescribed drugs for dogs are the cephalosporin or penicillin class: gentamicin, amoxicillin, sulfametox, or cephalexin. The most common choice is amoxicillin, which has fewer side effects and helps with a wide range of canine health problems:

• Gastrointestinal and respiratory infections;
• Infected Wounds
• Skin diseases;
• Dental abscesses;
• Infections affecting the urinary tract, etc.d.

Gentamicin is prescribed for open, infected wounds, ear and eye infections. The medicine is produced in the form of an ointment or spray; it is not recommended to give tablets to animals.

HOW MANY DAYS CAN I GIVE ANTIBIOTICS DOGS?

As a rule, these types of drugs are prescribed for no more than ten days; with longer use, they have too serious an effect on the body and begin to bring harm, not benefit.

ATTENTION! Any antibiotics can be given to dogs only as directed by a veterinarian, strictly observing the indicated dosage and course duration! By breaking this simple rule, you endanger the life and health of your pet! Be sure to consult your doctor.