MONOBACTMS

AND
CARBAPENEMS
MONOBACTAMS

Aztreonam
 Aztreonam
Parenteral b-lactam
drugs, with monocyclic
b-lactam ring
Similar to ceftazidime
(3ed gen. cephalosporin):
Structurally,
Its anti-gram negative
spectrum activity
 Spectrum of activity
Aztreonam - "the magic bullet for aerobic
gram-negative bacteria"
It is effective against GNB: H. influenzae,
Neisseria, Pseudomonas aeruginosa, Serratia
Not active against GPB or anaerobes
Resistant to β lactamases, Ambler class B

metallo-β-lactamases - useful for some infections

resistant to other beta-lactam antibiotics
Active against many strains that are

multiply-resistant to other antibiotics (pen,

ceph, aminoglycosides)
Synergistic with aminoglycosides - P.
aeruginosa, many strains of
Enterobacteriaceae, and other Gram-
negative aerobic bacilli
It has no cross allergic reactions with
penicillins, i.e. can be given to patients
hypersensitive to penicillins or
cephalosporins
Because of its structural similarity with
ceftazidime, there is potential for cross-
reactivity.
Mechanism of action
Pharmacokinetics
Route of administration - IM, IV or as a
nebulizer
Peak plasma concentrations is about 1-1.5 hrs
Penetrate well into CSF
Excreted unchanged in urine, by active tubular
secretion and glomerular filtration, with a half-
life = 1-2 hrs, increased to 4-7 hrs in impaired
renal function
Clinical uses
Urinary Tract Infections (uUTIs, cUTIs)
Pyelonephritis, Uncomplicated cystitis
Intra-abdominal infections that extend into the
urological tract
Lower Respiratory Tract Infections
Septicemia
Skin infections
Gynecologic Infections
Cystic fibrosis: in children - inhalational
Adjunctive therapy to surgery
 Dosage
UTIs
500 mg to 1 g, every 8 or 12 hrs
Sever infections: 1-2 g every 8 or 12 hrs
Pediatric dosage: 30 - 120 mg/kg/6 or 8 hrs.
Dosage adjustments - in patients with impaired
renal function.
Generally, aztreonam should be continued for at
least 48 hours after patient becomes asymptomatic
or evidence of bacterial eradication has been
obtained
Persistent infections may require treatment for
several weeks.
 Adverse effects
Relatively nontoxic
Local reactions – phlebitis/thrombophlebitis, IM-
discomfort/swelling
Skin rash and occasionally abnormal liver function test
Allergic reactions
Blood disorders: neutropenia, thrombocytopenia, anemia
Neurotoxicity: administration into ventricles → seizure,
confusion, encephalopathy, vertigo, paresthesia, insomnia
Superinfcetions: overgrowth of nonsusceptible GPB
(Staphylococcus aureus, Streptococcus faecalis) and fungi
→ vaginal candidiasis, viginitis
Contraindications and
precautions
Hypersensitivity to aztreonam or any other
component in the formulation
In patients with impaired renal function
With aminoglycosides - because of the
potential nephrotoxicity and ototoxicity of
aminoglycoside antibiotics – prolonged use of
high doses
CARBAPENEMS
Introduction
Imipenem
Imipenem/cilastatin (IMIP/CS) - Tienam
Imipenem/cilastatin/relebactam
Meropenem/vabrobactam
Doripenem
Tebipenem pivoxil
Ertapenem
Faropenem medoxomil (Orapem)
Binapem/betamipron (BIAP/BP)– newer
carbapenem with higher antimicrobial
activities
introduction
Similar structure to penicillins, cephalosporins
Beta lactam + penem ring
IV bactericidal b-lactam antibiotics with an
extremely broad spectrum against:
gram-negative rods (P. aeruginosa), many
GPB, and anaerobics organisms
Resistant to most β-lactamases but not to
carbapenemases or metallo-β-lactamases
Active against many penicillin-non-
susceptible pneumococci
Beta lactams
They are very active against Enterobacter,
because they are not destroyed by AmpC ẞ-
lactamases produced by this bacteria
Carbapenems are DOC for serious infections
caused by ESBLs producing-GNB
- Resistant organisms include:
 MRSA.
 Enterococcus faecalis (gram + ve cocci).
 Clostridium difficile (anaerobic bacterium)
Mechanism of action
Bactericidal - like other beta lactam
antibiotics, bind to critical PBPs,
inhibits the synthesis of
peptidoglycan and disrupting the
growth and structural integrity of
bacterial cell walls
Pharmacokinetics
Orally, poorly absorbed and require
parenteral administration
Imipenem - rapidly hydrolyzed in renal
tubules by dehydropeptidase I → low urinary
concentrations, so it is given with cilastatin, an
inhibitor of renal dehydropeptidase, for clinical
use to inhibit renal metabolism of imipenem
and prolongs its half-life.
Carbapenems generally have good tissue
penetration - CSF
Excreted largely unchanged in the urine with
 Clinical uses
Indicated for infections caused by susceptible
organisms, e.g. P. aeruginosa, which are resistant to
other available drugs
Treatment of mixed aerobic and anaerobic infections
Active against many highly penicillin-resistant strains
of pneumococci
beta-lactam of choice for the treatment of
Enterobacter infections - resistant to destruction by
b-lactamase produced by these organisms
Imipenem or meropenem with or without an
aminoglycoside may be an effective treatment for
febrile neutropenic patients
Clinical uses
Generally, when treatment with other
antibiotics fails, carbapenems are used as
the last-line antibiotics for treating severe
and/or resistant bacterial infections that are
associated with high morbidity and mortality
1. Complicated cUTIs – causative bacteria
are known or suspected to be multidrug-
resistant
2. Pyelonephritis: severe cases when
bacteria are resistant to other commonly used
antibiotics
3. Septicemia or bacteremia with
urological source: to treat the systemic
infection
4. Intra-abdominal infections involving
the urological tract, peritonitis, abdominal
abscesses
5. Prophylaxis in urological procedures:
high risk of postoperative infection
6. Respiratory tract infection
7. Skin and soft tissue infections.
8. Bone infections and arthritis.
9. Nosocomial infections
10. DOC for serious infections caused by
extended-spectrum Beta-lactamases
(ESBLs) producing GNB
11. Treatment of mixed aerobic/
anaerobic infections
12. Used (with or without aminoglycosides)
for treatment of febrile neutropenic patients
Compared with other β-lactams, carbapenems:
Potent, broad-spectrum antibacterial
activity - against GPB and GNB species
have the most extensive activity, particularly
against MDR Gram-negative pathogens
stability - highly resistant to beta-lactamases
low toxicity
For this reason, they are used for:
complicated cases where exact pathogen is
not immediately identified, and a broad-
spectrum antibiotic is needed to cover a wide
range of potential causative organisms
Adverse effects
Common - infusion site pain a phlebitis, diarrhea,
nausea, rash, pruritus, headache
Convulsions - high doses of imipenem
Reversible transient, mild increase in serum
aminotransferase – usually self-limited and
asymptomatic
Cholestatic liver injury/hepatotoxicity - rare
In patients with multiple medical problems and
other causes for liver disease (parenteral
nutrition, sepsis)
May be due to immunoallergic reactions -
excreted largely unchanged in urine
 Imepenem/Cilastatin
Because imipenem is rapidly inactivated in
renal tubules by dehydropeptidase I (DHP-1)
inactive metabolite (can be nephrotoxic)
Cilastatin, a DHP-I inhibitor, increases
spectrum of activity, half-life, concentrations in
urinary tract and tissue penetration of
imipenem
The combination is given IV
It may cause seizures at high doses
 Dosage
Adult:
IV; 500 mg to 1 gram, IV every 6 to 8 hrs
IM: no more than 1.5 g daily
Usually for 5 - 14 days
Children:
15 - 25 mg/kg every 6 hrs
Dosage adjustments are necessary in
patients with renal impairment
Imipenem/cilastatin/relebactam
(2019)

Newly approved anti-infective combination of

imipenem and a new β-lactamase inhibitor
Impenem: interferes with cell wall synthesis
Cilastatin - inhibit renal metabolism of imipenem
Relebactam: new β-lactamase inhibitor to
protect imipenem degradation by some types of
serine β-lactamases
Active against multidrug-resistant (MDR) -
Pseudomonas aeruginosa and carbapenem-resistant
Enterobacterales (CRE) such as Klebsiella
pneumoniae
Clinical uses
Treatment of cUTIs caused by susceptible GNB
with limited or no alternative treatment
options: pyelonephritis, and complicated
intra-abdominal infections (cIAIs)
Treatment of hospital-acquired bacterial
pneumonia (HABP) and ventilator-associated
bacterial pneumonia (VABP)
Reversed for hospital acquired infection in
AIDS, cancer patients
Dosage: cUTIs, Pyelonephritis: 1.25 g IV/6
hrs for 4 - 14 days
Meropenem/vaborbactam
Meropenem:
IV, Ultra broad spectrum
Active against aerobic and anaerobic,
GPB and GNB bacteria
Resistant to beta-lactamase enzymes
Do not need addition of cilastatin and has
greater activity against gram negative
aerobes and less activity against gram
positive aerobes than imipenem
Meropenem/vaborbactam
Vaborbactam - β-lactamase inhibitor that
protect meropenem from degradation by
some serine-lactamases, such as Klebsiella
pneumoniae carbapenemase
Meropenem/Vaborbactam combination is
mainly used in treatment of cUTIs
Dose:
The recommended dosage is 0.5 - 1 g IV/8
hours, with dose adjustment for renal
impairment
 Doripenem
has high chemical stability, and is resistant
to hydrolysis by dehydropeptidase
have more potent activity against
Pseudomonas species than the other
carbapenems
has a good safety profile despite a certain
degree of GI discomfort and allergic
reactions.
Dosage: 500 mg IV every 8 hrs for 5 - 14
days
Tebipenem pivoxil (TBPM-Pl)
Orally active, with broad-spectrum activity
against uropathogenic multidrug-resistant
gram-negative pathogens, including:
Fluoroquinolone-resistant strains
ESBL-producing Enterobacterales,
primarily E. coli, Klebsiella pneumoniae,
Enterobacter cloacae, and Proteus mirabilis
Clinically, shows stronger antibacterial
activity than penicillins and cephalosporins,
and exerts the same or better antibacterial
effect in comparison to the other carbapenem
antibiotics
Pharmacokinetics
Prodrug, rapidly metabolized to the active
moiety, tebipenem, by enterocytes
Orally, absorbed by multiple intestinal
transport routes and then metabolized to
TBPM or its metabolites by drug-
metabolizing enzymes - epoxide hydrolase
and renal dehydropeptidase-I
TBPM was mainly excreted in urine, with
cumulative urinary excretion of 60–70% by
24 h
Comparision to other carbapenems
Non-inferior to IV ertapenem for treatment of
cUTIs or acute pyelonephritis → 90% clinical cure
Oral tebipenem was as effective as IV ertapenem
Compared to ertapenem, it did not lead to a
greater risk of post-treatment enteric
colonization with carbapenem-resistant
Enterobacterales pathogens
No increased risk of C. difficile infection
associated with treatment with oral carbapenem
Diarrhea, headache, and nausea – 1% of patients
 Banipenem/betamiron
antibacterial activity is similar to that of other
carbapenems, but it has:
stability against renal dehydropeptidase-1
Betamipron is often added to panipenem to
form a stable and injectable formulation
for IV administration. It enhances shelf life
and solubility of panipenem. It does not
have antibiotic activity but serves a stabilizing
function
Has high activities against urinary isolates
Enterobacteriacae - Serratia
marcescens, Enterobacter cloacae,
Citrobacter freundii and E. coli containing
class C-beta-lactamase- and ESBL-
producing strains when compared to
piperacillin and ceftazidime
Pseudomonas aeruginosa,
Enterococcus faecalis, Staphylococcus
aureus and Staphylococcus
epidermidis
Showed clinical effectiveness for:
cUTIs,
complicated intra-abdominal infections
showed a rapid effectiveness in the
treatment of febrile complicated UTIs -
mainly caused by mixed infection of GNB
and GPB, especially those involving P.
aeruginosa and E. faecalis
Banipenem has almost no nephrotoxicity
or nervous system toxicity
Faropenem medoxomil (Orapem)
Orally active, an ester prodrug characterized by:
Improved oral bioavailability (70-80%)
higher systemic concentrations
Improved chemical stability and reduced CNS
effects, compared with imipenem
Resistant to hydrolysis by nearly all β-
lactamases, including ESBLs and AmpC β-
lactamases
Faropenem is not active against MRSA,
vancomycin -resistant Enterococcus
faecium, or Pseudomonas aeruginosa
Clinical uses
Urinary tract infections –
uncomplicated UTIs (uUTIs) - 300 mg twice
daily for 7 days. Its use is restricted to treatment
of infections with ESBL-producing bacteria
cUTIs - as a part of treatment regimen
Prostatitis
Post-operative infections
Upper and lower Respiratory tract infection
Skin infection
Gynaecological infections
Bacterial infections
Beta lactamases
Serine based
Metallo beta lactamases – have ability to
hydrolyze carbapenems, and to its resistance
to commerecially available beta lactamase
inhibitors but susceptibility to inhibition by
metal ion chelators.
The most common bacteria that make
this enzyme are GN such as E. coli and
Klebsiella pneumonia, Pseudomonas
aeroginosa
Extended spectra beta lactamase (ESBL):
enzymes that mediate resistance to extended
spectrum third generation cephalosporins
(cefazidime, cefotaxime, ceftriaxone) and
monobactams (aztreonam)
do not affect cephmycins (cefoxitin,
cefotetan) or carbenams (imipernem,
meropenem)
They are commonly found in Gram-negative
bacteria, particularly in Enterobacteriaceae such
as Escherichia coli and Klebsiella pneumoniae
(NF)