Beta Lactam Antibiotics


Article Author:
Neelanjana Pandey



Editors In Chief:
Dustin Constant
Donald Kushner


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
9/3/2019 2:27:42 PM

Indications

Beta-lactam antibiotics are one of the most commonly prescribed drug classes with numerous clinical indications. From a biochemical point of view, these drugs have a common feature, which is the 3-carbon and 1-nitrogen ring (beta-lactam ring) that is highly reactive. This class includes:

  • Penicillins. These antibiotics (most of which end in the suffix -cillin) contain a nucleus of 6-animopenicillanic acid (lactam plus thiazolidine) ring and other ringside chains. The group includes natural penicillins, beta-lactamase-resistant agents, aminopenicillins, carboxypenicillins, and ureidopenicillins.
  • Cephalosporins. They contain a 7-aminocephalosporanic acid nucleus and side-chain containing 3,6-dihydro-2 H-1,3- thiazane rings. Cephalosporins are traditionally divided into five classes or generations, although acceptance for this terminology is not universal. 
  • Carbapenems. Their defining structure is a carbapenem coupled to a beta-lactam ring that confers protection against most beta-lactamases although resistance to these compounds is a significant issue and occurs mainly among gram-negative pathogens (e.g., Klebsiella pneumoniaePseudomonas aeruginosa, and Acinetobacter baumannii) which produce different classes of beta-lactamases termed as carbapenemase. 
  • Monobactams. The beta-lactam ring stands alone and not fused to another ring.
  • Beta-lactamase inhibitors. They work primarily by inactivating serine beta-lactamases which are enzymes that hydrolyze and inactivate the beta-lactam ring (especially in gram-negative bacteria). These agents include the first-generation beta-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) and the newer avibactam and vaborbactam that are active against carbapenemase such as Klebsiella pneumoniae carbapenemase (KPC).

MECHANISM OF ACTION

Peptidoglycan is a vital constituent of the bacterial cell wall that provides mechanical stability to it. The beta-lactam antibiotics inhibit the last step in peptidoglycan synthesis by acylating the transpeptidase involved in cross-linking peptides to form peptidoglycan. The targets for the actions of beta-lactam antibiotics are known as penicillin-binding proteins (PBPs). This binding, in turn, interrupts the terminal transpeptidation process and induces loss of viability and lysis, also through autolytic processes within the bacterial cell.[1] 

MECHANISM OF RESISTANCE

Resistance to beta-lactams is an alarming and growing phenomenon and, in turn, a public health challenge. It concerns above all Streptococcus pneumoniae and individual gram-negative bacilli such as Pseudomonas aeruginosa. With emerging resistance for antibiotics, it makes sense to look into mechanisms of resistance as it can help to decide which drugs to prescribe in different scenarios and ways to overcome the same. Although bacterial resistance to beta-lactams mostly expresses through the production of beta-lactamases, other mechanisms are involved. Following are the mechanisms of resistance[2]:

  • Inactivation by the production of beta-lactamases 
  • Decreased penetration to the target site (e.g., the resistance of Pseudomonas aeruginosa 
  • Alteration of target site PBPs (e.g., penicillin resistance in pneumococci)
  • Efflux from the periplasmic space through specific pumping mechanisms

INDICATIONS FOR BETA-LACTAM ANTIBIOTICS[3]:

PENICILLINS

Natural penicillins [Penicillin G (IV), Penicillin V (PO)] are used to treat selected gram-positive and gram-negative infections:

  • Penicillin susceptible Streptococcus pneumonia and meningitis
  • Streptococcal pharyngitis
  • Endocarditis
  • Skin and soft tissue infections
  • Neisseria meningitides infections
  • Syphilis

Beta-lactamase-resistant agents

These agents [oxacillin (IV), nafcillin (IV), dicloxacillin (PO)] are active against gram-positive organisms. Despite the occurrence of widespread resistance among staphylococci, they remain antibiotics of choice in managing methicillin-susceptible staphylococci (MSSA):

  • Skin and soft tissue infections (MSSA)
  • Serious infections due to MSSA

Aminopenicillins

These antibiotics have activity against gram-positive and gram-negative bacteria (e.g., many Enterobacteriaceae) anaerobic organisms. They are commonly used together with beta-lactamase inhibitors.

Amoxicillin (PO), ampicillin (PO/IV):

  • Upper respiratory tract infections (sinusitis, pharyngitis, otitis media)
  • Enterococcus faecalis infections
  • Listeria infections
  • Aminopenicillins/beta-lactamase inhibitors: amoxicillin/clavulanate (PO), ampicillin-sulbactam (IV)
  • Upper respiratory tract infections (sinusitis, otitis media)
  • Intra-abdominal infections

Carboxypenicillins and ureidopenicillins

Ticarcillin (carboxypenicillin) and piperacillin (ureidopenicillin) have activity against aminopenicillin-resistant gram-negative bacilli (Pseudomonas aeruginosa). Are commonly combined with beta-lactamase inhibitors

CEPHALOSPORINS

First-generation cephalosporins

Cefazolin(IV), cephalexin (PO), cefadroxil (PO)

  • Skin and soft tissue infections serious infections due to MSSA 
  • Perioperative surgical prophylaxis

Second-generation cephalosporins

Cefuroxime (IV/PO), cefoxitin (IV), cefotetan (IV), cefaclor (PO) cefprozil (PO)

  • Upper respiratory tract infections (sinusitis, otitis media)
  • Cefoxitin, cefotetan-gynecologic infections,
  • perioperative surgical prophylaxis

Third-generation cephalosporins

Cefotaxime (IV), ceftriaxone (IV), cefpodoxime (PO), cefixime (PO), cefdinir (PO), cefditoren (PO), ceftibuten (PO)

  • Community-acquired pneumonia, meningitis
  • Urinary tract infections
  • Streptococcal endocarditis
  • Gonorrhea
  • Severe Lyme disease.

Anti-pseudomonal Cephalosporins

Ceftazidime (IV), ceftazidime/avibactam (IV), cefepime (IV) [Fourth-generation], ceftolozone/tazobactam (IV) [also been described as "fifth-generation"]

  • Nosocomial infections-pneumonia
  • Meningitis
  • Complicated Intra-abdominal Infections (cIAI) [ceftazolone plus beta-lactamase inhibitor]
  • Complicated Urinary Tract Infections (cUTI) [ceftazolone plus beta-lactamase inhibitor]

Anti-Methicillin-resistant Staphylococcus aureus (MRSA) cephalosporins

Ceftaroline (IV), ceftobiprole (IV) [Also been described as "fifth-generation"] 

  • Community-acquired pneumonia
  • Hospital-acquired pneumonia (excluding ventilator-acquired pneumonia)
  • Skin and soft tissue infection

CARBAPENEMS

Imipenem/cilastatin (IV), meropenem (IV), doripenem (IV)

  • Nosocomial infections-pneumonia, intra-abdominal infections, urinary tract infections
  • Meningitis (especially meropenem)      

Ertapenem (IV)

  • Community-acquired infections
  • Nosocomial infections.

MONOBACTAMS

Aztreonam (IV). It is effective only against aerobic gram-negative organisms but shows no activity against gram-positive bacteria or anaerobes.

  • Nosocomial infections, e.g., pneumonia
  • Urinary tract infections    

Because the emergence of antimicrobial resistance has become a progressively great concern, new beta-lactam, and beta-lactamase inhibitor combinations (ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, imipenem/cilastatin/relebactam, aztreonam/avibactam), siderophore-conjugated cephalosporins (cefiderocol), and siderophore-conjugated monobactams have been developed and represent options for the management of complicated infections,[4] especially in intensive care unit.[5]

Administration

When administered orally, one must consider that food can affect oral absorption. Moreover, the absorption of some molecules such as cefuroxime and cefpodoxime becomes decreased by H2 blockers or nonabsorbable antacids. Administration of these agents can be through different routes.

  • Penicillin V is preferrable for oral administration, given 30 min before the meal or 2 hours after.
  • Penicillin G is available in 2 parenteral preparations: benzathine and procaine.
  • Penicillin G benzathine is dosed once monthly as it has a longer half-life
  • Penicillin G procaine is given once daily due to a shorter half-life.
  • Neither should be given intravenously to avoid serious toxicity.
  • Penicillinase-resistant penicillins (oxacillin, cloxacillin and dicloxacillin) are available in oral and parenteral preparations.
  • Aminopenicillins: ampicillin and amoxicillin are available in both oral and parenteral preparations, though amoxicillin is preferred orally.
  • Antipseudomonal penicillins: piperacillin is only available for parenteral administration.
  • Most cephalosporins are absorbed readily after oral administration; the administration of others can be intramuscularly or intravenously. 

Continuous infusions of beta-lactam antibiotics may have advantages over standard intermittent bolus dosing. 

Adverse Effects

Compared to other classes, beta-lactam agents are usually safe and well-tolerated.[6]  The most frequent side effects are allergic reactions that vary from 0.7% to 10%. These reactions may occur with any dosage form of penicillin and are mostly maculopapular rashes, whereas reports of anaphylaxis appear in 0.004 to 0.015% of patients.[7]. Apart from allergic reactions, beta-lactams can induce other side-effects. In particular:

  • Penicillin G and piperacillin are also associated with impaired hemostasis due to defective platelet aggregation.
  • An IV injection of benzathine penicillin G has correlations with cardiorespiratory arrest and death.
  • Cephalosporins carry associations with rare instances of bone marrow depression including granulocytopenia
  • Some cephalosporins are potentially nephrotoxic and correlate with renal tubular necrosis. Ceftriaxone can cause jaundice in neonates by displacing bilirubin from albumin.
  • It can also lead to biliary pseudolithiasis due to its high affinity for biliary calcium.
  • Cefepime correlates with encephalopathy and nonconvulsive status epilepticus at high doses or in patients with renal dysfunction.
  • Imipenem is associated with seizures when given in high doses to patients with CNS lesions and those with renal insufficiency.[8]

Contraindications

Penicillins are contraindicated in patients with previous anaphylactic reaction or serious skin reaction, for example, Stevens-Johnson syndrome and toxic epidermal necrosis.[6]

Monitoring

Most of the available penicillins have a short half-life, less than an hour mostly. The parenteral agents are given four-hourly, usually when treating serious systemic infections with normal renal function. Piperacillin and ampicillin require dose adjustment when given in patients with renal insufficiency (GFR less than 10 ml/min). For ticarcillin, this dose adjustment is at 50 ml/min. Other agents like nafcillin, oxacillin, cloxacillin, and dicloxacillin have the hepato-biliary mode of excretion and therefore require no modification in renal impairment.

All penicillins achieve therapeutic levels in pleural, pericardial, peritoneal, synovial fluids, and urine. Of note, cerebrospinal fluid (CSF) penetration is poor in the absence of inflammation but achieves therapeutic levels in meningitis.[9]

Enhancing Healthcare Team Outcomes

Penicillins are the most commonly used broad-spectrum antibiotics by many clinicians, including primary care providers, internists, infectious disease experts, and nurse practitioners. Within the subgroups of penicillins, there are differences between the antibiotics in pharmacokinetics, coverage, safety, and cost, which gives a fair amount of choice to make in selecting which drug to use.[10]

Their use still requires the coordination of an interprofessional team. The clinicians above will be ordering/prescribing, but nursing will often administer (inpatient) or counsel on administration (outpatient).  Pharmacists need to involve themselves via medication reconciliation, looking for interactions, as well as reinforcing administration instructions. Nurses will often be the first line of contact in the event of adverse events and are also well-positioned to evaluate therapeutic effectiveness. Pharmacists shall verify dosing and duration of therapy, and contact the prescriber on encountering any discrepancy. All healthcare team members need to be mindful of anaphylactic reactions to beta-lactam agents and the potential for crossover allergies and communicate these to the team when present.

Beta-lactams may be common, but their effective use still requires an interprofessional team approach for optimal patient outcomes. [Level V]


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Beta Lactam Antibiotics - Questions

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A 36-year-old female arrives at the emergency department with complaints of high fever, malaise, painful urination, and severe flank pain. Lab tests indicate the presence of white blood cells and E.coli in her urine. A diagnosis of kidney infection (pyelonephritis) is made, and the decision is made to use a beta-lactam antibiotic that has both an appropriate antibacterial spectrum of activity, and good tissue penetration, yet is more resistant to beta-lactamases than narrow-spectrum penicillins. Which of the following drug is prescribed?



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A 12-year-old boy develops otitis media a few days after swimming in a lake. His previous medical history is unremarkable except for having had a minor skin rash two years ago after being treated with amoxicillin for a sore throat. Which of the following shares a common mechanism, but would be very unlikely to produce a similar allergic reaction?



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A 20-year-old man comes to the office with an ulcer on his penis, which he noticed four days ago. On physical examination, there is an indurated, painless ulcer with no surrounding erythema on the base of the penis. He is afebrile and has no past medical history. His family history is unremarkable. He does not report any drug allergies. The first-line treatment for this patient has a structural resemblance to which of the following?



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A 65-year-old man presents to the hospital with second and third-degree burns. He is admitted to the intensive care unit. He is started on intravenous fluids and analgesics, and his wounds are cleaned and debrided. During the course of his stay, he develops febrile illness and leukocytosis (16,000 cells/microliter). His electrolytes come in as Na 134 mEq/L, K 3.1 mEq/L, and HCO3 24 mEq/L. On physical examination, the wounds are still warm, indurated, and surrounded by erythema. Gram staining of the wound tissue shows pink rods and culture on MacConkey agar grows oxidase-positive colonies that do not ferment lactose. Which of the following is the best initial treatment for the patient?



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A 65-year-old man is admitted for suspected postoperative abdominal sepsis. On presentation, he is found to have a respiratory failure with mild hypoxemia. The patient is treated with vasopressor agents and invasive mechanical ventilation through orotracheal intubation. Over the course of three days, the patient's condition worsens, and a chest x-ray reveals acute respiratory distress syndrome. Further evaluation indicates the potential involvement of a multidrug (MDR) resistant strain of Pseudomonas aeruginosa. Which of the following is the most appropriate antibiotic therapy?



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Beta Lactam Antibiotics - References

References

Probst-Kepper M,Geginat G, [New Antibiotics for Treatment of Highly Resistant Gram-negative Bacteria]. Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie : AINS. 2018 Jul;     [PubMed]
Eckburg PB,Lister T,Walpole S,Keutzer T,Utley L,Tomayko J,Kopp E,Farinola N,Coleman S, Safety, Tolerability, Pharmacokinetics, and Drug Interaction Potential of SPR741, An Intravenous Potentiator, After Single and Multiple Ascending Doses and When Combined with Beta-Lactam Antibiotics in Healthy Subjects. Antimicrobial agents and chemotherapy. 2019 Jul 1;     [PubMed]
Mortensen JS,Jensen BP,Zhang M,Doogue M, Preanalytical Stability of Piperacillin, Tazobactam, Meropenem, and Ceftazidime in Plasma and Whole Blood Using Liquid Chromatography-Tandem Mass Spectrometry. Therapeutic drug monitoring. 2019 Aug;     [PubMed]
Ibrahim ME,Abbas M,Al-Shahrai AM,Elamin BK, Phenotypic Characterization and Antibiotic Resistance Patterns of Extended-Spectrum {i}β{/i}-Lactamase- and AmpC {i}β{/i}-Lactamase-Producing Gram-Negative Bacteria in a Referral Hospital, Saudi Arabia. The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale. 2019     [PubMed]
Leone S,Damiani G,Pezone I,Kelly ME,Cascella M,Alfieri A,Pace MC,Fiore M, New antimicrobial options for the management of complicated intra-abdominal infections. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2019 May     [PubMed]
Leone S,Cascella M,Pezone I,Fiore M, New antibiotics for the treatment of serious infections in intensive care unit patients. Current medical research and opinion. 2019 Aug     [PubMed]
Chiriac AM,Rerkpattanapipat T,Bousquet PJ,Molinari N,Demoly P, Optimal step doses for drug provocation tests to prove beta-lactam hypersensitivity. Allergy. 2017 Apr     [PubMed]
Miller RL,Shtessel M,Robinson LB,Banerji A, Advances in Drug Allergy, Urticaria, Angioedema and Anaphylaxis in 2018. The Journal of allergy and clinical immunology. 2019 Jun 24     [PubMed]
Podlecka D,Jerzynska J,Malewska-Kaczmarek K,Stelmach I, A Case of a Child With Several Anaphylactic Reactions to Drugs. Global pediatric health. 2019     [PubMed]
Han ML,Liu X,Velkov T,Lin YW,Zhu Y,Creek DJ,Barlow CK,Yu HH,Zhou Z,Zhang J,Li J, Comparative Metabolomics Reveals Key Pathways Associated With the Synergistic Killing of Colistin and Sulbactam Combination Against Multidrug-Resistant {i}Acinetobacter baumannii{/i}. Frontiers in pharmacology. 2019     [PubMed]

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