Neat logical categories are necessary

if one is to think profitably about the

Overview of Antibiotic Spectrum and Use
Peter L. Havens, MS, MD
Medical College of WI
Children’s Hospital of WI
07/19/02
real world, and to derive from it
lessons for broader application and
use.
Categories are only
a place to start.
Clinical decisions
will be different for Samuel Huntington
each patient.

Microbiology

Firmness in decision is often merely a • Bacteria/Fungus/Virus

form of stupidity. It indicates an
• Bacteria
inability to think the same thing out
twice. – Color
– Shape

H.L. Mencken
1880-1951

Gram positive cocci: Staph or strep Gram positive cocci, think strep
Clusters suggest Staph Chains, think enterococcus, viridans strep
Lancet-shaped diplococci, think pneumococcus

1
 Gram positive rods: Gram negative rods, think
Think Listeria, Anthrax enterics or pseudomonas

Plump Gram
negative rod with
a capsule, think
of Klebsiella

Gram negative cocco-

bacilli, think of
Haemophilus

Antibacterials 8 yo, T=38.7, sore throat, headache, abdominal

pain, Right tender tonsillar node with exudate

• Penicillins, extended spectrum penicillins Adenovirus, Mycoplasma, EBV,

• Differential diagnosis
• Cephalosporins Gonorrhea, Diphtheria,
• History Coxsackie (vesicles)
– 1st , 2nd, 3rd generation Laryngitis=viral
• Aminoglycosides, Aztreonam • Exam Group A, C, G Strep
• Quinolones • Labs
Sister with Group A Strep pharyngitis
– Gram negative focus (Cipro)
• Differential diagnosis Rapid strep screen negative, culture
– Gram positive focus (Gati/Moxi/Gemi) positive
• Carbapenems (Imipenem, meropenem) • Organisms to consider

• Others: Clinda, metronidazole Penicillin G Na: IV

• Antibiotics to start with
Penicillin G K: IV
• Best treatment Penicillin V K: PO

2
 Acute onset of dysuria, right flank pain, T=39,
Infant <1 mo, with fever. CSF gram stain = Gram
vomiting liquids and solids, decreased urine
positive rods
output with dark urine

• Differential diagnosis • Differential diagnosis Pyelonephritis

• History Listeria monocytogenes • History No prior UTI
Flank tenderness, dehydration
• Exam • Exam
Pyuria
• Labs
Ampicillin plus • Labs Plump GNR on stain=E. coli
gentamicin for synergy Gracile GNR=Pseudo
• Differential diagnosis • Differential diagnosis
Capsule=Klebs
• Organisms to consider • Organisms to consider now many E.coli resistant to Amp
• Antibiotics to start with • Antibiotics to start with
Ampicillin IV
Amoxicillin PO
• Best treatment • Best treatment

Acute onset of dysuria, right flank pain, T=39, Acute onset of dysuria, right flank pain, T=39,
vomiting liquids and solids, decreased urine vomiting liquids and solids, decreased urine
output with dark urine output with dark urine

• Differential diagnosis • Differential diagnosis

• History Just finished ampicillin/amoxicillin Rx for pyelonephritis • History

• Exam • Exam

• Labs Urine grows Pseudomonas aeruginosa • Labs Urine grows Klebsiella, Enterobacter, Serratia, or Proteus

• Differential diagnosis • Differential diagnosis

• Organisms to consider • Organisms to consider

• Antibiotics to start with • Antibiotics to start with

• Best treatment • Best treatment

Vomiting followed by right lower quadrant

abdominal pain, complained of rough roads on the
48 hr post-op abdominal surgery, with pus
way to the hospital. T=38.6. Delay in being seen,
draining from wound but stable vital signs
then decided to watch overnight, now with shock
and severe diffuse abdominal pain
• Differential diagnosis • Differential diagnosis
Gram stain: GPC, clusters
• History Ruptured appendicitis To kill anaerobes Staphylococcus aureus
• History
Rebound tenderness <24 hr: Group A strep
Penicillin/Ampicillin (mouth •>24
• Exam Fecal flora anaerobes)
hours: Staph aureus
Exam
Aerobic GNR Staph aureus:
• Labs • Labs
Enterococcus Clindamycin MSSA: Oxacillin, Nafcillin
• Anaerobes
Differential diagnosis Metronidazole MRSA:
• Differential diagnosis
Ampicillin/sulbactam BL/BLI Community acquired: Clinda, Vanco, Bactrim
• Organisms to consider Cefoxitin • Organisms to Hospital:
consider Vanco
Ticarcillin/clavulanate Imipenem
Piperacillin/tazobactam Meropenem Mixed GNR/GPC on stain: Cefazolin, Cefalothin
• Antibiotics to start with • Antibiotics to start with
chloramphenicol
• Best treatment • Best treatment

3

1 cm pustular lesion right calf, sunburn-like rash
(blanching erythroderm) and shock
• Differential diagnosis
• History
• Exam
• Labs
• Differential diagnosis
• Organisms to consider
• Antibiotics to start with
• Best treatment
Cough, fever, RLL consolidation
• Differential diagnosis
• History
• Exam
• Labs
• Differential diagnosis
• Organisms to consider
• Antibiotics to start with
• Best treatment
Beta-Lactam Resistance: Pneumococcus vs
Haemophilus/Moraxella
Resistance
M echanism
Treat w ith
Vomiting followed by right lower quadrant
abdominal pain, complained of rough roads on the
way to the hospital. T=38.6. Delay in being seen,
team decided to watch overnight, now with shock
and severe diffuse abdominal pain
Toxic Shock Syndrome: • Differential diagnosis
Cefoxitin is OK, but won’t
• History
kill Enterococci, and
Use an
• Exam selects for resistant
antistaphylococcal beta-
• Labs organisms really fast
lactam (or Vancomycin)
• Differential diagnosis
No cephalosporin kills
plus clindamycin • Organisms to consider
enterococci
• Antibiotics to start with
• Best treatment Cefotetan=cefoxitin
Community Acquired Pneumonia
• No co-morbidity: Mycoplasma, Chlamydia
pneumoniae, viral, Streptococcus
pneumoniae (uncommon)
• Smoker: SP, Moraxella catarrhalis,
Haemophilus influenzae
• Post-influenza: SP, MC, HI,
Staphylococcus aureus
• Alcohol: SP, anaerobes, KESP
• Birds: Psittacosis
• Rabbits: Tularemia
• Livestock: Coxiella burnetii
• Water exposure: Legionella
Penicillin Susceptibility of Streptococcus
Pneumoniae: Clinical Implications
NCCLS Category MIC (mcg/mL) Clinical Implications
Streptococcus Haem ophilus
pneum oniae Moraxella Susceptible < 0.06 penicillin OK
Change PBP Produce 8- Intermediate 0.1-1.0 penicillin usually*
Lactam ases OK
Resistant > 2.0 cefotax,
3 gen ceph 8-lactam ase vanco,clinda**
m acrolides inhibitor com bo
TM P/SM X, FQ 3 gen ceph * Exceptions=meningitis, ?pneumonia with effusion,
m acrolides abnormal host (sickle cell)
TM P/SM X, FQ
* po cephalosporins no better than penicillin.
Cross resistance: TMP/SMX, others
4
 Penicillin Susceptibility of Streptococcus
Pneumoniae: Clinical Implications
Macrolide Resistance
Susceptible Intermediate Resistant
MIC <=0.06 0.1-1.0 >=2.0 Resistance Abbreviation Mechanism Gene Erythro Clinda
Type
Penicillin Treat with Penicillin
Macrolide M Efflux pump mefE Resistant Susceptible
susceptible or (low or high)
intermediate Macrolide- MLSb Change erm Resistant Resistant
Penicillin No interpretation for treatment Lincosamide- Ribosome
Streptogramin Binding
nonsusceptible B
Penicillin Do not
resistant treat with
Penicillin
Does Azithro/Clarithro resistance follow Erythro or Clinda?

Streptococcus pneumoniae: three sites of PRSP are Resistant to Many Antibiotics:

resistance to antimicrobials Resistance of Streptococcus pneumoniae by
Penicillin Resistance
Percent Resistant
Pen S Pen I Pen R
(61%) (22%) (17%)
Cefotaxime 0 8 (48% I) 42 (58% I)
Clindamycin 3 8 0
Erythromycin 7 48 79
Tetracycline 0 17 37
TMP/SMX 23 64 79
N=113 respiratory isolates CHW, 1998
Swartz, MN. Attacking the pneumococcus—a hundred years’ war. NEJM 2002;346:722

Pharmacokinetic/Pharmacodynamic
Streptococcus Pneumoniae Predictors of Efficacy
%Resistance to Antibiotics: CHW, Parameters of Interest:

1996-2000: Ear / Respiratory Isolates Cmax (Peak) • Time > MIC

• Cmax/MIC ratio
• AUC/MIC ratio
Concentration

Yr N Pen Cefotax Eryth T/S Clinda

96 65 15 17 16 36 5 AUC
Area under the curve:
“how high for how long”

97 141 18 9 21 46 3 MIC= “how much abx is

required to inhibit growth
98 111 16 10 26 43 3 MIC
in a test tube”

Time > MIC

99 125 23 8 33 47 10
00 212 20 8 30 46 11
Time (hours)
Craig W. Pharmacokinetic/Pharmacodynamic Parameters: Rationale
for Antibacterial Dosing of Mice and Men. Clin Infect Dis. 1998; 26:1-12.

5
 Predictors of Bacterial Eradication: PK/PD Breakpoints
Pharmacokinetic/Pharmacodynamic Profiles • The MIC at which the pathogen is called susceptible or resistant
– the point at which T>MIC of 40% or AUC:MIC of 25-125 is met
with a specific antibiotic
Time >MIC AUC24 /MIC • Given the pharmacokinetics of a specific antibiotic, how low
(non-concentration-dependent) (concentration-dependent)
does the MIC have to be for the organism to be called
“susceptible” (where the goals for T>MIC or AUC:MIC are met)?
MIC MIC • Any pathogen with an MIC that falls below the breakpoint is
considered susceptible; MICs that are above the breakpoint is
40-50% 25-125 considered resistant Bacteriologic success would
not be predicted for a pathogen
with an MIC here (T>MIC not >40%)
• Penicillins • Quinolones MIC of
• Cephalosporins • Aminoglycosides Pathogen
(ug/ml)
• Erythromycins • Azithromycin Resistant pathogen
• Clarithromycin PK/PD
25 (gram-positive) breakpoint
125 (gram-negative) Susceptible pathogen

Craig W. Pharmacokinetic/Pharmacodynamic Parameters: Rationale

for Antibacterial Dosing of Mice and Men. Clin Infect Dis. 1998; 26:1-12.

“Gram Positive” Quinolones: AUC(0-24h)/MIC90 and

Cmax/MIC90 Ratios for S. pneumoniae
Telithromycin 800 mg/day qd

16
AUC=12.5 mg.l/hr
60-70% protein bound
Antimicrobial Dose AUC/MIC90 Cmax/MIC90 8
Serum
Gemifloxacin (320 mg) 280 53.3 conc. 4
(Factive) 8.4/0.03 1.6/0.03 (µg/ml) 2
Haemophilus: MIC90= 2 µg/ml; AUC:MIC ratio = 6
Moxifloxacin (400 mg) 192 18.0 1
(Avelox) 48.0/0.25 4.5/0.25 PK/PD bkpt. 0.5 µg/ml
0.5
Gatifloxacin (400 mg) 103 8.4 Macrolide R SP (ermB): MIC90= 0.5 µg/ml; AUC:MIC ratio 25
0.25
(Tequin) 51.3/0.5 4.2/0.5 Macrolide R SP (mefE): MIC90= 0.25 µg/ml; AUC:MIC ratio 50
0.12
Levofloxacin (500 mg) 48 5.7 M. cat: MIC90= 0.12 µg/ml; AUC:MIC ratio 100
0.06
(Levaquin) 47.5/1.0 5.7/1.0 Macrolide S SP: MIC90= 0.06 µg/ml; AUC:MIC ratio = 200
0.03
0.015
0 12 hr 24
Adapted fromFDA Anti-Infective Drugs Advisory Committee, 4/26/2001

CAP: Outpatient CAP: Inpatient

• Macrolide (erythro, clarithro) • Cepha-3 (cefotax/ceftriax or

• Azalide (azithromycin) cefepime, but not ceftazidime)
• Ketolide (telithromycin) – Plus erythro or azithro
• Gram positive quinolone (levo-, gati-, – Consider vanco for MRSA and
moxi-, alatro-, gemi-)
PRSP/CRSP
• Doxycycline (age >8)
• Gram positive quinolone (levo-, gati-,
• Cepha-2 (cefuroxime, cefdinir,
cefpodoxime, cefprozil NOT CEFIXIME) moxi-, alatro-, gemi-)

6
 Cough, fever, RLL consolidation. 2 weeks into
ICU stay for pneumonia/ARDS, on
Cough, initially with fever but now afebrile, 2
Cefotaxime/Azithro. New onset fever, hypoxemia,
weeks duration. Clear CXR .
increase in yellow tracheal secretions, LUL
infiltrate, GNR on tracheal Gram stain
• Differential diagnosis • Paroxysms of coughing
Differential diagnosis
Serratia Post-tussive emesis
• History
Pseudomonas Cefepime, Pip/Tazo • History
Family members with coryza and cough
•Acinetobacter
Exam Gent/Tobra/Amikacin • Exam

•Citrobacter Imipenem/Meropenem
Labs • Labs PCR of nasal secretions positive
Enterobacter Cipro
• Differential diagnosis • Differential diagnosis
Yersinia Bactrim for S. malto
• Organisms to consider •
Pertussis
Organisms to consider

•Stenotrophomonas
Antibiotics to start with maltophilia • Antibiotics to start with
Erythro
•Cefepime/gent
Best treatment resistant Enterobacter • Best treatment

1 day old, sepsis and meningitis 6 month old (=50 yo), fever, stiff neck, lethargy
Pyogenic bacterial meningitis:
• GBS
Differential diagnosis • Differential diagnosis

• History E. Coli / GNR •

Streptococcus pneumoniae
History
Listeria monocytogenes Neisseria meningitidis
• Exam • Exam
(Haemophilus influenzae)
• Labs • Labs
Amp/Gent
• Amp/Cefotaxime
Differential diagnosis • Polysaccharide-protein conjugate vaccines
Differential diagnosis

• Change when culture results known

Organisms to consider • Organisms to consider
Cefotaxime
• Antibiotics to start with • Antibiotics to start with
Plus vancomycin for PRSP
• Best treatment • Best treatment

Cancer Chemotherapy, now with fever and

neutropenia Cancer Chemotherapy, now with fever and
Gram positives neutropenia
viridans Streptococcus (AML)
• Staphylococcus
Differential diagnosis aureus • Differential diagnosis Coagulase negative Staphylococcus
Gram negatives Vancomycin
• History KESP • History
Pseudomonas Vanco-resistant enterococcus
• Exam • Exam
Fungi after 5-7 days Quinupristin/dalfopristin
• Labs • Labs Linezolid
Naf/ox plus
• Pip/Tazo
Differential or Ticar/clav or imipenem or ceftazidime or cefepime
diagnosis • Differential diagnosis
Plus perhaps Gent/Tobra/orAmikacin or aztreonam
• Organisms to consider • Organisms to consider
Vanco if indicated for positive culture (avoid VRE)
• Antibiotics to start with • Antibiotics to start with
Add amphotericin lipid preparation at 5-7 days if fever persists
• Best treatment • Best treatment

7
 6 wks of fever, lethargy, weight loss: Endocarditis
In hospital, develops diarrhea after 1 week of
antibiotics for pneumonia Dental work 2 months ago

New heart murmur, splenomegaly, evidence of emboli

• Differential diagnosis • Differential diagnosis

Multiplepos blood cultures with appropriate organism

• History
Clostridium dificile • History
Hematuria, ↑ ESR
• Exam Rx= metronidazole • Exam
Vegetation on ECHO
• Labs metronidazole • Labs
Viridans streptococci
po vanco Staph aureus
• Differential diagnosis • Differential diagnosis
Enterococci
• Organisms to consider
Viral enteritis • Organisms to consider
Pending culture results:
• Antibiotics to start with • Antibiotics to start with
Pen/Amp + Naf/Ox + gent, or
• Best treatment • Vanco/gent (synergistically nephrotoxic)
Best treatment

50 yo, postal worker, with fever, stiff neck. CSF Treatment of Inhalational Anthrax
gram stain = Gram positive rods
• Treat early, continue for 60 days
• Differential diagnosis • Doxycycline 2.2-2.5 mg/kg/dose BID (max
• History Anthrax 100 mg BID) or others in class
• Ciprofloxacin 30 mg/kg/day ÷ BID (max
• Exam
Flu-like illness 1000 mg/day) or others in class
• Labs
Mediastinal widening perhaps • Beta-lactamase producers: penicillin=no
• Differential diagnosis only visible on chest CT • Pen and tetracycline resistant strains
• Organisms to consider
engineered by Russian scientists
Dx easily missed
• Antibiotics to start with
MMWR Oct 26 2001;42:909
• Best treatment

Other drugs for treatment of

inhalational Anthrax
• Other agents with in vitro activity
– Rifampin, vancomycin, penicillin,
ampicillin, chloramphenicol, imipenem,
clindamycin, clarithromycin
• Clindamycin may decrease toxin
production
• Macrolides, cephalosporins:no
• CDC recommends cipro or doxy plus “one
or two others” for inhalational disease
• Cipro or doxy alone OK for cutaneous
MMWR Oct 26 2001;42:909
Recent Treatments for Anthrax
• NYC infant: Ampicillin-sulbactam +
clindamycin (Roche. NEJM 2001;345:1611)
• Florida : Vancomycin + Penicillin
(high dose) (Bush. NEJM 2001;345:1607)
• DC area: Ciprofloxacin (400mg IV q 8
hr), Clindamycin (900 mg IV q 8 hr),
Rifampin (300mg IV q 12 hr). (Mayer TA.
JAMA 2001;286:2549-2553)

8
 Vaccination to Prevent Anthrax Post-exposure Prophylaxis: 10/01

• Cell-free filtrate of B anthracis • Cipro, doxycycline (augmentin?)

• 6-dose initial series • Continue for 60 days
– Requires yearly booster – Doesn’t kill spores
• Military personnel only – Only kills germinating organisms
• Inoculation at 0 and 2 weeks
– 100% protective at 8 and 38 weeks
– 88% protective at 100 weeks
MMWR Oct 19, 2001;50:889

Post-exposure Prophylaxis: 12/01

• Cipro, doxycycline (augmentin?) We must learn to reawaken and keep

– Continue for 60 days ourselves awake…by an infinite
– Monitor for illness expectation of the dawn, which does
• Cipro, doxy, (augmentin?) not forsake us in our soundest sleep
– Additional 40 days
– Monitor for illness and adverse reaction
Thoreau
• Anthrax vaccine at 0, 2, 4 weeks plus 40
days of antibiotics

MMWR Dec 21, 2001;50:1142